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Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies. Wingstrand Vibe Lindeblad,Grønhøj Larsen Christian,Jensen David H,Bork Kristian,Sebbesen Lars,Balle Jesper,Fischer-Nielsen Anne,von Buchwald Christian PloS one OBJECTIVES:Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. DATA SOURCES:PubMed, Embase, the Cochrane Library and Google Scholar were searched. METHODS:Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. RESULTS:Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η') and elastic modulus (G'), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds. CONCLUSION:The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies. 10.1371/journal.pone.0162349
High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy. Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:Different rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Twenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses. RESULTS:Remissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3-9] and 9 [IQR, 6-12] months for NICE and GEMRITUX cohorts respectively (=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.3 µg/L [IQR, 0.0-10.8] versus 0.0 [IQR, 0.0-0.0] <0.001 and 0.0 [IQR, 0.0-2.0] versus 16.5 [IQR, 2.5-31.0] <0.001) at month 3, lower level of anti-PLA2R1 antibodies at month 6 (0.0 [IQR, 0.0-8.0] versus 8.3 [IQR, 0.0-73.5] =0.03). In the combined study population, lower epitope spreading at diagnosis and higher rituximab levels at month 3 were associated with remissions at month 6 (13/26 (50%) versus 22/29 (76%) =0.05 and 2.2 µg/ml [IQR, 0.0-10.9] versus 0.0 µg/ml [IQR, 0.0-0.0] <0.001 respectively). All non-spreaders entered into remission whatever the protocol. Eight of the 41 participants who reached remission had relapses. Epitope spreading at diagnosis (8/8 (100%) versus 16/33 (48%) =0.01) and incomplete depletion of anti-PLA2R1 antibodies at month 6 (4/8 (50%) versus 5/33 (9%) =0.05) were associated with relapses. CONCLUSIONS:Our work suggests that higher dose rituximab protocol is more effective on depletion of B-cells and lack of epitope spreading is associated with remission of membranous nephropathy. 10.2215/CJN.11791018
Mechanisms of anemia in CKD. Babitt Jodie L,Lin Herbert Y Journal of the American Society of Nephrology : JASN Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia. 10.1681/ASN.2011111078
The A2DS2 Score as a Predictor of Pneumonia and In-Hospital Death after Acute Ischemic Stroke in Chinese Populations. Zhang Xiaopei,Yu Shangzhen,Wei Lin,Ye Richun,Lin Meizhen,Li Xiaomin,Li Guoming,Cai Yefeng,Zhao Min PloS one BACKGROUND AND PURPOSE:Stroke-associated pneumonia (SAP) is a common complication and an important cause of death during hospitalization. The A2DS2 (Age, Atrial fibrillation, Dysphagia, Sex, Stroke Severity) score was developed from the Berlin Stroke Registry and showed good predictive value for predicting SAP. We sought to identify the association between the A2DS2 score and SAP, and, furthermore, to identify whether the A2DS2 score was a predictor for in-hospital death after acute ischemic stroke in a Chinese population. METHODS:This was a retrospective study. 1239 acute ischemic stroke patients were classified to low A2DS2 group (0-4) and high A2DS2 score (5-10) group. Primary outcome was in-hospital SAP. Logistic regression analyses were performed to identify the association between the A2DS2 score and SAP, and also the association between the A2DS2 score and in-hospital death. RESULTS:The overall incidence rates of SAP and in-hospital mortality after acute ischemic stroke were 7.3% and 2.4%, respectively. The incidence rate of SAP in low and high A2DS2 score groups was separately 3.3% and 24.7% (P<0.001). During hospitalization, 1.2% patients in low score group and 7.8% patients in high score group died (P<0.001). Multivariate regression demonstrated that patients in high score group had a higher risk of SAP (OR = 8.888, 95%CI: 5.552-14.229) and mortality (OR = 7.833, 95%CI: 3.580-17.137) than patients in low score group. CONCLUSIONS:The A2DS2 score was a strong predictor for SAP and in-hospital death of Chinese acute ischemic stroke patients. The A2DS2 score might be a useful tool for the identification of patients with a high risk of SAP and death during hospitalization. 10.1371/journal.pone.0150298
Strategies for Molecular Imprinting and the Evolution of MIP Nanoparticles as Plastic Antibodies-Synthesis and Applications. International journal of molecular sciences Materials that can mimic the molecular recognition-based functions found in biology are a significant goal for science and technology. Molecular imprinting is a technology that addresses this challenge by providing polymeric materials with antibody-like recognition characteristics. Recently, significant progress has been achieved in solving many of the practical problems traditionally associated with molecularly imprinted polymers (MIPs), such as difficulties with imprinting of proteins, poor compatibility with aqueous environments, template leakage, and the presence of heterogeneous populations of binding sites in the polymers that contribute to high levels of non-specific binding. This success is closely related to the technology-driven shift in MIP research from traditional bulk polymer formats into the nanomaterial domain. The aim of this article is to throw light on recent developments in this field and to present a critical discussion of the current state of molecular imprinting and its potential in real world applications. 10.3390/ijms20246304
Medicinal plant activity on Helicobacter pylori related diseases. Wang Yuan-Chuen World journal of gastroenterology More than 50% of the world population is infected with Helicobacter pylori (H. pylori). The bacterium highly links to peptic ulcer diseases and duodenal ulcer, which was classified as a group I carcinogen in 1994 by the WHO. The pathogenesis of H. pylori is contributed by its virulence factors including urease, flagella, vacuolating cytotoxin A (VacA), cytotoxin-associated gene antigen (Cag A), and others. Of those virulence factors, VacA and CagA play the key roles. Infection with H. pylori vacA-positive strains can lead to vacuolation and apoptosis, whereas infection with cagA-positive strains might result in severe gastric inflammation and gastric cancer. Numerous medicinal plants have been reported for their anti-H. pylori activity, and the relevant active compounds including polyphenols, flavonoids, quinones, coumarins, terpenoids, and alkaloids have been studied. The anti-H. pylori action mechanisms, including inhibition of enzymatic (urease, DNA gyrase, dihydrofolate reductase, N-acetyltransferase, and myeloperoxidase) and adhesive activities, high redox potential, and hydrophilic/hydrophobic natures of compounds, have also been discussed in detail. H. pylori-induced gastric inflammation may progress to superficial gastritis, atrophic gastritis, and finally gastric cancer. Many natural products have anti-H. pylori-induced inflammation activity and the relevant mechanisms include suppression of nuclear factor-κB and mitogen-activated protein kinase pathway activation and inhibition of oxidative stress. Anti-H. pylori induced gastric inflammatory effects of plant products, including quercetin, apigenin, carotenoids-rich algae, tea product, garlic extract, apple peel polyphenol, and finger-root extract, have been documented. In conclusion, many medicinal plant products possess anti-H. pylori activity as well as an anti-H. pylori-induced gastric inflammatory effect. Those plant products have showed great potential as pharmaceutical candidates for H. pylori eradication and H. pylori induced related gastric disease prevention. 10.3748/wjg.v20.i30.10368
Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study. JAMA oncology Importance:Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. Objective:To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. Evidence Review:We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. Findings:In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs). Conclusions and Relevance:The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care. 10.1001/jamaoncol.2019.2996
MYB Gene Family in Potato ( L.): Genome-Wide Identification of Hormone-Responsive Reveals Their Potential Functions in Growth and Development. Sun Wenjun,Ma Zhaotang,Chen Hui,Liu Moyang International journal of molecular sciences As an important nongrain crop, the growth and yield of potato ( L.) is often affected by an unfavorable external environment in the process of cultivation. The MYB family is one of the largest and most important gene families, participating in the regulation of plant growth and development and response to abiotic stresses. Several genes in potato that regulate anthocyanin synthesis and participate in abiotic stress responses have been identified. To identify all L. () genes involved in hormone or stress responses to potentially regulate potato growth and development, we identified the MYB gene family at the genome-wide level. In this work, 158 genes were found in the potato genome. According to the amino acid sequence of the MYB domain and gene structure, the genes were divided into R2R3-MYB and R1R2R3-MYB families, and the R2R3-MYB family was divided into 20 subgroups (SGs). The expression of 21 genes from different SGs in roots, stems, leaves, flowers, shoots, stolons, young tubers, and mature tubers was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The expression patterns of genes in potatoes treated with abscisic acid (ABA), indole-3-acetic acid (IAA), gibberellin acid 3 (GA3), NaCl, mannitol, and heat were also measured. We have identified several potential candidate genes that regulate the synthesis of potato flavonoids or participate in hormone or stress responses. This work provides a comprehensive understanding of the MYB family in potato and will lay a foundation for the future investigation of the potential functions of genes in the growth and development of potato. 10.3390/ijms20194847
Recent Advances in Microfluidic Paper-Based Analytical Devices toward High-Throughput Screening. Molecules (Basel, Switzerland) Microfluidic paper-based analytical devices (µPADs) have become promising tools offering various analytical applications for chemical and biological assays at the point-of-care (POC). Compared to traditional microfluidic devices, µPADs offer notable advantages; they are cost-effective, easily fabricated, disposable, and portable. Because of our better understanding and advanced engineering of µPADs, multistep assays, high detection sensitivity, and rapid result readout have become possible, and recently developed µPADs have gained extensive interest in parallel analyses to detect biomarkers of interest. In this review, we focus on recent developments in order to achieve µPADs with high-throughput capability. We discuss existing fabrication techniques and designs, and we introduce and discuss current detection methods and their applications to multiplexed detection assays in relation to clinical diagnosis, drug analysis and screening, environmental monitoring, and food and beverage quality control. A summary with future perspectives for µPADs is also presented. 10.3390/molecules25132970
The Role of Diet Quality in Mediating the Association between Ultra-Processed Food Intake, Obesity and Health-Related Outcomes: A Review of Prospective Cohort Studies. Nutrients Prospective cohort studies show that higher intakes of ultra-processed food (UPF) increase the risk of obesity and obesity-related outcomes, including cardiovascular disease, cancer and type 2 diabetes. Whether ultra-processing itself is detrimental, or whether UPFs just have a lower nutritional quality, is debated. Higher UPF intakes are inversely associated with fruit, vegetables, legumes and seafood consumption. Therefore, the association between UPFs and poor health could simply be from excess nutrient intake or from a less healthful dietary pattern. If so, adjustment for dietary quality or pattern should explain or greatly reduce the size of the significant associations between UPFs and health-related outcomes. Here, we provide an overview of the literature and by using a novel approach, review the relative impact of adjusting for diet quality/patterns on the reported associations between UPF intake and health-related outcomes in prospective cohort studies. We find that the majority of the associations between UPFs, obesity and health-related outcomes remain significant and unchanged in magnitude after adjustment for diet quality or pattern. Our findings suggest that the adverse consequences of UPFs are independent of dietary quality or pattern, questioning the utility of reformulation to mitigate against the obesity pandemic and wider negative health outcomes of UPFs. 10.3390/nu14010023
Food and Food Groups in Inflammatory Bowel Disease (IBD): The Design of the Groningen Anti-Inflammatory Diet (GrAID). Campmans-Kuijpers Marjo J E,Dijkstra Gerard Nutrients Diet plays a pivotal role in the onset and course of inflammatory bowel disease (IBD). Patients are keen to know what to eat to reduce symptoms and flares, but dietary guidelines are lacking. To advice patients, an overview of the current evidence on food (group) level is needed. This narrative review studies the effects of food (groups) on the onset and course of IBD and if not available the effects in healthy subjects or animal and in vitro IBD models. Based on this evidence the Groningen anti-inflammatory diet (GrAID) was designed and compared on food (group) level to other existing IBD diets. Although on several foods conflicting results were found, this review provides patients a good overview. Based on this evidence, the GrAID consists of lean meat, eggs, fish, plain dairy (such as milk, yoghurt, kefir and hard cheeses), fruit, vegetables, legumes, wheat, coffee, tea and honey. Red meat, other dairy products and sugar should be limited. Canned and processed foods, alcohol and sweetened beverages should be avoided. This comprehensive review focuses on anti-inflammatory properties of foods providing IBD patients with the best evidence on which foods they should eat or avoid to reduce flares. This was used to design the GrAID. 10.3390/nu13041067
The EF-hand calcium-binding protein tescalcin is a potential oncotarget in colorectal cancer. Kang Yun Hee,Han Seung Ro,Kim Jong-Tae,Lee Seon-Jin,Yeom Young Il,Min Jeong-Ki,Lee Chul-Ho,Kim Jae Wha,Yoon Suk Ran,Yoon Do-Young,Hong Kwan Soo,Hwang Geum-Sook,Kim Hee Cheol,Lee Young-Ha,Lee Hee Gu Oncotarget Tescalcin (TESC) is an EF-hand calcium binding protein that is differentially expressed in several tissues, however it is not reported that the expression and functional roles of TESC in colorectal cancer. Levels of messenger RNA (mRNA) and protein expression of TESC in colorectal cancer tissues were assessed using RT-PCR, real time PCR, immunohistochemistry, and clinicopathologic analyses. Quantitative analysis of TESC levels in serum specimens was performed using sandwich ELISA. Colorectal cancer cells transfected with TESC small interfering RNA and short hairpin RNA were examined in cell proliferation assays, phospho-MAPK array, and mouse xenograft models. Here we demonstrated that TESC is overexpressed in colorectal cancer (CRC), but was not expressed in normal mucosa and premalignant dysplastic lesions. Furthermore, serum TESC levels were elevated in patients with CRC. Knockdown of TESC inhibited the Akt-dependent NF-κB pathway and decreased cell survival in vitro. Depletion of TESC reduced tumor growth in a CRC xenograft model. Thus, TESC is a potential diagnostic marker and oncotarget in colorectal cancer. 10.18632/oncotarget.1851
New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia. Frontiers in immunology Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a clonal lymphoproliferative disorder, and secondary cold agglutinin syndrome (CAS), in which a similar picture of cold-hemolytic anemia occurs secondary to another distinct clinical disease. Thus, the pathogenesis in CAD is quite different from that of polyclonal autoimmune diseases such as warm-antibody AIHA. In both CAD and CAS, hemolysis is mediated by the classical complement pathway and therefore can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. On the other hand, infection and inflammation can act as triggers and drivers of hemolysis, exemplified by exacerbation of CAD in situations with acute phase reaction and the role of specific infections (particularly and Epstein-Barr virus) as causes of CAS. In this review, the putative mechanisms behind these phenomena will be explained along with other recent achievements in the understanding of pathogenesis in these disorders. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS. Currently, novel targeted treatments, in particular complement-directed therapies, are also being rapidly developed and will be reviewed. 10.3389/fimmu.2020.00590
Porcine Endogenous Retrovirus (PERV) - Molecular Structure and Replication Strategy in the Context of Retroviral Infection Risk of Human Cells. Łopata Krzysztof,Wojdas Emilia,Nowak Roman,Łopata Paweł,Mazurek Urszula Frontiers in microbiology The xenotransplantation of porcine tissues may help overcome the shortage of human organs for transplantation. However, there are some concerns about recipient safety because the risk of porcine endogenous retrovirus (PERV) transmission to human cells remains unknown. Although, to date, no PERV infections have been noted , the possibility of such infections has been confirmed . Better understanding of the structure and replication cycle of PERVs is a prerequisite for determining the risk of infection and planning PERV-detection strategies. This review presents the current state of knowledge about the structure and replication cycle of PERVs in the context of retroviral infection risk. 10.3389/fmicb.2018.00730
Aging and the optimal viewing position effect in Chinese. Liu Pingping,Liu Danlu,Han Buxin,Paterson Kevin B Frontiers in psychology Substantial evidence indicates that where readers fixate within a word affects the efficiency with which that word is recognized. Indeed, words in alphabetic languages (e.g., English, French) are recognized most efficiently when fixated at their optimal viewing position (OVP), which is near the word center. However, little is known about the effects of fixation location on word recognition in non-alphabetic languages, such as Chinese. Moreover, studies to date have not investigated if effects of fixation location vary across adult age-groups, although it is well-established that older readers experience greater difficulty recognizing words due to visual and cognitive declines. Accordingly, the present research examined OVP effects by young and older adult readers when recognizing Chinese words presented in isolation. Most words in Chinese are formed from two or more logograms called characters and so the present experiment investigated the influence of fixation location on the recognition of 2-, 3-, and 4-character words (and nonwords). The older adults experienced generally greater word recognition difficulty. But whereas the young adults recognized words most efficiently when initially fixating the first character of 2-character words and second character of 3- and 4-character words, the older adults recognized words most efficiently when initially fixating the first character for words of each length. The findings therefore reveal subtle but potentially important adult age differences in the effects of fixation location on Chinese word recognition. Moreover, the similarity in effects for words and nonwords implies a more general age-related change in oculomotor strategy when processing Chinese character-strings. 10.3389/fpsyg.2015.01656
Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. ,Cavalcanti Alexandre Biasi,Suzumura Érica Aranha,Laranjeira Ligia Nasi,Paisani Denise de Moraes,Damiani Lucas Petri,Guimarães Helio Penna,Romano Edson Renato,Regenga Marisa de Moraes,Taniguchi Luzia Noriko Takahashi,Teixeira Cassiano,Pinheiro de Oliveira Roselaine,Machado Flavia Ribeiro,Diaz-Quijano Fredi Alexander,Filho Meton Soares de Alencar,Maia Israel Silva,Caser Eliana Bernardete,Filho Wilson de Oliveira,Borges Marcos de Carvalho,Martins Priscilla de Aquino,Matsui Mirna,Ospina-Tascón Gustavo Adolfo,Giancursi Thiago Simões,Giraldo-Ramirez Nelson Dario,Vieira Silvia Regina Rios,Assef Maria da Graça Pasquotto de Lima,Hasan Mohd Shahnaz,Szczeklik Wojciech,Rios Fernando,Amato Marcelo Britto Passos,Berwanger Otávio,Ribeiro de Carvalho Carlos Roberto JAMA Importance:The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain. Objective:To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy. Design, Setting, and Participants:Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS. Interventions:An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning. Main Outcomes and Measures:The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. Results:A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, -1.1; 95% CI, -2.1 to -0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality. Conclusions and Relevance:In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients. Trial Registration:clinicaltrials.gov Identifier: NCT01374022. 10.1001/jama.2017.14171
Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. ,Williamson Jeff D,Pajewski Nicholas M,Auchus Alexander P,Bryan R Nick,Chelune Gordon,Cheung Alfred K,Cleveland Maryjo L,Coker Laura H,Crowe Michael G,Cushman William C,Cutler Jeffrey A,Davatzikos Christos,Desiderio Lisa,Erus Guray,Fine Larry J,Gaussoin Sarah A,Harris Darrin,Hsieh Meng-Kang,Johnson Karen C,Kimmel Paul L,Tamura Manjula Kurella,Launer Lenore J,Lerner Alan J,Lewis Cora E,Martindale-Adams Jennifer,Moy Claudia S,Nasrallah Ilya M,Nichols Linda O,Oparil Suzanne,Ogrocki Paula K,Rahman Mahboob,Rapp Stephen R,Reboussin David M,Rocco Michael V,Sachs Bonnie C,Sink Kaycee M,Still Carolyn H,Supiano Mark A,Snyder Joni K,Wadley Virginia G,Walker Jennifer,Weiner Daniel E,Whelton Paul K,Wilson Valerie M,Woolard Nancy,Wright Jackson T,Wright Clinton B JAMA Importance:There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. Objective:To evaluate the effect of intensive blood pressure control on risk of dementia. Design, Setting, and Participants:Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018. Interventions:Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures:The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. Results:Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97). Conclusions and Relevance:Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point. Trial Registration:ClinicalTrials.gov Identifier: NCT01206062. 10.1001/jama.2018.21442
Preterm Gut Microbiome Depending on Feeding Type: Significance of Donor Human Milk. Parra-Llorca Anna,Gormaz María,Alcántara Cristina,Cernada María,Nuñez-Ramiro Antonio,Vento Máximo,Collado Maria C Frontiers in microbiology Preterm microbial colonization is affected by gestational age, antibiotic treatment, type of birth, but also by type of feeding. Breast milk has been acknowledged as the gold standard for human nutrition. In preterm infants breast milk has been associated with improved growth and cognitive development and a reduced risk of necrotizing enterocolitis and late onset sepsis. In the absence of their mother's own milk (MOM), pasteurized donor human milk (DHM) could be the best available alternative due to its similarity to the former. However, little is known about the effect of DHM upon preterm microbiota and potential biological implications. Our objective was to determine the impact of DHM upon preterm gut microbiota admitted in a referral neonatal intensive care unit (NICU). A prospective observational cohort study in NICU of 69 neonates <32 weeks of gestation and with a birth weight ≤1,500 g was conducted. Neonates were classified in three groups according to feeding practices consisting in their MOM, DHM, or formula. Fecal samples were collected when full enteral feeding (defined as ≥150 cc/kg/day) was achieved. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Despite the higher variability, no differences in microbial diversity and richness were found, although feeding type significantly influenced the preterm microbiota composition and predictive functional profiles. Preterm infants fed MOM showed a significant greater presence of Bifidobacteriaceae and lower of Staphylococcaceae, Clostridiaceae, and Pasteurellaceae compared to preterm fed DHM. Formula fed microbial profile was different to those observed in preterm fed MOM. Remarkably, preterm infants fed DHM showed closer microbial profiles to preterm fed their MOM. Inferred metagenomic analyses showed higher presence of genus in mother's milk group was related to enrichment in the Glycan biosynthesis and metabolism pathway that was not identified in the DHM or in the formula fed groups. In conclusion, DHM favors an intestinal microbiome more similar to MOM than formula despite the differences between MOM and DHM. This may have potential beneficial long-term effects on intestinal functionality, immune system, and metabolic activities. 10.3389/fmicb.2018.01376
Antibacterial activity of fresh pomegranate juice against clinical strains of Staphylococcus epidermidis. Food & nutrition research BACKGROUND:Polyphenols have received a great deal of attention due to their biological functions. Pomegranate (Punica granatum L.) is a polyphenol-rich fruit. In the past decade, studies testing the antimicrobial activity of pomegranates almost exclusively used solvent extracts instead of fresh pomegranate juice (FPJ). The use of FPJ instead of solvent extracts would reduce toxicity issues while increasing patient acceptance. We established a model to test FPJ as a natural antimicrobial agent. OBJECTIVE:To evaluate the antimicrobial activity of FPJ on clinical isolates of multidrug-resistant Staphylococcus epidermidis strains. DESIGN:Sixty strains of S. epidermidis isolated from ocular infections were grown in the presence of FPJ, and minimum inhibitory concentration (MIC) was determined by broth and agar dilution methods. RESULTS:FPJ at 20% had a MIC equal to 100% (MIC100%) on all 60 strains tested. This inhibition of FPJ was confirmed by the growth kinetics of a multidrug-resistant strain exposed to different concentrations of FPJ. Additionally, the antimicrobial activity of FPJ was compared against commercial beverages containing pomegranate: Ocean Spray(®) had a MIC100% at 20%, followed by Del Valle(®) with a MIC15% at 20% concentration only. The beverages Jumex(®) and Sonrisa(®) did not have any antimicrobial activity. FPJ had the highest polyphenol content and antioxidant capacity. CONCLUSIONS:Overall, FPJ had antimicrobial activity, which might be attributed to its high polyphenol content and antioxidant capacity. 10.3402/fnr.v59.27620
The quick-phase system. Robinson David A Progress in brain research Two types of rapid eye movements, saccades and quick phases (QP), share the same neural circuits, but have different purposes. Quick phases reset the eye in the orbit, avoiding an attempt to move the eyes beyond the oculomotor range. In general, QP move the eyes into the direction one is turning. This is useful because it brings the world toward which one is turning into view more quickly. Algorithms for deciding when to begin a QP, and how large it should be, move the eyes, on average, into the direction of turning. This makes it reasonable to assume that the afoveate QP system evolved to provide commands in a head-coordinate system. The saccadic system evolved in foveate animals on top of this system, and thus it is reasonable to assume it also provides commands in head coordinates. 10.1016/bs.pbr.2021.10.015
Assessment of Lung Cancer Risk on the Basis of a Biomarker Panel of Circulating Proteins. JAMA oncology Importance:There is an urgent need to improve lung cancer risk assessment because current screening criteria miss a large proportion of cases. Objective:To investigate whether a lung cancer risk prediction model based on a panel of selected circulating protein biomarkers can outperform a traditional risk prediction model and current US screening criteria. Design, Setting, and Participants:Prediagnostic samples from 108 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and samples from 216 smoking-matched controls from the Carotene and Retinol Efficacy Trial (CARET) cohort were used to develop a biomarker risk score based on 4 proteins (cancer antigen 125 [CA125], carcinoembryonic antigen [CEA], cytokeratin-19 fragment [CYFRA 21-1], and the precursor form of surfactant protein B [Pro-SFTPB]). The biomarker score was subsequently validated blindly using absolute risk estimates among 63 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and 90 matched controls from 2 large European population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS). Main Outcomes and Measures:Model validity in discriminating between future lung cancer cases and controls. Discrimination estimates were weighted to reflect the background populations of EPIC and NSHDS validation studies (area under the receiver-operating characteristics curve [AUC], sensitivity, and specificity). Results:In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls (mean [SD] age, 57.7 [8.7] years; 68.6% men) from EPIC and NSHDS, an integrated risk prediction model that combined smoking exposure with the biomarker score yielded an AUC of 0.83 (95% CI, 0.76-0.90) compared with 0.73 (95% CI, 0.64-0.82) for a model based on smoking exposure alone (P = .003 for difference in AUC). At an overall specificity of 0.83, based on the US Preventive Services Task Force screening criteria, the sensitivity of the integrated risk prediction (biomarker) model was 0.63 compared with 0.43 for the smoking model. Conversely, at an overall sensitivity of 0.42, based on the US Preventive Services Task Force screening criteria, the integrated risk prediction model yielded a specificity of 0.95 compared with 0.86 for the smoking model. Conclusions and Relevance:This study provided a proof of principle in showing that a panel of circulating protein biomarkers may improve lung cancer risk assessment and may be used to define eligibility for computed tomography screening. 10.1001/jamaoncol.2018.2078
IL-10 enhances cell-to-cell communication in chondrocytes via STAT3 signaling pathway. Cellular signalling Gap junction intercellular communication (GJIC) allows the transfer of material, message and energy between cells, which influences cell behaviors including cell proliferation, migration, differentiation and apoptosis and determines cell fate. Interleukin-10 (IL-10), a versatile cytokine, attracts more and more attention in the cartilage pathology such as osteoarthritis (OA) due to its potential in anti-inflammation and wound repair. However, whether IL-10 can mediate GJIC in chondrocytes remains elusive. In the current study, we aimed to explore the role of IL-10 on GJIC and its underlying mechanism. We found that IL-10 can promote GJIC in living chondrocytes. IL-10-enhanced GJIC in chondrocytes was dependent on the up-regulation of connexin 43 (Cx43). Knockdown experiment based on siRNA interference then confirmed that IL-10-enhanced GJIC required participation of IL-10 receptor 1 (IL-10R1). IL-10 activated signal transducer and activator of transcription 3 (STAT3) signaling and promoted the nuclear accumulation of p-STAT3 through IL-10 receptor 1. Inhibitor experiment further confirmed the importance of STAT3 signaling in IL-10-mediated GJIC. Taking together, our results provided a thorough process of IL-10-modulated cell-to-cell communication in chondrocytes and established a bridge between inflammatory factor, IL-10, and GJIC, which can increase our understanding about the physiology and pathology of cartilage. 10.1016/j.cellsig.2023.110605
A Critical Evaluation of Current Concepts in Cerebral Palsy. Physiology (Bethesda, Md.) Spastic cerebral palsy (CP), despite the name, is not consistently identifiable by specific brain lesions. CP animal models focus on risk factors for development of CP, yet few reproduce the diagnostic symptoms. Animal models of CP must advance beyond risk factors to etiologies, including both the brain and spinal cord. 10.1152/physiol.00054.2018
In vitro cytotoxicity and in vivo acute and chronic toxicity of Xanthii Fructus and its processed product. Yu Jie,Song Mei-Zhen,Wang Jing,Li Yun-Fei,Lin Pei,Que Lin,Bao Zhaorigetu BioMed research international Xanthii Fructus (XF), the fruit of Xanthium sibiricum Patr., was used in the treatment of rhinitis and related nasal disease. Adverse effects of Xanthii Fructus are frequently reported these years. In the paper, in vitro renal cytotoxicity and in vivo acute and chronic toxicity researches of Xanthii Fructus (XF) and its processed product (processed Xanthii Fructus (PXF)) were carried out. Water extraction of XF displayed no cell membrane damage effects even in the highest concentration (100 μg/mL); however, it might affect the function of renal cell mitochondria. Acute toxicities were observed only in high and middle dosage groups. Fortunately, the single dose administration of XF or PXF was safe even at the highest daily dosage. Twelve-week chronic toxicity assays were performed in SD rats with low, middle, and high dosage. Notable changes in body weight and blood cell and BUN and Scr changes sporadically occurred in middle and high groups after the 9th week. Serum HA and HPCIII values were sustained increasing from the 4th week to the 8th week in Group V male rats, which indicated that the renal fibrosis risks still existed although no fibrosis was found in the pathological examination of the liver and kidney. 10.1155/2013/403491
Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Winstein Carolee J,Stein Joel,Arena Ross,Bates Barbara,Cherney Leora R,Cramer Steven C,Deruyter Frank,Eng Janice J,Fisher Beth,Harvey Richard L,Lang Catherine E,MacKay-Lyons Marilyn,Ottenbacher Kenneth J,Pugh Sue,Reeves Mathew J,Richards Lorie G,Stiers William,Zorowitz Richard D, Stroke PURPOSE:The aim of this guideline is to provide a synopsis of best clinical practices in the rehabilitative care of adults recovering from stroke. METHODS:Writing group members were nominated by the committee chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association (AHA) Stroke Council's Scientific Statement Oversight Committee and the AHA's Manuscript Oversight Committee. The panel reviewed relevant articles on adults using computerized searches of the medical literature through 2014. The evidence is organized within the context of the AHA framework and is classified according to the joint AHA/American College of Cardiology and supplementary AHA methods of classifying the level of certainty and the class and level of evidence. The document underwent extensive AHA internal and external peer review, Stroke Council Leadership review, and Scientific Statements Oversight Committee review before consideration and approval by the AHA Science Advisory and Coordinating Committee. RESULTS:Stroke rehabilitation requires a sustained and coordinated effort from a large team, including the patient and his or her goals, family and friends, other caregivers (eg, personal care attendants), physicians, nurses, physical and occupational therapists, speech-language pathologists, recreation therapists, psychologists, nutritionists, social workers, and others. Communication and coordination among these team members are paramount in maximizing the effectiveness and efficiency of rehabilitation and underlie this entire guideline. Without communication and coordination, isolated efforts to rehabilitate the stroke survivor are unlikely to achieve their full potential. CONCLUSIONS:As systems of care evolve in response to healthcare reform efforts, postacute care and rehabilitation are often considered a costly area of care to be trimmed but without recognition of their clinical impact and ability to reduce the risk of downstream medical morbidity resulting from immobility, depression, loss of autonomy, and reduced functional independence. The provision of comprehensive rehabilitation programs with adequate resources, dose, and duration is an essential aspect of stroke care and should be a priority in these redesign efforts. (Stroke.2016;47:e98-e169. DOI: 10.1161/STR.0000000000000098.). 10.1161/STR.0000000000000098
A missense mutation in reduces but does not eliminate mGluR6 expression or rod depolarizing bipolar cell function. Peachey Neal S,Hasan Nazarul,FitzMaurice Bernard,Burrill Samantha,Pangeni Gobinda,Karst Son Yong,Reinholdt Laura,Berry Melissa L,Strobel Marge,Gregg Ronald G,McCall Maureen A,Chang Bo Journal of neurophysiology encodes the metabotropic glutamate receptor 6 (mGluR6) used by retinal depolarizing bipolar cells (DBCs). Mutations in lead to DBC dysfunction and underlie the human condition autosomal recessive complete congenital stationary night blindness. Mouse mutants for are important models for this condition. Here we report a new mutant, identified in an electroretinogram (ERG) screen of mice maintained at The Jackson Laboratory. The mouse has a reduced-amplitude b-wave component of the ERG, which reflects light-evoked DBC activity. Sequencing identified a missense mutation that converts a highly conserved methionine within the ligand binding domain to leucine (p.Met66Leu). Consistent with prior studies of mutant mice, the laminar size and structure in the retina were comparable to control. The phenotype is distinguished from other mutants that carry a null allele by a reduced but not absent ERG b-wave, decreased but present expression of mGluR6 at DBC dendritic tips, and mislocalization of mGluR6 to DBC somas. Consistent with a reduced but not absent b-wave, there were a subset of retinal ganglion cells whose responses to light onset have times to peak within the range of those in control retinas. These data indicate that the p.Met66Leu mutant mGluR6 is trafficked less than control. However, the mGluR6 that is localized to the DBC dendritic tips is able to initiate DBC signal transduction. The mouse extends the allelic series and will be useful for elucidating the role of mGluR6 in DBC signal transduction and in human disease. This article describes a mouse model of the human disease complete congenital stationary night blindness in which the mutation reduces but does not eliminate GRM6 expression and bipolar cell function, a distinct phenotype from that seen in other mouse models. 10.1152/jn.00888.2016
A New Case of DRESS Syndrome Induced by Sulfasalazine and Triggered by Amoxicillin. Girelli Francesco,Bernardi Simone,Gardelli Lucia,Bassi Bruna,Parente Gianluca,Dubini Alessandra,Serra Luigi,Nizzoli Maurizio Case reports in rheumatology Drug Rash Eosinophilia Systemic Symptoms (DRESS) syndrome is a systemic hypersensitivity reaction characterized by exfoliative dermatitis and maculopapular rash, lymphadenopathy, fever, eosinophilia, leukocytosis, and involvement of internal organs as liver, lung, heart, and kidney; the disorder starts within 2-6 weeks after taking a drug with an incidence that ranges from 1/1000 to 1/10000 exposures. Fatal cases are reported. The exact pathogenesis of DRESS syndrome is not completely understood, while it is reported that amoxicillin could trigger it in patients who are taking allopurinol, sulfasalazine, NSAIDs, carbamazepine, strontium ranelate, lisinopril, lansoprazole, and minocycline. Amoxicillin could act directly, inducing the reactivation of a viral infection (HHV 6 and EBV) with symptoms similar to DRESS syndrome or by reducing the patients' ability to detoxify the body from substances chronically taken. We describe a case of a patient admitted to our hospital for a DRESS syndrome flared after amoxicilline intake during treatment with sulfasalazine; this combination can activate severe reactions often with an insidious onset that can mimic an infectious disease. 10.1155/2013/409152
Diversity and Biology of Cancer-Associated Fibroblasts. Physiological reviews Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation. 10.1152/physrev.00048.2019
Healing after COVID-19: are survivors at risk for pulmonary fibrosis? American journal of physiology. Lung cellular and molecular physiology The novel SARS-CoV-2 coronavirus, which is responsible for COVID-19 disease, was first reported in Wuhan, China, in December of 2019. The virus rapidly spread, and the World Health Organization declared a pandemic by March 2020. With millions of confirmed cases worldwide, there is growing concern and considerable debate regarding the potential for coronavirus infection to contribute to an appreciable burden of chronic respiratory symptoms or fibrotic disease among recovered individuals. Because the first case of COVID-19 was documented less than one year ago, data regarding long-term clinical outcomes are not yet available, and predictions for long-term outcome are speculative at best. However, due to the staggering number of cases and the severity of disease in many individuals, there is a critical need to consider the potential long-term implications of COVID-19. This review examines current basic and clinical data regarding fibrogenic mechanisms of viral injury in the context of SARS-CoV-2. Several intersecting mechanisms between coronavirus infection and fibrotic pathways are discussed to highlight factors and processes that may be targetable to improve patient outcome. Reports of post-infection sequelae from previous coronavirus outbreaks are presented toward the goal of improved recognition of potential contributing risk factors for fibrotic disease. 10.1152/ajplung.00238.2020
Resveratrol alleviates alcoholic fatty liver in mice. Ajmo Joanne M,Liang Xiaomei,Rogers Christopher Q,Pennock Brandi,You Min American journal of physiology. Gastrointestinal and liver physiology Alcoholic fatty liver is associated with inhibition of sirtuin 1 (SIRT1) and AMP-activated kinase (AMPK), two critical signaling molecules regulating the pathways of hepatic lipid metabolism in animals. Resveratrol, a dietary polyphenol, has been identified as a potent activator for both SIRT1 and AMPK. In the present study, we have carried out in vivo animal experiments that test the ability of resveratrol to reverse the inhibitory effects of chronic ethanol feeding on hepatic SIRT1-AMPK signaling system and to prevent the development of alcoholic liver steatosis. Resveratrol treatment increased SIRT1 expression levels and stimulated AMPK activity in livers of ethanol-fed mice. The resveratrol-mediated increase in activities of SIRT1 and AMPK was associated with suppression of sterol regulatory element binding protein 1 (SREBP-1) and activation of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha). In parallel, in ethanol-fed mice, resveratrol administration markedly increased circulating adiponectin levels and enhanced mRNA expression of hepatic adiponectin receptors (AdipoR1/R2). In conclusion, resveratrol treatment led to reduced lipid synthesis and increased rates of fatty acid oxidation and prevented alcoholic liver steatosis. The protective action of resveratrol is in whole or in part mediated through the upregulation of a SIRT1-AMPK signaling system in the livers of ethanol-fed mice. Our study suggests that resveratrol may serve as a promising agent for preventing or treating human alcoholic fatty liver disease. 10.1152/ajpgi.90358.2008
The gastrointestinal microbiota and colorectal cancer. American journal of physiology. Gastrointestinal and liver physiology The human gut is home to a complex and diverse microbiota that contributes to the overall homeostasis of the host. Increasingly, the intestinal microbiota is recognized as an important player in human illness such as colorectal cancer (CRC), inflammatory bowel diseases, and obesity. CRC in itself is one of the major causes of cancer mortality in the Western world. The mechanisms by which bacteria contribute to CRC are complex and not fully understood, but increasing evidence suggests a link between the intestinal microbiota and CRC as well as diet and inflammation, which are believed to play a role in carcinogenesis. It is thought that the gut microbiota interact with dietary factors to promote chronic inflammation and CRC through direct influence on host cell physiology, cellular homeostasis, energy regulation, and/or metabolism of xenobiotics. This review provides an overview on the role of commensal gut microbiota in the development of human CRC and explores its association with diet and inflammation. 10.1152/ajpgi.00360.2012
Helicobacter pylori strains vary cell shape and flagellum number to maintain robust motility in viscous environments. Molecular microbiology The helical shape of the human stomach pathogen Helicobacter pylori has been suggested to provide mechanical advantage for penetrating the viscous stomach mucus layer. Using single-cell tracking and quantitative morphology analysis, we document marked variation in cell body helical parameters and flagellum number among H. pylori strains leading to distinct and broad speed distributions in broth and viscous gastric mucin media. These distributions reflect both temporal variation in swimming speed and morphologic variation within the population. Isogenic mutants with straight-rod morphology showed 7-21% reduction in speed and a lower fraction of motile bacteria. Mutational perturbation of flagellum number revealed a 19% increase in speed with 4 versus 3 median flagellum number. Resistive force theory modeling incorporating variation of both cell shape and flagellum number predicts qualitative speed differences of 10-30% among strains. However, quantitative comparisons suggest resistive force theory underestimates the influence of cell body shape on speed for helical shaped bacteria. 10.1111/mmi.13218
The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer. Affo Silvia,Yu Le-Xing,Schwabe Robert F Annual review of pathology Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix-associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy. 10.1146/annurev-pathol-052016-100322
Postnatal development of testicular capillaries and the effect of experimental cryptorchid on capillaries in rats. The Japanese journal of veterinary research
The Helicobacter pylori flaA1 and wbpB genes control lipopolysaccharide and flagellum synthesis and function. Merkx-Jacques A,Obhi R K,Bethune G,Creuzenet C Journal of bacteriology flaA1 and wbpB are conserved genes with unknown biological function in Helicobacter pylori. Since both genes are predicted to be involved in lipopolysaccharide (LPS) biosynthesis, flagellum assembly, or protein glycosylation, they could play an important role in the pathogenesis of H. pylori. To determine their biological role, both genes were disrupted in strain NCTC 11637. Both mutants exhibited altered LPS, with loss of most O-antigen and core modification, and increased sensitivity to sodium dodecyl sulfate compared to wild-type bacteria. These defects could be complemented in a gene-specific manner. Also, flaA1 could complement these defects in the wbpB mutant, suggesting a potential redundancy of the reductase activity encoded by both genes. Both mutants were nonmotile, although the wbpB mutant still produced flagella. The defect in the flagellum functionality of this mutant was not due to a defect in flagellin glycosylation since flagellins from wild-type strain NCTC 11637 were shown not to be glycosylated. The flaA1 mutant produced flagellins but no flagellum. Overall, the similar phenotypes observed for both mutants and the complementation of the wbpB mutant by flaA1 suggest that both genes belong to the same biosynthesis pathway. The data also suggest that flaA1 and wbpB are at the interface between several pathways that govern the expression of different virulence factors. We propose that FlaA1 and WbpB synthesize sugar derivatives dedicated to the glycosylation of proteins which are involved in LPS and flagellum production and that glycosylation regulates the activity of these proteins. 10.1128/JB.186.8.2253-2265.2004
Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension. American journal of physiology. Heart and circulatory physiology Pulmonary arterial hypertension (PAH) is characterized by remodeling of the extracellular matrix (ECM) of the pulmonary arteries with increased collagen deposition, cross-linkage of collagen, and breakdown of elastic laminae. Extracellular matrix remodeling occurs due to an imbalance in the proteolytic enzymes, such as matrix metalloproteinases, elastases, and lysyl oxidases, and tissue inhibitor of matrix metalloproteinases, which, in turn, results from endothelial cell dysfunction, endothelial-to-mesenchymal transition, and inflammation. ECM remodeling and pulmonary vascular stiffness occur early in the disease process, before the onset of the increase in the intimal and medial thickness and pulmonary artery pressure, suggesting that the ECM is a cause rather than a consequence of distal pulmonary vascular remodeling. ECM remodeling and increased pulmonary arterial stiffness promote proliferation of pulmonary vascular cells (endothelial cells, smooth muscle cells, and adventitial fibroblasts) through mechanoactivation of various signaling pathways, including transcriptional cofactors YAP/TAZ, transforming growth factor-β, transient receptor potential channels, Toll-like receptor, and NF-κB. Inhibition of ECM remodeling and mechanotransduction prevents and reverses experimental pulmonary hypertension. These data support a central role for ECM remodeling in the pathogenesis of the PAH, making it an attractive novel therapeutic target. 10.1152/ajpheart.00136.2018
Calcium-activated K+ channels increase cell proliferation independent of K+ conductance. Millership Joanne E,Devor Daniel C,Hamilton Kirk L,Balut Corina M,Bruce Jason I E,Fearon Ian M American journal of physiology. Cell physiology The intermediate-conductance calcium-activated potassium channel (IK1) promotes cell proliferation of numerous cell types including endothelial cells, T lymphocytes, and several cancer cell lines. The mechanism underlying IK1-mediated cell proliferation was examined in human embryonic kidney 293 (HEK293) cells expressing recombinant human IK1 (hIK1) channels. Inhibition of hIK1 with TRAM-34 reduced cell proliferation, while expression of hIK1 in HEK293 cells increased proliferation. When HEK293 cells were transfected with a mutant (GYG/AAA) hIK1 channel, which neither conducts K(+) ions nor promotes Ca(2+) entry, proliferation was increased relative to mock-transfected cells. Furthermore, when HEK293 cells were transfected with a trafficking mutant (L18A/L25A) hIK1 channel, proliferation was also increased relative to control cells. The lack of functional activity of hIK1 mutants at the cell membrane was confirmed by a combination of whole cell patch-clamp electrophysiology and fura-2 imaging to assess store-operated Ca(2+) entry and cell surface immunoprecipitation assays. Moreover, in cells expressing hIK1, inhibition of ERK1/2 and JNK kinases, but not of p38 MAP kinase, reduced cell proliferation. We conclude that functional K(+) efflux at the plasma membrane and the consequent hyperpolarization and enhanced Ca(2+) entry are not necessary for hIK1-induced HEK293 cell proliferation. Rather, our data suggest that hIK1-induced proliferation occurs by a direct interaction with ERK1/2 and JNK signaling pathways. 10.1152/ajpcell.00274.2010
Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohort. Fiolet Thibault,Srour Bernard,Sellem Laury,Kesse-Guyot Emmanuelle,Allès Benjamin,Méjean Caroline,Deschasaux Mélanie,Fassier Philippine,Latino-Martel Paule,Beslay Marie,Hercberg Serge,Lavalette Céline,Monteiro Carlos A,Julia Chantal,Touvier Mathilde BMJ (Clinical research ed.) OBJECTIVE:To assess the prospective associations between consumption of ultra-processed food and risk of cancer. DESIGN:Population based cohort study. SETTING AND PARTICIPANTS:104 980 participants aged at least 18 years (median age 42.8 years) from the French NutriNet-Santé cohort (2009-17). Dietary intakes were collected using repeated 24 hour dietary records, designed to register participants' usual consumption for 3300 different food items. These were categorised according to their degree of processing by the NOVA classification. MAIN OUTCOME MEASURES:Associations between ultra-processed food intake and risk of overall, breast, prostate, and colorectal cancer assessed by multivariable Cox proportional hazard models adjusted for known risk factors. RESULTS:Ultra-processed food intake was associated with higher overall cancer risk (n=2228 cases; hazard ratio for a 10% increment in the proportion of ultra-processed food in the diet 1.12 (95% confidence interval 1.06 to 1.18); P for trend<0.001) and breast cancer risk (n=739 cases; hazard ratio 1.11 (1.02 to 1.22); P for trend=0.02). These results remained statistically significant after adjustment for several markers of the nutritional quality of the diet (lipid, sodium, and carbohydrate intakes and/or a Western pattern derived by principal component analysis). CONCLUSIONS:In this large prospective study, a 10% increase in the proportion of ultra-processed foods in the diet was associated with a significant increase of greater than 10% in risks of overall and breast cancer. Further studies are needed to better understand the relative effect of the various dimensions of processing (nutritional composition, food additives, contact materials, and neoformed contaminants) in these associations. STUDY REGISTRATION:Clinicaltrials.gov NCT03335644. 10.1136/bmj.k322
2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Lipsky Benjamin A,Berendt Anthony R,Cornia Paul B,Pile James C,Peters Edgar J G,Armstrong David G,Deery H Gunner,Embil John M,Joseph Warren S,Karchmer Adolf W,Pinzur Michael S,Senneville Eric, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Foot infections are a common and serious problem in persons with diabetes. Diabetic foot infections (DFIs) typically begin in a wound, most often a neuropathic ulceration. While all wounds are colonized with microorganisms, the presence of infection is defined by ≥2 classic findings of inflammation or purulence. Infections are then classified into mild (superficial and limited in size and depth), moderate (deeper or more extensive), or severe (accompanied by systemic signs or metabolic perturbations). This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation. Most DFIs are polymicrobial, with aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms. Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds. Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy. For infected wounds, obtain a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture. Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens. Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific. Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy). Most DFIs require some surgical intervention, ranging from minor (debridement) to major (resection, amputation). Wounds must also be properly dressed and off-loaded of pressure, and patients need regular follow-up. An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures. Employing multidisciplinary foot teams improves outcomes. Clinicians and healthcare organizations should attempt to monitor, and thereby improve, their outcomes and processes in caring for DFIs. 10.1093/cid/cis346
Tension pneumothorax--time for a re-think? Leigh-Smith S,Harris T Emergency medicine journal : EMJ This review examines the present understanding of tension pneumothorax and produces recommendations for improving the diagnostic and treatment decision process. 10.1136/emj.2003.010421
Spontaneous and cytokine induced expression and activity of matrix metalloproteinases in human colonic epithelium. Pedersen G,Saermark T,Kirkegaard T,Brynskov J Clinical and experimental immunology Matrix metalloproteinases (MMPs) have been implicated in tissue damage associated with inflammatory bowel disease (IBD).As the role of the intestinal epithelium in this process is unknown, we determined MMP expression and enzyme activity in human colonic epithelial cells (CEC). MMP mRNA expression was assessed by reverse transcription-polymerase chain reaction in HT-29 and DLD-1 cells and in CEC isolated from biopsies from IBD and control patients. Total MMP activity in the cells was measured by a functional assay, based on degradation of a fluorescent synthetic peptide containing the specific bond for MMP cleavage. HT-29 and DLD-1 expressed several MMPs and levels of MMP-3, -10 and -13 mRNA expression were increased significantly by tumour necrosis factor (TNF)-alpha exposure. Transcripts of MMP-1, -3, -7, -9, -10 and -12 were detected in CECs and all, except MMP12, at significantly increased levels in cells from inflamed IBD mucosa. MMP-2 and -8 mRNA were expressed inconsistently and MMP-11, -13 and -14 mRNA undetectable. Proteolytic MMP activity was detected in CEC supernatants and the level was increased significantly in inflamed IBD epithelium. The enzyme activity was inhibited strongly by a specific MMP inhibitor (GM 6001). A significant TNF-alpha-mediated increase in MMP enzyme activity was also detected in HT-29 cells in vitro. In conclusion, the expression of several MMPs as well as the level of functional MMPactivity is increased in CEC from patients with active IBD. The results suggest that MMPs released by the intestinal epithelium may be involved in the pathogenesis of IBD by promoting local mucosal damage. 10.1111/j.1365-2249.2008.03836.x
Continuous subcutaneous insulin infusion versus multiple daily injection regimens in children and young people at diagnosis of type 1 diabetes: pragmatic randomised controlled trial and economic evaluation. Blair Joanne C,McKay Andrew,Ridyard Colin,Thornborough Keith,Bedson Emma,Peak Matthew,Didi Mohammed,Annan Francesca,Gregory John W,Hughes Dyfrig A,Gamble Carrol, BMJ (Clinical research ed.) OBJECTIVE:To compare the efficacy, safety, and cost utility of continuous subcutaneous insulin infusion (CSII) with multiple daily injection (MDI) regimens during the first year following diagnosis of type 1 diabetes in children and young people. DESIGN:Pragmatic, multicentre, open label, parallel group, randomised controlled trial and economic evaluation. SETTING:15 paediatric National Health Service (NHS) diabetes services in England and Wales. The study opened to recruitment in May 2011 and closed in January 2017. PARTICIPANTS:Patients aged between 7 months and 15 years, with a new diagnosis of type 1 diabetes were eligible to participate. Patients who had a sibling with the disease, and those who took drug treatments or had additional diagnoses that could have affected glycaemic control were ineligible. INTERVENTIONS:Participants were randomised, stratified by age and treating centre, to start treatment with CSII or MDI within 14 days of diagnosis. Starting doses of aspart (CSII and MDI) and glargine or detemir (MDI) were calculated according to weight and age, and titrated according to blood glucose measurements and according to local clinical practice. MAIN OUTCOME MEASURES:Primary outcome was glycaemic control (as measured by glycated haemoglobin; HbA1c) at 12 months. Secondary outcomes were percentage of patients in each treatment arm with HbA1c within the national target range, incidence of severe hypoglycaemia and diabetic ketoacidosis, change in height and body mass index (as measured by standard deviation scores), insulin requirements (units/kg/day), partial remission rate (insulin dose adjusted HbA1c <9), paediatric quality of life inventory score, and cost utility based on the incremental cost per quality adjusted life year (QALY) gained from an NHS costing perspective. RESULTS:294 participants were randomised and 293 included in intention to treat analyses (CSI, n=144; MDI, n=149). At 12 months, mean HbA1c was comparable with clinically unimportant differences between CSII and MDI participants (60.9 mmol/mol 58.5 mmol/mol, mean difference 2.4 mmol/mol (95% confidence interval -0.4 to 5.3), P=0.09). Achievement of HbA1c lower than 58 mmol/mol was low among the two groups (66/143 (46%) CSII participants 78/142 (55%) MDI participants; relative risk 0.84 (95% confidence interval 0.67 to 1.06)). Incidence of severe hypoglycaemia and diabetic ketoacidosis were low in both groups. Fifty four non-serious and 14 serious adverse events were reported during CSII treatment, and 17 non-serious and eight serious adverse events during MDI treatment. Parents (but not children) reported superior PedsQL scores for those patients treated with CSII compared to those treated with MDI. CSII was more expensive than MDI by £1863 (€2179; $2474; 95% confidence interval £1620 to £2137) per patient, with no additional QALY gains (difference -0.006 (95% confidence interval -0.031 to 0.018)). CONCLUSION:During the first year following type 1 diabetes diagnosis, no clinical benefit of CSII over MDI was identified in children and young people in the UK setting, and treatment with either regimen was suboptimal in achieving HbA1c thresholds. CSII was not cost effective. TRIAL REGISTRATION:Current Controlled Trials ISRCTN29255275; European Clinical Trials Database 2010-023792-25. 10.1136/bmj.l1226
Epigenetic histone modification of Epstein-Barr virus BZLF1 promoter during latency and reactivation in Raji cells. Murata Takayuki,Kondo Yutaka,Sugimoto Atsuko,Kawashima Daisuke,Saito Shinichi,Isomura Hiroki,Kanda Teru,Tsurumi Tatsuya Journal of virology The Epstein-Barr virus (EBV) predominantly establishes latent infection in B cells, and the reactivation of the virus from latency is dependent on the expression of the viral BZLF1 protein. The BZLF1 promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), calcium ionophores, or histone deacetylase (HDAC) inhibitors. In some cell lines latently infected with EBV, an HDAC inhibitor alone can induce BZLF1 transcription, while the treatment does not enhance expression in other cell lines, such as B95-8 or Raji cells, suggesting unknown suppressive mechanisms besides histone deacetylation in those cells. Here, we found the epigenetic modification of the BZLF1 promoter in latent Raji cells by histone H3 lysine 27 trimethylation (H3K27me3), H3K9me2/me3, and H4K20me3. Levels of active markers such as histone acetylation and H3K4me3 were low in latent cells but increased upon reactivation. Treatment with 3-deazaneplanocin A (DZNep), an inhibitor of H3K27me3 and H4K20me3, significantly enhanced the BZLF1 transcription in Raji cells when in combination with an HDAC inhibitor, trichostatin A (TSA). The knockdown of Ezh2 or Suv420h1, histone methyltransferases for H3K27me3 or H4K20me3, respectively, further proved the suppression of Zp by the methylations. Taken together, the results indicate that H3K27 methylation and H4K20 methylation are involved, at least partly, in the maintenance of latency, and histone acetylation and H3K4 methylation correlate with the reactivation of the virus in Raji cells. 10.1128/JVI.06768-11
Hysterectomy, endometrial ablation, and levonorgestrel releasing intrauterine system (Mirena) for treatment of heavy menstrual bleeding: cost effectiveness analysis. Roberts T E,Tsourapas A,Middleton L J,Champaneria R,Daniels J P,Cooper K G,Bhattacharya S,Barton P M BMJ (Clinical research ed.) OBJECTIVE:To undertake a cost effectiveness analysis comparing first and second generation endometrial ablative techniques, hysterectomy, and the levonorgestrel releasing intrauterine system (Mirena) for treating heavy menstrual bleeding. DESIGN:Model based economic evaluation with data from an individual patient data meta-analysis supplemented with cost and outcome data from published sources taking an NHS (National Health Service) perspective. A state transition (Markov) model was developed, the structure being informed by the reviews of the trials and clinical input. A subgroup analysis, one way sensitivity analysis, and probabilistic sensitivity analysis were also carried out. POPULATION:Four hypothetical cohorts of women with heavy menstrual bleeding. INTERVENTIONS:One of four alternative strategies: Mirena, first or second generation endometrial ablation techniques, or hysterectomy. MAIN OUTCOME MEASURES:Cost effectiveness based on incremental cost per quality adjusted life year (QALY). RESULTS:Hysterectomy is the preferred strategy for the first intervention for heavy menstrual bleeding. Although hysterectomy is more expensive, it produces more QALYs relative to other remaining strategies and is likely to be considered cost effective. The incremental cost effectiveness ratio for hysterectomy compared with Mirena is £1440 (€1633, $2350) per additional QALY. The incremental cost effectiveness ratio for hysterectomy compared with second generation ablation is £970 per additional QALY. CONCLUSION:In light of the acceptable thresholds used by the National Institute for Health and Clinical Excellence, hysterectomy would be considered the preferred strategy for the treatment of heavy menstrual bleeding. The results concur with those of other studies but are highly sensitive to utility values used in the analysis. 10.1136/bmj.d2202
Negative Nasopharyngeal and Oropharyngeal Swabs Do Not Rule Out COVID-19. Winichakoon Poramed,Chaiwarith Romanee,Liwsrisakun Chalerm,Salee Parichat,Goonna Aree,Limsukon Atikun,Kaewpoowat Quanhathai Journal of clinical microbiology 10.1128/JCM.00297-20
Predicted lean body mass, fat mass, and all cause and cause specific mortality in men: prospective US cohort study. Lee Dong Hoon,Keum NaNa,Hu Frank B,Orav E John,Rimm Eric B,Willett Walter C,Giovannucci Edward L BMJ (Clinical research ed.) OBJECTIVE:To investigate the association of predicted lean body mass, fat mass, and body mass index (BMI) with all cause and cause specific mortality in men. DESIGN:Prospective cohort study. SETTING:Health professionals in the United States PARTICIPANTS: 38 006 men (aged 40-75 years) from the Health Professionals Follow-up Study, followed up for death (1987-2012). MAIN OUTCOME MEASURES:All cause and cause specific mortality. RESULTS:Using validated anthropometric prediction equations previously developed from the National Health and Nutrition Examination Survey, lean body mass and fat mass were estimated for all participants. During a mean of 21.4 years of follow-up, 12 356 deaths were identified. A J shaped association was consistently observed between BMI and all cause mortality. Multivariable adjusted Cox models including predicted fat mass and lean body mass showed a strong positive monotonic association between predicted fat mass and all cause mortality. Compared with those in the lowest fifth of predicted fat mass, men in the highest fifth had a hazard ratio of 1.35 (95% confidence interval 1.26 to 1.46) for mortality from all causes. In contrast, a U shaped association was found between predicted lean body mass and all cause mortality. Compared with those in the lowest fifth of predicted lean body mass, men in the second to fourth fifths had 8-10% lower risk of mortality from all causes. In the restricted cubic spline models, the risk of all cause mortality was relatively flat until 21 kg of predicted fat mass and increased rapidly afterwards, with a hazard ratio of 1.22 (1.18 to 1.26) per standard deviation. For predicted lean body mass, a large reduction of the risk was seen within the lower range until 56 kg, with a hazard ratio of 0.87 (0.82 to 0.92) per standard deviation, which increased thereafter (P for non-linearity <0.001). For cause specific mortality, men in the highest fifth of predicted fat mass had hazard ratios of 1.67 (1.47 to 1.89) for cardiovascular disease, 1.24 (1.09 to 1.43) for cancer, and 1.26 (0.97 to 1.64) for respiratory disease. On the other hand, a U shaped association was found between predicted lean body mass and mortality from cardiovascular disease and cancer. However, a strong inverse association existed between predicted lean body mass and mortality from respiratory disease (P for trend <0.001). CONCLUSIONS:The shape of the association between BMI and mortality was determined by the relation between two body components (lean body mass and fat mass) and mortality. This finding suggests that the "obesity paradox" controversy may be largely explained by low lean body mass, rather than low fat mass, in the lower range of BMI. 10.1136/bmj.k2575
Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases. Journal of inflammation research Microglia are tissue-resident macrophages of the central nervous system (CNS). In the CNS, microglia play an important role in the monitoring and intervention of synaptic and neuron-level activities. Interventions targeting microglia have been shown to improve the prognosis of various neurological diseases. Recently, studies have observed the activation of microglia in different cardiovascular diseases. In addition, different approaches that regulate the activity of microglia have been shown to modulate the incidence and progression of cardiovascular diseases. The change in autonomic nervous system activity after neuroinflammation may be a potential intermediate link between microglia and cardiovascular diseases. Here, in this review, we will discuss recent updates on the regulatory role of microglia in hypertension, myocardial infarction and ischemia/reperfusion injury. We propose that microglia serve as neuroimmune modulators and potential targets for cardiovascular diseases. 10.2147/JIR.S350109
A adenosine receptors control pancreatic dysfunction in high-fat-diet-induced obesity. Csóka Balázs,Törő Gábor,Vindeirinho Joana,Varga Zoltán V,Koscsó Balázs,Németh Zoltán H,Kókai Endre,Antonioli Luca,Suleiman Mara,Marchetti Piero,Cseri Karolina,Deák Ádám,Virág László,Pacher Pál,Bai Péter,Haskó György FASEB journal : official publication of the Federation of American Societies for Experimental Biology Adenosine, a key extracellular signaling mediator, regulates several aspects of metabolism by activating 4 G-protein-coupled receptors, the A, A, A, and A adenosine receptors (ARs). The role of AARs in regulating high-fat-diet (HFD)-induced metabolic derangements is unknown. To evaluate the role of AARs in regulating glucose and insulin homeostasis in obesity, we fed AAR-knockout (KO) and control mice an HFD for 16 wk to initiate HFD-induced metabolic disorder. We found that genetic deletion of AARs caused impaired glucose tolerance in mice fed an HFD. This impaired glucose tolerance was caused by a decrease in insulin secretion but not in insulin sensitivity. Islet size and insulin content in pancreata of AAR-deficient mice were decreased compared with control mice after consuming an HFD. AAR-KO mice had decreased expression of the β-cell-specific markers pdx1, glut2, mafA, and nkx6.1 and increased expression of the dedifferentiation markers sox2 and hes1. islet experiments confirmed the role of AARs in protecting against decreased insulin content and release caused by HFD. Other experiments with bone marrow chimeras revealed that inflammation was not the primary cause of decreased insulin secretion in AAR-KO mice. Altogether, our data showed that AARs control pancreatic dysfunction in HFD-induced obesity.-Csóka, B., Törő, G., Vindeirinho, J., Varga, Z. V., Koscsó, B., Németh, Z. H., Kókai, E., Antonioli, L., Suleiman, M., Marchetti, P., Cseri, K., Deák, Á., Virág, L., Pacher, P., Bai, P., Haskó, G. A adenosine receptors control pancreatic dysfunction in high-fat-diet-induced obesity. 10.1096/fj.201700398R
Microglia in neurodegeneration. Hickman Suzanne,Izzy Saef,Sen Pritha,Morsett Liza,El Khoury Joseph Nature neuroscience The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection. Microglia use a defined armamentarium of genes to perform these tasks. In response to specific stimuli, or with neuroinflammation, microglia also have the capacity to damage and kill neurons. Injury to neurons in Alzheimer's, Parkinson's, Huntington's, and prion diseases, as well as in amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy, results from disruption of the sentinel or housekeeping functions and dysregulation of the defense function and neuroinflammation. Pathways associated with such injury include several sensing and housekeeping pathways, such as the Trem2, Cx3cr1 and progranulin pathways, which act as immune checkpoints to keep the microglial inflammatory response under control, and the scavenger receptor pathways, which promote clearance of injurious stimuli. Peripheral interference from systemic inflammation or the gut microbiome can also alter progression of such injury. Initiation or exacerbation of neurodegeneration results from an imbalance between these microglial functions; correcting such imbalance may be a potential mode for therapy. 10.1038/s41593-018-0242-x
Acute skeletal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repair. Lu Haiyan,Huang Danping,Ransohoff Richard M,Zhou Lan FASEB journal : official publication of the Federation of American Societies for Experimental Biology CC chemokine ligand 2 (CCL2), a ligand of CC chemokine receptor 2 (CCR2), is essential to mount an adequate inflammatory response to repair acute skeletal muscle injury. We studied the mechanisms by which CCL2 regulates muscle inflammation and regeneration. Mobilization of monocytes/macrophages (MOs/MPs) but not lymphocytes or neutrophils was impaired from bone marrow to blood and from blood to injured muscles in Ccl2(-/-) mice. This was accompanied by poor phagocytosis, reduced up-regulation of insulin-like growth factor-1 (IGF-1), and impaired muscle regeneration. Bone marrow transfer from wild-type mice to irradiated Ccr2(-/-) but not Ccl2(-/-) mice restored muscle inflammation. Intravenously injected CCL2-deficient bone marrow monocytes could not enter wild-type injured muscles as well as wild-type bone marrow monocytes. Intravenously injected wild-type bone marrow monocytes could not enter CCL2-deficient injured muscles as well as wild-type injured muscles. CCL2 stimulated IGF-1 expression by wild-type but not CCR2-deficient intramuscular macrophages. A single intramuscular injection of IGF-1, but not PBS, markedly improved muscle regeneration in Ccl2(-/-) mice. We conclude that CCL2 is a major ligand of CCR2 to recruit MOs/MPs into injured muscles to conduct phagocytosis and produce IGF-1 for injury repair. CCL2 needs to be expressed by bone marrow cells, circulating monocytes, and injured muscle tissue cells to recruit MOs/MPs into injured muscles. CCL2/CCR2 signaling also up-regulates IGF-1 expression by intramuscular macrophages to promote acute skeletal muscle injury repair. 10.1096/fj.10-178939
Chronic inflammation in the etiology of disease across the life span. Nature medicine Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI. 10.1038/s41591-019-0675-0
Inorganic nanohybrids combat antibiotic-resistant bacteria hiding within human macrophages. Nanoscale Bacterial infections are one of the main health concerns humanity faces today and bacterial resistances and protection mechanisms are set to aggravate the issue in the coming years. An increasing number of bacterial strains evades antibiotic treatment by hiding inside cells. Conventional antimicrobial agents are unable to penetrate or be retained in the infected mammalian cells. Recent approaches to overcome these limitations have focused on load-carrier systems, requiring a triggered discharge leading to complex release kinetics. The unison of potent antimicrobial activity with high mammalian cell compatibility is a prerequisite for intracellular activity, which is not well-met by otherwise well-established inorganic systems, such as silver-based nanoparticles. In this work, load and carrier are combined into one functional inorganic nanoparticle system, which unites antimicrobial activity with mammalian cell compatibility. These multicomponent nanohybrids based on cerium oxide are produced in one step, yet unite complex materials. The nanoparticles form suprastructures of similar size and surface charge as bacteria, therefore facilitating the uptake into the same subcellular compartments, where they unleash their antibacterial effect. Such intrinsically antibacterial nanohybrids significantly reduce bacterial survival inside macrophages without harming the latter. Furthermore, blocking of nanoparticle endocytosis and subcellular electron microscopy elucidate the mechanism of action. Taken together, this work presents the first demonstration of antibacterial activity of ceria-based nanoparticles inside of mammalian cells and offers a route to straightforward and robust intracellular antibacterial agents that do not depend on payload delivery or biological constituents. 10.1039/d0nr08285f
c-Rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells. Neo Wen Hao,Lim Jun Feng,Grumont Raelene,Gerondakis Steve,Su I-Hsin The Journal of biological chemistry The polycomb group protein Ezh2 is a histone methyltransferase that modifies chromatin structure to alter gene expression during embryonic development, lymphocyte activation, and tumorigenesis. The mechanism by which Ezh2 expression is regulated is not well defined. In the current study, we report that c-Rel is a critical activator of Ezh2 transcription in lymphoid cells. In activated primary murine B and T cells, plus human leukemia and multiple myeloma cell lines, recruitment of c-Rel to the first intron of the Ezh2 locus promoted Ezh2 mRNA expression. This up-regulation was abolished in activated c-Rel-deficient lymphocytes and by c-Rel knockdown in Jurkat T cells. Treatment of malignant cells with the c-Rel inhibitor pentoxifylline not only reduced c-Rel nuclear translocation and Ezh2 expression, but also enhanced their sensitivity to the Ezh2-specific drug, GSK126 through increased growth inhibition and cell death. In summary, our demonstration that c-Rel regulates Ezh2 expression in lymphocytes and malignant lymphoid cells reveals a novel transcriptional network in transformed lymphoid cells expressing high levels of Ezh2 that provides a molecular justification for combinatorial drug therapy. 10.1074/jbc.M114.574517
Role of FEN1 S187 phosphorylation in counteracting oxygen-induced stress and regulating postnatal heart development. Zhou Lina,Dai Huifang,Wu Jian,Zhou Mian,Yuan Hua,Du Juan,Yang Lu,Wu Xiwei,Xu Hong,Hua Yuejin,Xu Jian,Zheng Li,Shen Binghui FASEB journal : official publication of the Federation of American Societies for Experimental Biology Flap endonuclease 1 (FEN1) phosphorylation is proposed to regulate the action of FEN1 in DNA repair as well as Okazaki fragment maturation. However, the biologic significance of FEN1 phosphorylation in response to DNA damage remains unknown. Here, we report an in vivo role for FEN1 phosphorylation, using a mouse line carrying S187A FEN1, which abolishes FEN1 phosphorylation. Although S187A mouse embryonic fibroblast cells showed normal proliferation under low oxygen levels (2%), the mutant cells accumulated oxidative DNA damage, activated DNA damage checkpoints, and showed G-phase arrest at atmospheric oxygen levels (21%). This suggests an essential role for FEN1 phosphorylation in repairing oxygen-induced DNA damage and maintaining proper cell cycle progression. Consistently, the mutant cardiomyocytes showed G-phase arrest due to activation of the p53-mediated DNA damage response at the neonatal stage, which reduces the proliferation potential of the cardiomyocytes and impairs heart development. Nearly 50% of newborns with the S187A mutant died in the first week due to failure to undergo the peroxisome proliferator-activated receptor signaling-dependent switch from glycolysis to fatty acid oxidation. The adult mutant mice developed dilated hearts and showed significantly shorter life spans. Altogether, our results reveal an important role of FEN1 phosphorylation to counteract oxygen-induced stress in the heart during the fetal-to-neonatal transition.-Zhou, L., Dai, H., Wu, J., Zhou, M., Yuan, H., Du, J., Yang, L., Wu, X., Xu, H., Hua, Y., Xu, J., Zheng, L., Shen, B. Role of FEN1 S187 phosphorylation in counteracting oxygen-induced stress and regulating postnatal heart development. 10.1096/fj.201600631R
LPA receptor-mediated thromboxane A release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction. Dancs Péter Tibor,Ruisanchez Éva,Balogh Andrea,Panta Cecília Rita,Miklós Zsuzsanna,Nüsing Rolf M,Aoki Junken,Chun Jerold,Offermanns Stefan,Tigyi Gábor,Benyó Zoltán FASEB journal : official publication of the Federation of American Societies for Experimental Biology Lysophosphatidic acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSMCs), thereby contributing to vasoregulation and remodeling. In the present study, mRNA expression of all 6 LPA receptor genes was detected in murine aortic VSMCs, with the highest levels of LPA, LPA, LPA, and LPA In endothelium-denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1-oleoyl-LPA and the LPA agonist VPC31143 induced dose-dependent vasoconstriction. VPC31143-induced AA contraction was sensitive to pertussis toxin (PTX), the LPA antagonist Ki16425, and genetic deletion of LPA but not that of LPA or inhibition of LPA, by diacylglycerol pyrophosphate. Surprisingly, vasoconstriction was also diminished in vessels lacking cyclooxygenase-1 [COX1 knockout (KO)] or the thromboxane prostanoid (TP) receptor (TP KO). VPC31143 increased thromboxane A (TXA) release from TA of wild-type, TP-KO, and LPA-KO mice but not from LPA-KO or COX1-KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA-, G-, and COX1-dependent autocrine/paracrine TXA release and consequent TP activation. We propose that this new-found interaction between the LPA/LPA and TXA/TP pathways plays significant roles in vasoregulation, hemostasis, thrombosis, and vascular remodeling.-Dancs, P. T., Ruisanchez, E., Balogh, A., Panta, C. R., Miklós, Z., Nüsing, R. M., Aoki, J., Chun, J., Offermanns, S., Tigyi, G., Benyó, Z. LPA receptor-mediated thromboxane A release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction. 10.1096/fj.201600735R
Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors. Oncoimmunology We carried out a retrospective cohort study on patients with advanced cancer treated with immune checkpoint inhibitors (ICIs) to determine whether antibiotics affect treatment outcome. Sixty consecutive patients were identified, and 17 received systemic antibiotics within 2 weeks before and/or after first dose of ICI. Antibiotic-treated patients were significantly younger ( = 0.0008) and less likely to receive nivolumab ( = 0.08) or had neutrophil:lymphocyte ratio < 5 ( = 0.08). They had a lower response rate (RR) (29.4% 62.8%) ( = 0.024) and more inferior progression-free survival (PFS) ( = 0.048). Narrow-spectrum antibiotics did not affect the RR. However, broad-spectrum antibiotics were associated with a lower RR (25% 61%) ( = 0.02) and a trend towards longer time to response (median: 14 weeks 12 weeks) ( = 0.1). They also had shorter PFS ( = 0.012). Multivariate analysis identified antibiotics as the only factor affecting RR ( = 0.0038) and PFS ( = 0.01). We next examined the 21 patients whose PFS lasted for 12 weeks or more. Five of the 21 patients received broad-spectrum antibiotics within 10 weeks before disease progression. There was a trend towards shorter PFS in these patients ( = 0.1). Finally, antibiotic-treated patients experienced shorter overall survival (OS) (median: 24 months 89 months) ( = 0.003). Multivariate analysis found age ( = 0.035) and antibiotics ( = 0.038) to be the only factors affecting OS. Our results point to a detrimental effect of broad-spectrum antibiotics on treatment outcome to ICI therapy. 10.1080/2162402X.2018.1507670
Opposing roles of RAGE and Myd88 signaling in extensive liver resection. Zeng Shan,Zhang Qing Yin,Huang Jianzhong,Vedantham Srinivasan,Rosario Rosa,Ananthakrishnan Radha,Yan Shi Fang,Ramasamy Ravichandran,DeMatteo Ronald P,Emond Jean C,Friedman Richard A,Schmidt Ann Marie FASEB journal : official publication of the Federation of American Societies for Experimental Biology In extensive liver resection secondary to primary or metastatic liver tumors, or in living donor liver transplantation, strategies to quell deleterious inflammatory responses and facilitate regeneration are essential. The receptor for advanced glycation endproducts (RAGE) and myeloid differentiating factor 88 (Myd88) are implicated in the inflammatory response. To establish the contributions of RAGE vs. Myd88 signaling in extensive liver resection, we probed the effect of RAGE and/or Myd88, the latter primarily a key transducer of major toll-like receptors and also implicated in interleukin-1 (Il1) signaling, in a murine model of extensive (85%) hepatectomy. We report that, although Myd88 is thoroughly essential for survival via regulation of NF-κB and TNF-α, deletion of RAGE significantly improved survival compared to wild-type, Myd88-null, or RAGE-null/Myd88-null mice. RAGE opposes Myd88 signaling at multiple levels: by suppression of p65 levels, thereby reducing activation of NF-κB and consequent production of cyclin D1, and by suppression of Il6-mediated phosphorylation of Stat3, thereby down-regulating Pim1 and suppressing the hyperplastic response. Further, RAGE-dependent suppression of glyoxalase1, a detoxification pathway for pre-AGEs, enhances AGE levels and suppresses Il6 action. We conclude that blockade of RAGE may rescue liver remnants from the multiple signals that preclude adaptive proliferation triggered primarily by Myd88 signaling pathways. 10.1096/fj.11-192997
Change Management in Health Care. Campbell Robert James The health care manager This article introduces health care managers to the theories and philosophies of John Kotter and William Bridges, 2 leaders in the evolving field of change management. For Kotter, change has both an emotional and situational component, and methods for managing each are expressed in his 8-step model (developing urgency, building a guiding team, creating a vision, communicating for buy-in, enabling action, creating short-term wins, don't let up, and making it stick). Bridges deals with change at a more granular, individual level, suggesting that change within a health care organization means that individuals must transition from one identity to a new identity when they are involved in a process of change. According to Bridges, transitions occur in 3 steps: endings, the neutral zone, and beginnings. The major steps and important concepts within the models of each are addressed, and examples are provided to demonstrate how health care managers can actualize the models within their health care organizations. 10.1097/HCM.0000000000000290
Mendelian randomization: potential use of genetics to enable causal inferences regarding HIV-associated biomarkers and outcomes. He Weijing,Castiblanco John,Walter Elizabeth A,Okulicz Jason F,Ahuja Sunil K Current opinion in HIV and AIDS PURPOSE OF REVIEW:It is unknown whether biomarkers simply correlate with or are causal for HIV-associated outcomes. Mendelian randomization is a genetic epidemiologic approach used to disentangle causation from association. Here, we discuss the potential use of Mendelian randomization for differentiating whether biomarkers are correlating with or causal for HIV-associated outcomes. RECENT FINDINGS:Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. In observational epidemiology, this refers to the use of genetic variants to estimate a causal effect between a modifiable risk factor and an outcome of interest. A formal Mendelian randomization study using a genetic marker as a proxy for the biomarker has not been conducted in the HIV field. However, in the postgenomic era, this approach is being used increasingly. Examples are evidence for the causal role of BMI in blood pressure and noncausal role of C-reactive protein in coronary heart disease. We discuss the conceptual framework, uses, and limitations of Mendelian randomization in the context of HIV infection as well as specific biomarkers (IL-6, C-reactive protein) and genetic determinants (e.g., in CCR5, chemokine, and DARC genes) that associate with HIV-related outcomes. SUMMARY:Making the distinction between correlation and causality has particular relevance when a biomarker (e.g., IL-6) is potentially modifiable, in which case a biomarker-guided targeted treatment strategy may be feasible. Although the tenets of Mendelian randomization rest on strong assumptions, and conducting a Mendelian randomization study in HIV infection presents many challenges, it may offer the potential to identify causal biomarkers for HIV-associated outcomes. 10.1097/COH.0b013e32833f2087
Biomechanical Screening of Cell Therapies for Vocal Fold Scar. Bartlett Rebecca S,Gaston Joel D,Yen Tom Y,Ye Shuyun,Kendziorski Christina,Thibeault Susan L Tissue engineering. Part A Candidate cell sources for vocal fold scar treatment include mesenchymal stromal cells from bone marrow (BM-MSC) and adipose tissue (AT-MSC). Mechanosensitivity of MSC can alter highly relevant aspects of their behavior, yet virtually nothing is known about how MSC might respond to the dynamic mechanical environment of the larynx. Our objective was to evaluate MSC as a potential cell source for vocal fold tissue engineering in a mechanically relevant context. A vibratory strain bioreactor and cDNA microarray were used to evaluate the similarity of AT-MSC and BM-MSC to the native cell source, vocal fold fibroblasts (VFF). Posterior probabilities for each of the microarray transcripts fitting into specific expression patterns were calculated, and the data were analyzed for Gene Ontology (GO) enrichment. Significant wound healing and cell differentiation GO terms are reported. In addition, proliferation and apoptosis were evaluated with immunohistochemistry. Results revealed that VFF shared more GO terms related to epithelial development, extracellular matrix (ECM) remodeling, growth factor activity, and immune response with BM-MSC than with AT-MSC. Similarity in glycosaminoglycan and proteoglycan activity dominated the ECM analysis. Analysis of GO terms relating to MSC differentiation toward osteogenic, adipogenic, and chondrogenic lineages revealed that BM-MSC expressed fewer osteogenesis GO terms in the vibrated and scaffold-only conditions compared to polystyrene. We did not evaluate if vibrated BM-MSC recover osteogenic expression markers when returned to polystyrene culture. Immunostaining for Ki67 and cleaved caspase 3 did not vary with cell type or mechanical condition. We conclude that VFF may have a more similar wound healing capacity to BM-MSC than to AT-MSC in response to short-term vibratory strain. Furthermore, BM-MSC appear to lose osteogenic potential in the vibrated and scaffold-only conditions compared to polystyrene, potentially attenuating the risk of osteogenesis for in vivo applications. 10.1089/ten.TEA.2015.0168
Kawasaki disease: etiopathogenesis and novel treatment strategies. Agarwal Shreya,Agrawal Devendra K Expert review of clinical immunology INTRODUCTION:Kawasaki disease is an acute febrile systemic vasculitis that predominantly occurs in children below five years of age. Its etiopathogenesis is still not clear, but it is thought to be a complex interplay of genetic factors, infections and immunity. Areas covered: This review article discusses in detail Kawasaki disease, with particular emphasis on the recent updates on its pathogenesis and upcoming alternate treatment options. Though self-limiting in many cases, it can lead to severe complications like coronary artery aneurysms and thrombo-embolic occlusions, and hence requires early diagnosis and urgent attention to avoid them. Intravenous immunoglobulin (IVIG) with or without aspirin has remained the sole treatment option for these cases, but 10-15% cases develop resistance to this treatment. Expert commentary: There is a need to develop additional treatment strategies for children with Kawasaki disease. Targeting different steps of pathogenesis could provide us with alternate therapeutic options. 10.1080/1744666X.2017.1232165
Food Insecurity and Health Care Expenditures in the United States, 2011-2013. Health services research OBJECTIVE:To determine whether food insecurity, limited or uncertain food access owing to cost, is associated with greater health care expenditures. DATA SOURCE/STUDY SETTING:Nationally representative sample of the civilian noninstitutionalized population of the United States (2011 National Health Interview Survey [NHIS] linked to 2012-2013 Medication Expenditure Panel Survey [MEPS]). STUDY DESIGN:Longitudinal retrospective cohort. DATA COLLECTION/EXTRACTION METHODS:A total of 16,663 individuals underwent assessment of food insecurity, using the 10-item adult 30-day food security module, in the 2011 NHIS. Their total health care expenditures in 2012 and 2013 were recorded in MEPS. Expenditure data were analyzed using zero-inflated negative binomial regression and adjusted for age, gender, race/ethnicity, education, income, insurance, and residence area. PRINCIPAL FINDINGS:Fourteen percent of individuals reported food insecurity, representing 41,616,255 Americans. Mean annualized total expenditures were $4,113 (standard error $115); 9.2 percent of all individuals had no health care expenditures. In multivariable analyses, those with food insecurity had significantly greater estimated mean annualized health care expenditures ($6,072 vs. $4,208, p < .0001), an extra $1,863 in health care expenditure per year, or $77.5 billion in additional health care expenditure annually. CONCLUSIONS:Food insecurity was associated with greater subsequent health care expenditures. Future studies should determine whether food insecurity interventions can improve health and reduce health care costs. 10.1111/1475-6773.12730
Hypoglycemia at admission is associated with inhospital mortality in Ugandan patients with severe sepsis. Critical care medicine OBJECTIVE:Dysglycemia during sepsis is associated with poor outcomes in resource-rich settings. In resource-limited settings, hypoglycemia is often diagnosed clinically without the benefit of laboratory support. We studied the utility of point-of-care glucose monitoring to predict mortality in severely septic patients in Uganda. DESIGN:Prospective observational study. SETTING:One national and two regional referral hospitals in Uganda. PATIENTS:We enrolled 532 patients with sepsis at three hospitals in Uganda. The analysis included 418 patients from the three sites with inhospital mortality data, a documented admission blood glucose concentration, and evidence of organ dysfunction at admission (systolic blood pressure≤100 mm Hg, lactate>4 mmol/L, platelet number<100,000/μL, or altered mental status). INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We evaluated the association between admission point-of-care blood glucose concentration and inhospital mortality. We also assessed the accuracy of altered mental status as a predictor of hypoglycemia. Euglycemia occurred in 33.5% (140 of 418) of patients, whereas 16.3% (68 of 418) of patients were hypoglycemic and 50.2% (210 of 418) were hyperglycemic. Univariate Cox regression analyses comparing in-hospital mortality among hypoglycemic (35.3% [24 of 68], hazard ratio 2.0, 95% confidence interval 1.2-3.6, p=.013) and hyperglycemic (29.5% [62 of 210], hazard ratio 1.5, 95% confidence interval 0.96-2.4, p=.08) patients to euglycemic (19.3% [27 of 140]) patients showed statistically significantly higher rates of inhospital mortality for patients with hypoglycemia. Hypoglycemia (adjusted hazard ratio 1.9, 95% confidence interval 1.1-3.3, p=.03) remained significantly and independently associated with inhospital mortality in the multivariate model. The sensitivity and specificity of altered mental status for hypoglycemia were 25% and 86%, respectively. CONCLUSION:Hypoglycemia is an independent risk factor for inhospital mortality in patients with severe sepsis and cannot be adequately assessed by clinical examination. Correction of hypoglycemia may improve outcomes of critically ill patients in resource-limited settings. 10.1097/CCM.0b013e3182227bd2
Stem cell-based meniscus tissue engineering. Mandal Biman B,Park Sang-Hyug,Gil Eun Seok,Kaplan David L Tissue engineering. Part A Knee meniscus, a fibrocartilaginous tissue, is characterized by heterogeneity in extracellular matrix (ECM) and biomechanical properties, and critical for orthopedic stability, load transmission, shock absorption, and stress distribution within the knee joint. Most damage to the meniscus cannot be effectively healed by the body due to its partial avascular nature; thus, damage caused by injury or age impairs normal knee function, predisposing patients to osteoarthritis. Meniscus tissue engineering offers a possible solution to this problem by generating replacement tissue that may be implanted into the defect site to mimic the function of natural meniscal tissue. To address this need, a multiporous, multilamellar meniscus was formed using silk protein scaffolds and stem cells. The silk scaffolds were seeded with human bone marrow stem cells and differentiated over time in chondrogenic culture in the presence of transforming growth factor-beta 3 to generate meniscus-like tissue in vitro. High cellularity along with abundant ECM leading to enhanced biomechanics similar to native tissue was found. Higher levels of collagen type I and II, sulfated glycosaminoglycans along with enhanced collagen 1-α1, aggrecan, and SOX9 gene expression further confirmed differentiation and matured cell phenotype. The results of this study are a step forward toward biomechanically competent meniscus engineering, reconstituting both form and function of the native meniscus. 10.1089/ten.TEA.2011.0031
Patient satisfaction and quality of surgical care in US hospitals. Tsai Thomas C,Orav E John,Jha Ashish K Annals of surgery OBJECTIVE:The relationship between patient satisfaction and surgical quality is unclear for US hospitals. Using national data, we examined if hospitals with high patient satisfaction have lower levels of performance on accepted measures of the quality and efficiency of surgical care. BACKGROUND:Federal policymakers have made patient satisfaction a core measure for the way hospitals are evaluated and paid through the value-based purchasing program. There is broad concern that performance on patient satisfaction may have little or even a negative correlation with the quality of surgical care, leading to potential trade-offs in efforts to improve patient experience with other surgical quality measures. METHODS:We used the Hospital Consumer Assessment of Healthcare Providers and Systems survey data from 2010 and 2011 to assess performance on patient experience. We used national Medicare data on 6 common surgical procedures to calculate measures of surgical efficiency and quality: risk-adjusted length of stay, process score, risk-adjusted mortality rate, risk-adjusted readmission rate, and a composite z score across all 4 metrics. Multivariate models adjusting for hospital characteristics were used to assess the independent relationships between patient satisfaction and measures of surgical efficiency and quality. RESULTS:Of the 2953 US hospitals that perform one of these 6 procedures, the median patient satisfaction score was 69.5% (interquartile range, 63%-75.5%). Length of stay was shorter in hospitals with the highest levels of patient satisfaction (7.1 days vs 7.7 days, P < 0.001). Adjusting for procedural volume and structural characteristics, institutions in the highest quartile of patient satisfaction had the higher process of care performance (96.5 vs 95.5, P < 0.001), lower readmission rates (12.3% vs 13.6%, P < 0.001), and lower mortality (3.1% vs 3.6%) than those in the lowest quartile. Hospitals with high patient satisfaction also had a higher composite score for quality across all measures (P < 0.001). CONCLUSIONS:Among US hospitals that perform major surgical procedures, hospitals with high patient satisfaction provided more efficient care and were associated with higher surgical quality. Our findings suggest there need not be a trade-off between good quality of care for surgical patients and ensuring a positive patient experience. 10.1097/SLA.0000000000000765
Plasma Aβ analysis using magnetically-labeled immunoassays and PET F-florbetapir binding in non-demented patients with major depressive disorder. Wu Kuan-Yi,Hsiao Ing-Tsung,Chen Chia-Hsiang,Liu Chia-Yih,Hsu Jung-Lung,Huang Sheng-Yao,Yen Tzu-Chen,Lin Kun-Ju Scientific reports An increased level of brain amyloid deposition and a decreased level of cerebral spinal fluid (CSF) Aβ42 are currently considered reliable biomarkers of Alzheimer's disease (AD); however, the usefulness of plasma Aβ levels are not well-established. This study investigated the relationships between plasma Aβ levels and cerebral amyloidosis in 36 non-demented patients with major depressive disorder (MDD). All participants underwent F-florbetapir PET imaging and provided a blood sample at the same time for immunomagnetic reduction assay to measure the plasma levels of Aβ40 and Aβ42. We found inverse associations of the plasma Aβ42 level and the Aβ42/Aβ40 ratio, and a positive association of the plasma Aβ40 level, with cerebral amyloid deposition in the precuneus, parietal and posterior cingulate cortex. Subgroup analyses in subjects with higher F-florbetapir uptake values or MDD with amnestic mild cognitive impairment revealed more pervasive relationships of plasma Aβ measures with F-florbetapir binding across the brain regions examined. The study suggested that regional brain amyloid deposition in terms of F-florbetapir PET uptake had weak-to-moderate associations with plasma Aβ42 and Aβ40 levels, and the Aβ42/Aβ40 ratio. Validation in a larger population of subjects of known cerebral amyloidosis status is needed. Careful interpretation of plasma data is warranted. 10.1038/s41598-018-21140-3
Global burden of 87 risk factors in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet (London, England) BACKGROUND:Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. METHODS:GBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk-outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk-outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk-outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each age-sex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. FINDINGS:The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95% uncertainty interval [UI] 9·51-12·1) deaths (19·2% [16·9-21·3] of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12-9·31) deaths (15·4% [14·6-16·2] of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253-350) DALYs (11·6% [10·3-13·1] of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0-9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10-24 years, alcohol use for those aged 25-49 years, and high systolic blood pressure for those aged 50-74 years and 75 years and older. INTERPRETATION:Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. FUNDING:Bill & Melinda Gates Foundation. 10.1016/S0140-6736(20)30752-2
Tissue-Specific Near-Infrared Fluorescence Imaging. Owens Eric A,Henary Maged,El Fakhri Georges,Choi Hak Soo Accounts of chemical research Near-infrared (NIR) fluorescence light has been widely utilized in clinical imaging by providing surgeons highly specific images of target tissue. The "NIR window" from 650 to 900 nm is especially useful due to several special features such as minimal autofluorescence and absorption of biomolecules in tissue, as well as low light scattering. Compared with visible wavelengths, NIR fluorescence light is invisible, thus allowing highly sensitivity real-time image guidance in human surgery without changing the surgical field. The benefit of using NIR fluorescence light as a clinical imaging technology can be attributed to its molecular fluorescence as an exogenous contrast agent. Indeed, whole body preoperative imaging of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) remains important in diagnostic utility, but they lack the efficacy of innocuous and targeted NIR fluorophores to simultaneously facilitate the real-time delineation of diseased tissue while preserving vital tissues. Admittedly, NIR imaging technology has been slow to enter clinical use mostly due to the late-coming development of truly breakthrough contrast agents for use with current imaging systems. Therefore, clearly defining the physical margins of tumorous tissue remains of paramount importance in bioimaging and targeted therapy. An equally noteworthy yet less researched goal is the ability to outline healthy vital tissues that should be carefully navigated without transection during the intraoperative surgery. Both of these paths require optimizing a gauntlet of design considerations to obtain not only an effective imaging agent in the NIR window but also high molecular brightness, water solubility, biocompatibility, and tissue-specific targetability. The imaging community recognizes three strategic approaches which include (1) passive targeting via the EPR effect, (2) active targeting using the innate overall biodistribution of known molecules, and (3) activatable targeting through an internal stimulus, which turns on fluorescence from an off state. Recent advances in nanomedicine and bioimaging offer much needed promise toward fulfilling these stringent requirements as we develop a successful catalog of targeted contrast agents for illuminating both tumors and vital tissues in the same surgical space by employing spectrally distinct fluorophores in real time. These tissue-specific contrast agents can be versatile arsenals to physicians for real-time intraoperative navigation as well as image-guided targeted therapy. There is a versatile library of tissue-specific fluorophores available in the literature, with many discussed herein, which offers clinicians an array of possibilities that will undoubtedly improve intraoperative success and long-term postoperation prognosis. 10.1021/acs.accounts.6b00239
High-fat diet alters gut microbiota physiology in mice. Daniel Hannelore,Gholami Amin Moghaddas,Berry David,Desmarchelier Charles,Hahne Hannes,Loh Gunnar,Mondot Stanislas,Lepage Patricia,Rothballer Michael,Walker Alesia,Böhm Christoph,Wenning Mareike,Wagner Michael,Blaut Michael,Schmitt-Kopplin Philippe,Kuster Bernhard,Haller Dirk,Clavel Thomas The ISME journal The intestinal microbiota is known to regulate host energy homeostasis and can be influenced by high-calorie diets. However, changes affecting the ecosystem at the functional level are still not well characterized. We measured shifts in cecal bacterial communities in mice fed a carbohydrate or high-fat (HF) diet for 12 weeks at the level of the following: (i) diversity and taxa distribution by high-throughput 16S ribosomal RNA gene sequencing; (ii) bulk and single-cell chemical composition by Fourier-transform infrared- (FT-IR) and Raman micro-spectroscopy and (iii) metaproteome and metabolome via high-resolution mass spectrometry. High-fat diet caused shifts in the diversity of dominant gut bacteria and altered the proportion of Ruminococcaceae (decrease) and Rikenellaceae (increase). FT-IR spectroscopy revealed that the impact of the diet on cecal chemical fingerprints is greater than the impact of microbiota composition. Diet-driven changes in biochemical fingerprints of members of the Bacteroidales and Lachnospiraceae were also observed at the level of single cells, indicating that there were distinct differences in cellular composition of dominant phylotypes under different diets. Metaproteome and metabolome analyses based on the occurrence of 1760 bacterial proteins and 86 annotated metabolites revealed distinct HF diet-specific profiles. Alteration of hormonal and anti-microbial networks, bile acid and bilirubin metabolism and shifts towards amino acid and simple sugars metabolism were observed. We conclude that a HF diet markedly affects the gut bacterial ecosystem at the functional level. 10.1038/ismej.2013.155
Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis. Zhou Xinyu,Teng Teng,Zhang Yuqing,Del Giovane Cinzia,Furukawa Toshi A,Weisz John R,Li Xuemei,Cuijpers Pim,Coghill David,Xiang Yajie,Hetrick Sarah E,Leucht Stefan,Qin Mengchang,Barth Jürgen,Ravindran Arun V,Yang Lining,Curry John,Fan Li,Silva Susan G,Cipriani Andrea,Xie Peng The lancet. Psychiatry BACKGROUND:Depressive disorders are common in children and adolescents. Antidepressants, psychotherapies, and their combination are often used in routine clinical practice; however, available evidence on the comparative efficacy and safety of these interventions is inconclusive. Therefore, we sought to compare and rank all available treatment interventions for the acute treatment of depressive disorders in children and adolescents. METHODS:We did a systematic review and network meta-analysis. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, PsycINFO, ProQuest, CINAHL, LiLACS, international trial registries, and the websites of regulatory agencies for published and unpublished randomised controlled trials from database inception until Jan 1, 2019. We included placebo-controlled and head-to-head trials of 16 antidepressants, seven psychotherapies, and five combinations of antidepressant and psychotherapy that are used for the acute treatment of children and adolescents (≤18 years old and of both sexes) with depressive disorder diagnosed according to standard operationalised criteria. Trials recruiting participants with treatment-resistant depression, bipolar disorder, psychotic depression, treatment duration of less than 4 weeks, or an overall sample size of fewer than ten patients were excluded. We extracted data following a predefined hierarchy of outcome measures, and assessed risk of bias and certainty of evidence using validated methods. Primary outcomes were efficacy (change in depressive symptoms) and acceptability (treatment discontinuation due to any cause). We estimated summary standardised mean differences (SMDs) or odds ratios (ORs) with credible intervals (CrIs) using network meta-analysis with random effects. This study was registered with PROSPERO, number CRD42015020841. FINDINGS:From 20 366 publications, we included 71 trials (9510 participants). Depressive disorders in most studies were moderate to severe. In terms of efficacy, fluoxetine plus cognitive behavioural therapy (CBT) was more effective than CBT alone (-0·78, 95% CrI -1·55 to -0·01) and psychodynamic therapy (-1·14, -2·20 to -0·08), but not more effective than fluoxetine alone (-0·22, -0·86 to 0·42). No pharmacotherapy alone was more effective than psychotherapy alone. Only fluoxetine plus CBT and fluoxetine were significantly more effective than pill placebo or psychological controls (SMDs ranged from -1·73 to -0·51); and only interpersonal therapy was more effective than all psychological controls (-1·37 to -0·66). Nortriptyline (SMDs ranged from 1·04 to 2·22) and waiting list (SMDs ranged from 0·67 to 2·08) were less effective than most active interventions. In terms of acceptability, nefazodone and fluoxetine were associated with fewer dropouts than sertraline, imipramine, and desipramine (ORs ranged from 0·17 to 0·50); imipramine was associated with more dropouts than pill placebo, desvenlafaxine, fluoxetine plus CBT, and vilazodone (2·51 to 5·06). Most of the results were rated as "low" to "very low" in terms of confidence of evidence according to Confidence In Network Meta-Analysis. INTERPRETATION:Despite the scarcity of high-quality evidence, fluoxetine (alone or in combination with CBT) seems to be the best choice for the acute treatment of moderate-to-severe depressive disorder in children and adolescents. However, the effects of these interventions might vary between individuals, so patients, carers, and clinicians should carefully balance the risk-benefit profile of efficacy, acceptability, and suicide risk of all active interventions in young patients with depression on a case-by-case basis. FUNDING:National Key Research and Development Program of China. 10.1016/S2215-0366(20)30137-1
Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet (London, England) BACKGROUND:Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017. METHODS:We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990-2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates. FINDINGS:In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9-62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1-12·0) sepsis-related deaths were reported, representing 19·7% (18·2-21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8-54·5) and mortality decreased by 52·8% (47·7-57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia. INTERPRETATION:Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa. FUNDING:The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund. 10.1016/S0140-6736(19)32989-7
Designing hydrogels for controlled drug delivery. Nature reviews. Materials Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel-drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems. 10.1038/natrevmats.2016.71
Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study. , The Lancet. Global health BACKGROUND:Many causes of vision impairment can be prevented or treated. With an ageing global population, the demands for eye health services are increasing. We estimated the prevalence and relative contribution of avoidable causes of blindness and vision impairment globally from 1990 to 2020. We aimed to compare the results with the World Health Assembly Global Action Plan (WHA GAP) target of a 25% global reduction from 2010 to 2019 in avoidable vision impairment, defined as cataract and undercorrected refractive error. METHODS:We did a systematic review and meta-analysis of population-based surveys of eye disease from January, 1980, to October, 2018. We fitted hierarchical models to estimate prevalence (with 95% uncertainty intervals [UIs]) of moderate and severe vision impairment (MSVI; presenting visual acuity from <6/18 to 3/60) and blindness (<3/60 or less than 10° visual field around central fixation) by cause, age, region, and year. Because of data sparsity at younger ages, our analysis focused on adults aged 50 years and older. FINDINGS:Global crude prevalence of avoidable vision impairment and blindness in adults aged 50 years and older did not change between 2010 and 2019 (percentage change -0·2% [95% UI -1·5 to 1·0]; 2019 prevalence 9·58 cases per 1000 people [95% IU 8·51 to 10·8], 2010 prevalence 96·0 cases per 1000 people [86·0 to 107·0]). Age-standardised prevalence of avoidable blindness decreased by -15·4% [-16·8 to -14·3], while avoidable MSVI showed no change (0·5% [-0·8 to 1·6]). However, the number of cases increased for both avoidable blindness (10·8% [8·9 to 12·4]) and MSVI (31·5% [30·0 to 33·1]). The leading global causes of blindness in those aged 50 years and older in 2020 were cataract (15·2 million cases [9% IU 12·7-18·0]), followed by glaucoma (3·6 million cases [2·8-4·4]), undercorrected refractive error (2·3 million cases [1·8-2·8]), age-related macular degeneration (1·8 million cases [1·3-2·4]), and diabetic retinopathy (0·86 million cases [0·59-1·23]). Leading causes of MSVI were undercorrected refractive error (86·1 million cases [74·2-101·0]) and cataract (78·8 million cases [67·2-91·4]). INTERPRETATION:Results suggest eye care services contributed to the observed reduction of age-standardised rates of avoidable blindness but not of MSVI, and that the target in an ageing global population was not reached. FUNDING:Brien Holden Vision Institute, Fondation Théa, The Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation, Sightsavers International, and University of Heidelberg. 10.1016/S2214-109X(20)30489-7
Cognitive and social activities and long-term dementia risk: the prospective UK Million Women Study. The Lancet. Public health BACKGROUND:Although dementia is associated with non-participation in cognitive and social activities, this association might merely reflect the consequences of dementia, rather than any direct effect of non-participation on the subsequent incidence of dementia. Because of the slowness with which dementia can develop, unbiased assessment of any such direct effects must relate non-participation in such activities to dementia detection rates many years later. Prospective studies with long-term follow-up can help achieve this by analysing separately the first and second decade of follow-up. We report such analyses of a large, 20-year study. METHODS:The UK Million Women Study is a population-based prospective study of 1·3 million women invited for National Health Service (NHS) breast cancer screening in median year 1998 (IQR 1997-1999). In median year 2001 (IQR 2001-2003), women were asked about participation in adult education, groups for art, craft, or music, and voluntary work, and in median year 2006 (IQR 2006-2006), they were asked about reading. All participants were followed up through electronic linkage to NHS records of hospital admission with mention of dementia, the first mention of which was the main outcome. Comparing non-participation with participation in a particular activity, we used Cox regression to assess fully adjusted dementia risk ratios (RRs) during 0-4, 5-9, and 10 or more years, after information on that activity was obtained. FINDINGS:In 2001, 851 307 women with a mean age of 60 years (SD 5) provided information on participation in adult education, groups for art, craft, or music, and voluntary work. After 10 years, only 9591 (1%) had been lost to follow-up and 789 339 (93%) remained alive with no recorded dementia. Follow-up was for a mean of 16 years (SD 3), during which 31 187 (4%) had at least one hospital admission with mention of dementia, including 25 636 (3%) with a hospital admission with dementia mentioned for the first time 10 years or more after follow-up began. Non-participation in cognitive or social activities was associated with higher relative risks of dementia detection only during the first decade after participation was recorded. During the second decade, there was little association. This was true for non-participation in adult education (RR 1·04, 99% CI 0·98-1·09), in groups for art, craft, or music (RR 1·04, 0·99-1·09), in voluntary work (RR 0·96, 0·92-1·00), or in any of these three (RR 0·99, 0·95-1·03). In 2006, 655 118 women provided information on reading. For non-reading versus any reading, there were similar associations with dementia, again with strong attenuation over time since reading was recorded, but longer follow-up is needed to assess this reliably. INTERPRETATION:Life has to be lived forwards, but can be understood only backwards. Long before dementia is diagnosed, there is a progressive reduction in various mental and physical activities, but this is chiefly because its gradual onset causes inactivity and not because inactivity causes dementia. FUNDING:UK Medical Research Council, Cancer Research UK. 10.1016/S2468-2667(20)30284-X
Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson's disease. Drui G,Carnicella S,Carcenac C,Favier M,Bertrand A,Boulet S,Savasta M Molecular psychiatry Parkinson's disease (PD) involves the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that is thought to cause the classical motor symptoms of this disease. However, motivational and affective impairments are also often observed in PD patients. These are usually attributed to a psychological reaction to the general motor impairment and to a loss of some of the neurons within the ventral tegmental area (VTA). We induced selective lesions of the VTA and SNc DA neurons that did not provoke motor deficits, and showed that bilateral dopamine loss within the SNc, but not within the VTA, induces motivational deficits and affective impairments that mimicked the symptoms of PD patients. Thus, motivational and affective deficits are a core impairment of PD, as they stem from the loss of the major group of neurons that degenerates in this disease (DA SNc neurons) and are independent of motor deficits. 10.1038/mp.2013.3
Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Seymour Matthew T,Brown Sarah R,Middleton Gary,Maughan Timothy,Richman Susan,Gwyther Stephen,Lowe Catherine,Seligmann Jennifer F,Wadsley Jonathan,Maisey Nick,Chau Ian,Hill Mark,Dawson Lesley,Falk Stephen,O'Callaghan Ann,Benstead Kim,Chambers Philip,Oliver Alfred,Marshall Helen,Napp Vicky,Quirke Phil The Lancet. Oncology BACKGROUND:Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. METHODS:In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m(2) intravenous irinotecan every 3 weeks (300 mg/m(2) if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. RESULTS:Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12-13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83-1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64-0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group. INTERPRETATION:Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents. FUNDING:Cancer Research UK, Amgen Inc. 10.1016/S1470-2045(13)70163-3
A mindfulness-based intervention to increase resilience to stress in university students (the Mindful Student Study): a pragmatic randomised controlled trial. Galante Julieta,Dufour Géraldine,Vainre Maris,Wagner Adam P,Stochl Jan,Benton Alice,Lathia Neal,Howarth Emma,Jones Peter B The Lancet. Public health BACKGROUND:The rising number of young people going to university has led to concerns about an increasing demand for student mental health services. We aimed to assess whether provision of mindfulness courses to university students would improve their resilience to stress. METHODS:We did this pragmatic randomised controlled trial at the University of Cambridge, UK. Students aged 18 years or older with no severe mental illness or crisis (self-assessed) were randomly assigned (1:1), via remote survey software using computer-generated random numbers, to receive either an 8 week mindfulness course adapted for university students (Mindfulness Skills for Students [MSS]) plus mental health support as usual, or mental health support as usual alone. Participants and the study management team were aware of group allocation, but allocation was concealed from the researchers, outcome assessors, and study statistician. The primary outcome was self-reported psychological distress during the examination period, as measured with the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM), with higher scores indicating more distress. The primary analysis was by intention to treat. This trial is registered with the Australia and New Zealand Clinical Trials Registry, number ACTRN12615001160527. FINDINGS:Between Sept 28, 2015, and Jan 15, 2016, we randomly assigned 616 students to the MSS group (n=309) or the support as usual group (n=307). 453 (74%) participants completed the CORE-OM during the examination period and 182 (59%) MSS participants completed at least half of the course. MSS reduced distress scores during the examination period compared with support as usual, with mean CORE-OM scores of 0·87 (SD 0·50) in 237 MSS participants versus 1·11 (0·57) in 216 support as usual participants (adjusted mean difference -0·14, 95% CI -0·22 to -0·06; p=0·001), showing a moderate effect size (β -0·44, 95% CI -0·60 to -0·29; p<0·0001). 123 (57%) of 214 participants in the support as usual group had distress scores above an accepted clinical threshold compared with 88 (37%) of 235 participants in the MSS group. On average, six students (95% CI four to ten) needed to be offered the MSS course to prevent one from experiencing clinical levels of distress. No participants had adverse reactions related to self-harm, suicidality, or harm to others. INTERPRETATION:Our findings show that provision of mindfulness training could be an effective component of a wider student mental health strategy. Further comparative effectiveness research with inclusion of controls for non-specific effects is needed to define a range of additional, effective interventions to increase resilience to stress in university students. FUNDING:University of Cambridge and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care East of England. 10.1016/S2468-2667(17)30231-1
Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Cipriani Andrea,Furukawa Toshi A,Salanti Georgia,Chaimani Anna,Atkinson Lauren Z,Ogawa Yusuke,Leucht Stefan,Ruhe Henricus G,Turner Erick H,Higgins Julian P T,Egger Matthias,Takeshima Nozomi,Hayasaka Yu,Imai Hissei,Shinohara Kiyomi,Tajika Aran,Ioannidis John P A,Geddes John R Lancet (London, England) BACKGROUND:Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. METHODS:We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. FINDINGS:We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. INTERPRETATION:All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. FUNDING:National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science. 10.1016/S0140-6736(17)32802-7
Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet (London, England) BACKGROUND:Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. METHODS:We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. FINDINGS:Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82-1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). INTERPRETATION:We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial. FUNDING:UK National Institute for Health Research Health Technology Assessment Programme. 10.1016/S0140-6736(20)30848-5
Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. The lancet. Psychiatry BACKGROUND:Antipsychotic treatment is associated with metabolic disturbance. However, the degree to which metabolic alterations occur in treatment with different antipsychotics is unclear. Predictors of metabolic dysregulation are poorly understood and the association between metabolic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the basis of their metabolic side-effects, identify physiological and demographic predictors of antipsychotic-induced metabolic dysregulation, and investigate the relationship between change in psychotic symptoms and change in metabolic parameters with antipsychotic treatment. METHODS:We searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included blinded, randomised controlled trials comparing 18 antipsychotics and placebo in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships between metabolic change and age, sex, ethnicity, baseline weight, and baseline metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change. FINDINGS:Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6-8). Mean differences for weight gain compared with placebo ranged from -0·23 kg (95% CI -0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine; for BMI from -0·25 kg/m (-0·68 to 0·17) for haloperidol to 1·07 kg/m (0·90 to 1·25) for olanzapine; for total-cholesterol from -0·09 mmol/L (-0·24 to 0·07) for cariprazine to 0·56 mmol/L (0·26-0·86) for clozapine; for LDL cholesterol from -0·13 mmol/L (-0.21 to -0·05) for cariprazine to 0·20 mmol/L (0·14 to 0·26) for olanzapine; for HDL cholesterol from 0·05 mmol/L (0·00 to 0·10) for brexpiprazole to -0·10 mmol/L (-0·33 to 0·14) for amisulpride; for triglycerides from -0·01 mmol/L (-0·10 to 0·08) for brexpiprazole to 0·98 mmol/L (0·48 to 1·49) for clozapine; for glucose from -0·29 mmol/L (-0·55 to -0·03) for lurasidone to 1·05 mmol/L (0·41 to 1·70) for clozapine. Greater increases in glucose were predicted by higher baseline weight (p=0·0015) and male sex (p=0·0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0·36, p=0·0021), BMI (r=0·84, p<0·0001), total-cholesterol (r=0·31, p=0·047), and LDL cholesterol (r=0·42, p=0·013), and decreases in HDL cholesterol (r=-0·35, p=0·035). INTERPRETATION:Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Increased baseline weight, male sex, and non-white ethnicity are predictors of susceptibility to antipsychotic-induced metabolic change, and improvements in psychopathology are associated with metabolic disturbance. Treatment guidelines should be updated to reflect our findings. However, the choice of antipsychotic should be made on an individual basis, considering the clinical circumstances and preferences of patients, carers, and clinicians. FUNDING:UK Medical Research Council, Wellcome Trust, National Institute for Health Research Oxford Health Biomedical Research Centre. 10.1016/S2215-0366(19)30416-X
School-based interventions to prevent anxiety and depression in children and young people: a systematic review and network meta-analysis. The lancet. Psychiatry BACKGROUND:Rates of anxiety and depression are increasing among children and young people. Recent policies have focused on primary prevention of mental disorders in children and young people, with schools at the forefront of implementation. There is limited information for the comparative effectiveness of the multiple interventions available. METHODS:We did a systematic review and network meta-analysis, searching MEDLINE, Embase, PsycINFO, and Cochrane Central Register of Controlled trials for published and unpublished, passive and active-controlled randomised and quasi-randomised trials. We included educational setting-based, universal, or targeted interventions in which the primary aim was the prevention of anxiety and depression in children and young people aged 4-18 years. Primary outcomes were post-intervention self-report anxiety and depression, wellbeing, suicidal ideation, or self-harm. We assessed risk of bias following the Cochrane Handbook for Systematic Reviews of Interventions. We estimated standardised mean differences (SMD) using random effects network meta-analysis in a Bayesian framework. The study is registered with PROPSERO, number CRD42016048184. FINDINGS:1512 full-text articles were independently screened for inclusion by two reviewers, from which 137 studies of 56 620 participants were included. 20 studies were assessed as being at low risk of bias for both random sequence generation and allocation concealment. There was weak evidence to suggest that cognitive behavioural interventions might reduce anxiety in primary and secondary settings. In universal secondary settings, mindfulness and relaxation-based interventions showed a reduction in anxiety symptoms relative to usual curriculum (SMD -0·65, 95% credible interval -1·14 to -0·19). There was a lack of evidence to support any one type of intervention being effective to prevent depression in universal or targeted primary or secondary settings. Comparison-adjusted funnel plots suggest the presence of small-study effects for the universal secondary anxiety analysis. Network meta-analysis was not feasible for wellbeing or suicidal ideation or self-harm outcomes, and results are reported narratively. INTERPRETATION:Considering unclear risk of bias and probable small study effects for anxiety, we conclude there is little evidence that educational setting-based interventions focused solely on the prevention of depression or anxiety are effective. Future research could consider multilevel, systems-based interventions as an alternative to the downstream interventions considered here. FUNDING:UK National Institute for Health Research. 10.1016/S2215-0366(19)30403-1
Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet (London, England) BACKGROUND:In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. METHODS:GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. FINDINGS:Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990-2010 time period, with the greatest annualised rate of decline occurring in the 0-9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10-24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10-24 years were also in the top ten in the 25-49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50-74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. INTERPRETATION:As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and development investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. FUNDING:Bill & Melinda Gates Foundation. 10.1016/S0140-6736(20)30925-9
XRCC1 prevents toxic PARP1 trapping during DNA base excision repair. Demin Annie A,Hirota Kouji,Tsuda Masataka,Adamowicz Marek,Hailstone Richard,Brazina Jan,Gittens William,Kalasova Ilona,Shao Zhengping,Zha Shan,Sasanuma Hiroyuki,Hanzlikova Hana,Takeda Shunichi,Caldecott Keith W Molecular cell Mammalian DNA base excision repair (BER) is accelerated by poly(ADP-ribose) polymerases (PARPs) and the scaffold protein XRCC1. PARPs are sensors that detect single-strand break intermediates, but the critical role of XRCC1 during BER is unknown. Here, we show that protein complexes containing DNA polymerase β and DNA ligase III that are assembled by XRCC1 prevent excessive engagement and activity of PARP1 during BER. As a result, PARP1 becomes "trapped" on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease. This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase β and impedes their repair. Consequently, PARP1 deletion rescues BER and resistance to base damage in XRCC1 cells. These data reveal excessive PARP1 engagement during BER as a threat to genome integrity and identify XRCC1 as an "anti-trapper" that prevents toxic PARP1 activity. 10.1016/j.molcel.2021.05.009
Diversity and modularity of G protein-coupled receptor structures. Katritch Vsevolod,Cherezov Vadim,Stevens Raymond C Trends in pharmacological sciences G protein-coupled receptors (GPCRs) comprise the most 'prolific' family of cell membrane proteins, which share a general mechanism of signal transduction, but greatly vary in ligand recognition and function. Crystal structures are now available for rhodopsin, adrenergic, and adenosine receptors in both inactive and activated forms, as well as for chemokine, dopamine, and histamine receptors in inactive conformations. Here we review common structural features, outline the scope of structural diversity of GPCRs at different levels of homology, and briefly discuss the impact of the structures on drug discovery. Given the current set of GPCR crystal structures, a distinct modularity is now being observed between the extracellular (ligand-binding) and intracellular (signaling) regions. The rapidly expanding repertoire of GPCR structures provides a solid framework for experimental and molecular modeling studies, and helps to chart a roadmap for comprehensive structural coverage of the whole superfamily and an understanding of GPCR biological and therapeutic mechanisms. 10.1016/j.tips.2011.09.003
Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage. Dunphy Gillian,Flannery Sinéad M,Almine Jessica F,Connolly Dympna J,Paulus Christina,Jønsson Kasper L,Jakobsen Martin R,Nevels Michael M,Bowie Andrew G,Unterholzner Leonie Molecular cell DNA damage can be sensed as a danger-associated molecular pattern by the innate immune system. Here we find that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involves the DNA sensing adaptor STING but is independent of the cytosolic DNA receptor cGAS. This non-canonical activation of STING is mediated by the DNA binding protein IFI16, together with the DNA damage response factors ATM and PARP-1, resulting in the assembly of an alternative STING signaling complex that includes the tumor suppressor p53 and the E3 ubiquitin ligase TRAF6. TRAF6 catalyzes the formation of K63-linked ubiquitin chains on STING, leading to the activation of the transcription factor NF-κB and the induction of an alternative STING-dependent gene expression program. We propose that STING acts as a signaling hub that coordinates a transcriptional response depending on its mode of activation. 10.1016/j.molcel.2018.07.034
Molecular Mechanism of HIV-1 Entry. Chen Bing Trends in microbiology HIV-1 envelope glycoprotein [Env; trimeric (gp160) cleaved to (gp120/gp41)] attaches the virion to a susceptible cell and induces fusion of viral and cell membranes to initiate infection. It interacts with the primary receptor CD4 and coreceptor (e.g., chemokine receptor CCR5 or CXCR4) to allow viral entry by triggering large structural rearrangements and unleashing the fusogenic potential of gp41 to induce membrane fusion. Recent advances in structural biology of HIV-1 Env and its complexes with the cellular receptors have revealed molecular details of HIV-1 entry and yielded new mechanistic insights. In this review, I summarize our latest understanding of the HIV-1 membrane fusion process and discuss possible pathways for productive viral entry. 10.1016/j.tim.2019.06.002
Meta-analyses of the neural mechanisms and predictors of response to psychotherapy in depression and anxiety. Neuroscience and biobehavioral reviews Understanding the neural mechanisms underlying psychological therapy could aid understanding of recovery processes and help target treatments. The dual-process model hypothesises that psychological therapy is associated with increased emotional-regulation in prefrontal brain regions and decreased implicit emotional-reactivity in limbic regions; however, research has yielded inconsistent findings. Meta-analyses of brain activity changes accompanying psychological therapy (22 studies, n = 352) and neural predictors of symptomatic improvement (11 studies, n = 293) in depression and anxiety were conducted using seed-based d mapping. Both resting-state and task-based studies were included, and analysed together and separately. The most robust findings were significant decreases in anterior cingulate/paracingulate gyrus, inferior frontal gyrus and insula activation after therapy. Cuneus activation was predictive of subsequent symptom change. The results are in agreement with neural models of improved emotional-reactivity following therapy as evidenced by decreased activity within the anterior cingulate and insula. We propose compensatory as well as corrective neural mechanisms of action underlie therapeutic efficacy, and suggest the dual-process model may be too simplistic to account fully for treatment mechanisms. More research on predictors of psychotherapeutic response is required to provide reliable predictors of response. 10.1016/j.neubiorev.2018.09.022
Cognitive behavioral therapy for eating disorders. Murphy Rebecca,Straebler Suzanne,Cooper Zafra,Fairburn Christopher G The Psychiatric clinics of North America Cognitive behavioral therapy (CBT) is the leading evidence-based treatment for bulimia nervosa. A new "enhanced" version of the treatment appears to be more potent and has the added advantage of being suitable for all eating disorders, including anorexia nervosa and eating disorder not otherwise specified. This article reviews the evidence supporting CBT in the treatment of eating disorders and provides an account of the "transdiagnostic" theory that underpins the enhanced form of the treatment. It ends with an outline of the treatment's main strategies and procedures. 10.1016/j.psc.2010.04.004
Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges. Neuroscience letters Microglia have emerged as a critical component of neurodegenerative diseases. Genetic manipulation of microglia can elucidate their functional impact in disease. In neuroscience, recombinant viruses such as lentiviruses and adeno-associated viruses (AAVs) have been successfully used to target various cell types in the brain, although effective transduction of microglia is rare. In this review, we provide a short background of lentiviruses and AAVs, and strategies for designing recombinant viral vectors. Then, we will summarize recent literature on successful microglial transductions in vitro and in vivo, and discuss the current challenges. Finally, we provide guidelines for reporting the efficiency and specificity of viral targeting in microglia, which will enable the microglial research community to assess and improve methodologies for future studies. 10.1016/j.neulet.2019.134310
Perinatal acidosis and hypoxic-ischemic encephalopathy in preterm infants of 33 to 35 weeks' gestation. Chalak Lina F,Rollins Nancy,Morriss Michael C,Brion Luc P,Heyne Roy,Sánchez Pablo J The Journal of pediatrics OBJECTIVES:To determine the frequency of hypoxic-ischemic encephalopathy (HIE) in preterm infants of 33 to 35 weeks' gestational age on the basis of physiological screening for perinatal acidosis and neurological assessment of encephalopathy and to correlate neurodevelopmental outcomes with brain magnetic resonance imaging findings. STUDY DESIGN:This retrospective cohort study included all inborn infants of 33 to 35 weeks' gestation admitted to the neonatal intensive care unit at Parkland Memorial Hospital with perinatal acidosis from October 2005 to September 2008. Their medical records were reviewed, and pertinent data were recorded. RESULTS:Of 1305 newborns, 2.5% (n=33) had perinatal acidosis, and 27% (n=9) of these had HIE (2, mild; 4, moderate; 3, severe). Persistence of metabolic acidosis on the first arterial blood gas obtained in the first hour of age was significantly associated with HIE (P<.005). Magnetic resonance imaging results were abnormal in 3 of 4 infants with moderate HIE and in both survivors with severe HIE. Death or disability occurred in no infants with mild or moderate HIE, but in all infants with severe HIE. CONCLUSION:Screening criteria for HIE that use biochemical and neurological assessments as performed in term newborns can be applied to preterm infants of 33 to 35 weeks' gestation. 10.1016/j.jpeds.2011.09.001
Adaptive deep brain stimulation in Parkinson's disease. Beudel M,Brown P Parkinsonism & related disorders Although Deep Brain Stimulation (DBS) is an established treatment for Parkinson's disease (PD), there are still limitations in terms of effectivity, side-effects and battery consumption. One of the reasons for this may be that not only pathological but also physiological neural activity can be suppressed whilst stimulating. For this reason, adaptive DBS (aDBS), where stimulation is applied according to the level of pathological activity, might be advantageous. Initial studies of aDBS demonstrate effectiveness in PD, but there are still many questions to be answered before aDBS can be applied clinically. Here we discuss the feedback signals and stimulation algorithms involved in adaptive stimulation in PD and sketch a potential road-map towards clinical application. 10.1016/j.parkreldis.2015.09.028
Retraction notice. JAAD case reports [This retracts the article DOI: 10.1016/j.jdcr.2017.10.009.]. 10.1016/j.jdcr.2018.08.026
G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling. 10.1016/j.cell.2020.12.024
Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4 T Cell Metabolic Rewiring. Cell metabolism Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4 T cells. SLC5A12-mediated lactate uptake into CD4 T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4 T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders. 10.1016/j.cmet.2019.10.004
Stem Cell Differentiation as a Non-Markov Stochastic Process. Stumpf Patrick S,Smith Rosanna C G,Lenz Michael,Schuppert Andreas,Müller Franz-Josef,Babtie Ann,Chan Thalia E,Stumpf Michael P H,Please Colin P,Howison Sam D,Arai Fumio,MacArthur Ben D Cell systems Pluripotent stem cells can self-renew in culture and differentiate along all somatic lineages in vivo. While much is known about the molecular basis of pluripotency, the mechanisms of differentiation remain unclear. Here, we profile individual mouse embryonic stem cells as they progress along the neuronal lineage. We observe that cells pass from the pluripotent state to the neuronal state via an intermediate epiblast-like state. However, analysis of the rate at which cells enter and exit these observed cell states using a hidden Markov model indicates the presence of a chain of unobserved molecular states that each cell transits through stochastically in sequence. This chain of hidden states allows individual cells to record their position on the differentiation trajectory, thereby encoding a simple form of cellular memory. We suggest a statistical mechanics interpretation of these results that distinguishes between functionally distinct cellular "macrostates" and functionally similar molecular "microstates" and propose a model of stem cell differentiation as a non-Markov stochastic process. 10.1016/j.cels.2017.08.009
Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. Journal of the American College of Cardiology Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases. 10.1016/j.jacc.2020.11.010
Common Regulatory Pathways Mediate Activity of MicroRNAs Inducing Cardiomyocyte Proliferation. Torrini Consuelo,Cubero Ryan John,Dirkx Ellen,Braga Luca,Ali Hashim,Prosdocimo Giulia,Gutierrez Maria Ines,Collesi Chiara,Licastro Danilo,Zentilin Lorena,Mano Miguel,Zacchigna Serena,Vendruscolo Michele,Marsili Matteo,Samal Areejit,Giacca Mauro Cell reports Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin ligase β-TrCP, which leads to YAP degradation. Several of the pro-proliferative miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization by targeting Cofilin2, a process that by itself activates YAP nuclear translocation. Thus, activation of YAP and modulation of the actin cytoskeleton are major components of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte proliferation. 10.1016/j.celrep.2019.05.005
The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity. Schneider Katharina S,Groß Christina J,Dreier Roland F,Saller Benedikt S,Mishra Ritu,Gorka Oliver,Heilig Rosalie,Meunier Etienne,Dick Mathias S,Ćiković Tamara,Sodenkamp Jan,Médard Guillaume,Naumann Ronald,Ruland Jürgen,Kuster Bernhard,Broz Petr,Groß Olaf Cell reports Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1, we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis. 10.1016/j.celrep.2017.12.018
Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage. Fafián-Labora Juan Antonio,Rodríguez-Navarro Jose Antonio,O'Loghlen Ana Cell metabolism Aging is a process of cellular and tissue dysfunction characterized by different hallmarks, including cellular senescence. However, there is proof that certain features of aging and senescence can be ameliorated. Here, we provide evidence that small extracellular vesicles (sEVs) isolated from primary fibroblasts of young human donors ameliorate certain biomarkers of senescence in cells derived from old and Hutchinson-Gilford progeria syndrome donors. Importantly, sEVs from young cells ameliorate senescence in a variety of tissues in old mice. Mechanistically, we identified sEVs to have intrinsic glutathione-S-transferase activity partially due to the high levels of expression of the glutathione-related protein (GSTM2). Transfection of recombinant GSTM2 into sEVs derived from old fibroblasts restores their antioxidant capacity. sEVs increase the levels of reduced glutathione and decrease oxidative stress and lipid peroxidation both in vivo and in vitro. Altogether, our data provide an indication of the potential of sEVs as regenerative therapy in aging. 10.1016/j.cmet.2020.06.004
Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4 T Cell Pathogenicity and Suppresses Autoimmunity. Cell metabolism Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 has been shown to control macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. Here, we report PKM2 upregulation, phosphorylation, and nuclear accumulation in murine and human CD4 T cells following activation in vitro. Treatment of T cells with TEPP-46, an allosteric activator that induces PKM2 tetramerization and blocks its nuclear translocation, strongly reduces their activation, proliferation, and cytokine production by inhibiting essential signaling pathways and thus preventing the engagement of glycolysis. TEPP-46 limits the development of both T helper 17 (Th17) and Th1 cells in vitro and ameliorates experimental autoimmune encephalomyelitis (EAE) in vivo. Overall, our results suggest that pharmacological targeting of PKM2 may represent a valuable therapeutic approach in T cell-mediated inflammation and autoimmunity. 10.1016/j.cmet.2019.10.015
Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function. Field Cameron S,Baixauli Francesc,Kyle Ryan L,Puleston Daniel J,Cameron Alanna M,Sanin David E,Hippen Keli L,Loschi Michael,Thangavelu Govindarajan,Corrado Mauro,Edwards-Hicks Joy,Grzes Katarzyna M,Pearce Edward J,Blazar Bruce R,Pearce Erika L Cell metabolism Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function. 10.1016/j.cmet.2019.11.021
LUBAC-Recruited CYLD and A20 Regulate Gene Activation and Cell Death by Exerting Opposing Effects on Linear Ubiquitin in Signaling Complexes. Draber Peter,Kupka Sebastian,Reichert Matthias,Draberova Helena,Lafont Elodie,de Miguel Diego,Spilgies Lisanne,Surinova Silvia,Taraborrelli Lucia,Hartwig Torsten,Rieser Eva,Martino Luigi,Rittinger Katrin,Walczak Henning Cell reports Ubiquitination and deubiquitination are crucial for assembly and disassembly of signaling complexes. LUBAC-generated linear (M1) ubiquitin is important for signaling via various immune receptors. We show here that the deubiquitinases CYLD and A20, but not OTULIN, are recruited to the TNFR1- and NOD2-associated signaling complexes (TNF-RSC and NOD2-SC), at which they cooperate to limit gene activation. Whereas CYLD recruitment depends on its interaction with LUBAC, but not on LUBAC's M1-chain-forming capacity, A20 recruitment requires this activity. Intriguingly, CYLD and A20 exert opposing effects on M1 chain stability in the TNF-RSC and NOD2-SC. While CYLD cleaves M1 chains, and thereby sensitizes cells to TNF-induced death, A20 binding to them prevents their removal and, consequently, inhibits cell death. Thus, CYLD and A20 cooperatively restrict gene activation and regulate cell death via their respective activities on M1 chains. Hence, the interplay between LUBAC, M1-ubiquitin, CYLD, and A20 is central for physiological signaling through innate immune receptors. 10.1016/j.celrep.2015.11.009
UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition. Ezponda Teresa,Dupéré-Richer Daphné,Will Christine M,Small Eliza C,Varghese Nobish,Patel Tej,Nabet Behnam,Popovic Relja,Oyer Jon,Bulic Marinka,Zheng Yupeng,Huang Xiaoxiao,Shah Mrinal Y,Maji Sayantan,Riva Alberto,Occhionorelli Manuela,Tonon Giovanni,Kelleher Neil,Keats Jonathan,Licht Jonathan D Cell reports Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1. Rebalance of H3K27me3 levels at specific genes through EZH2 inhibitors may be a therapeutic strategy in MM cases harboring UTX mutations. 10.1016/j.celrep.2017.09.078
MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Okoye Isobel S,Coomes Stephanie M,Pelly Victoria S,Czieso Stephanie,Papayannopoulos Venizelos,Tolmachova Tanya,Seabra Miguel C,Wilson Mark S Immunity Foxp3(+) T regulatory (Treg) cells prevent inflammatory disease but the mechanistic basis of suppression is not understood completely. Gene silencing by RNA interference can act in a cell-autonomous and non-cell-autonomous manner, providing mechanisms of intercellular regulation. Here, we demonstrate that non-cell-autonomous gene silencing, mediated by miRNA-containing exosomes, is a mechanism employed by Treg cells to suppress T-cell-mediated disease. Treg cells transferred microRNAs (miRNA) to various immune cells, including T helper 1 (Th1) cells, suppressing Th1 cell proliferation and cytokine secretion. Use of Dicer-deficient or Rab27a and Rab27b double-deficient Treg cells to disrupt miRNA biogenesis or the exosomal pathway, respectively, established a requirement for miRNAs and exosomes for Treg-cell-mediated suppression. Transcriptional analysis and miRNA inhibitor studies showed that exosome-mediated transfer of Let-7d from Treg cell to Th1 cells contributed to suppression and prevention of systemic disease. These studies reveal a mechanism of Treg-cell-mediated suppression mediated by miRNA-containing exosomes. 10.1016/j.immuni.2014.05.019
Mesenchymal stromal cell injection promotes vocal fold scar repair without long-term engraftment. Bartlett R S,Guille J T,Chen X,Christensen M B,Wang S F,Thibeault S L Cytotherapy BACKGROUND:Regenerative medicine holds promise for restoring voice in patients with vocal fold scarring. As experimental treatments approach clinical translation, several considerations remain. Our objective was to evaluate efficacy and biocompatibility of four bone marrow mesenchymal stromal cell (BM-MSC) and tunable hyaluronic acid based hydrogel (HyStem-VF) treatments for vocal fold scar using clinically acceptable materials, a preclinical sample size and a dosing comparison. METHODS:Vocal folds of 84 rabbits were injured and injected with four treatment variations (BM-MSC, HyStem-VF, and BM-MSC in HyStem-VF at two concentrations) 6 weeks later. Efficacy was assessed with rheometry, real-time polymerase chain reaction (RT-PCR) and histology at 2, 4 and 10 weeks following treatment. Lung, liver, kidney, spleen and vocal folds were screened for biocompatibility by a pathologist. RESULTS AND DISCUSSION:Persistent inflammation was identified in all hydrogel-injected groups. The BM-MSC alone treatment appeared to be the most efficacious and safe, providing an early resolution of viscoelasticity, gene expression consistent with desirable extracellular matrix remodeling (less fibronectin, collagen 1α2, collagen 3, procollagen, transforming growth factor [TGF]β1, alpha smooth muscle actin, interleukin-1β, interleukin-17β and tumor necrosis factor [TNF] than injured controls) and minimal inflammation. Human beta actin expression in BM-MSC-treated vocal folds was minimal after 2 weeks, suggesting that paracrine signaling from the BM-MSCs may have facilitated tissue repair. 10.1016/j.jcyt.2016.07.005
Outcomes of a Noninferiority Randomised Controlled Trial of Surgery for Men with Urodynamic Stress Incontinence After Prostate Surgery (MASTER). European urology BACKGROUND:Stress urinary incontinence (SUI) is common after radical prostatectomy and likely to persist despite conservative treatment. The sling is an emerging operation for persistent SUI, but randomised controlled trial (RCT) comparison with the established artificial urinary sphincter (AUS) is lacking. OBJECTIVE:To compare the outcomes of surgery in men with bothersome urodynamic SUI after prostate surgery. DESIGN, SETTING, AND PARTICIPANTS:A noninferiority RCT was conducted among men with bothersome urodynamic SUI from 27 UK centres. Blinding was not possible due the surgeries. INTERVENTION:Participants were randomly assigned (1:1) to the male transobturator sling (n = 190) or the AUS (n = 190) group. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The primary outcome was patient-reported SUI 12 mo after randomisation, collected from postal questionnaire using a composite outcome from two items in validated International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form questionnaire (ICIQ-UI SF). Noninferiority margin was 15%, thought to be of acceptable lower effectiveness, in return for reduced adverse events (AEs) and easier operation, for the sling. Secondary outcomes were operative and postoperative details, patient-reported measures, and AEs, up to 12 mo after surgery. RESULTS AND LIMITATIONS:A total of 380 participants were included. At 12 mo after randomisation, incontinence rates were 134/154 (87.0%) for male sling versus 133/158 (84.2%) for AUS (difference 3.6% [95% confidence interval {CI} -11.6 to 4.6], p = 0.003), showing noninferiority. Incontinence symptoms (ICIQ-UI SF) reduced from scores of 16.1 and 16.4 at baseline to 8.7 and 7.5 for male sling and AUS, respectively (mean difference 1.4 [95% CI 0.2-2.6], p =  0.02). Serious AEs (SAEs) were few: n = 6 and n = 13 for male sling and AUS (one man had three SAEs), respectively. Quality of life scores improved, and satisfaction was high in both groups. All other secondary outcomes that show statistically significant differences favour the AUS. CONCLUSIONS:Using a strict definition, urinary incontinence rates remained high, with no evidence of difference between male sling and AUS. Symptoms and quality of life improved significantly in both groups, and men were generally satisfied with both procedures. Overall, secondary and post hoc analyses were in favour of AUS. PATIENT SUMMARY:Urinary incontinence after prostatectomy has considerable effect on men's quality of life. MASTER shows that if surgery is needed, both surgical options result in fewer symptoms and high satisfaction, despite most men not being completely dry. However, most other results indicate that men having an artificial urinary sphincter have better outcomes than those who have a sling. 10.1016/j.eururo.2021.01.024
The effect of targeting tolerance of children's negative emotions among anxious parents of children with anxiety disorders: A pilot randomised controlled trial. Hiller Rachel M,Apetroaia Adela,Clarke Kiri,Hughes Zoe,Orchard Faith,Parkinson Monika,Creswell Cathy Journal of anxiety disorders Following cognitive behavioural therapy for child anxiety a significant minority of children fail to lose their diagnosis status. One potential barrier is high parental anxiety. We designed a pilot RCT to test claims that parental intolerance of the child's negative emotions may impact treatment outcomes. Parents of 60 children with an anxiety disorder, who were themselves highly anxious, received either brief parent-delivered treatment for child anxiety or the same treatment with strategies specifically targeting parental tolerance of their child's negative emotions. Consistent with predictions, parental tolerance of the child's negative emotions significantly improved from pre- to post-treatment. However, there was no evidence to inform the direction of this association as improvements were substantial in both groups. Moreover, while there were significant improvements in child anxiety in both conditions, there was little evidence that this was associated with the improvement in parental tolerance. Nevertheless, findings provide important clinical insight, including that parent-led treatments are appropriate even when the parent is highly anxious and that it may not be necessary to adjust interventions for many families. 10.1016/j.janxdis.2016.05.009
Influence of oat components on lipid digestion using an model: Impact of viscosity and depletion flocculation mechanism. Grundy Myriam M L,McClements David J,Ballance Simon,Wilde Peter J Food hydrocolloids Depletion flocculation is a well-known instability mechanism that can occur in oil-in-water emulsions when the concentration of non-adsorbed polysaccharide exceeds a certain level. This critical flocculation concentration depends on the molecular characteristics of the polysaccharide molecules, such as their molecular weight and hydrodynamic radius. In this study, a range of analytical methods (dynamic shear rheology, optical microscopy, and static light-scattering) were used to investigate the interaction between lipid droplets and polysaccharides (guar gum and β-glucans) of varying weight-average molecular weight and hydrodynamic radius, and concentration. The aim of this work was to see if the health benefits of soluble fibers like β-glucans could be explained by their influence on the structure and digestibility of lipid emulsions. The apparent viscosity of the emulsions increased with increasing polysaccharide concentration, molecular weight, and hydrodynamic radius. Droplet flocculation was observed in the emulsions only at certain polysaccharide concentrations, which was attributed to a depletion effect. In addition, the water-soluble components in oat flakes, flour, and bran were extracted using aqueous solutions, to examine their impact on emulsion stability and properties. Then, the rate and extent of lipolysis of a sunflower oil-in-water emulsion in the presence of these oat extracts were monitored using the pH-stat method. However, the inhibition of lipolysis was not linearly related to the viscosity of the oat solutions. The water-soluble extracts of β-glucan collected from oat flakes had a significant inhibitory effect on lipolysis. The results of this study increase our understanding of the possible mechanisms influencing the impact of oat constituents on lipid digestion. This work also highlights the importance of considering the molecular properties of polysaccharides, and not just their impact on solution viscosity. 10.1016/j.foodhyd.2018.05.018
Conservation of proteins involved in oocyst wall formation in Eimeria maxima, Eimeria tenella and Eimeria acervulina. International journal for parasitology Vaccination with proteins from gametocytes of Eimeria maxima protects chickens, via transfer of maternal antibodies, against infection with several species of Eimeria. Antibodies to E. maxima gametocyte proteins recognise proteins in the wall forming bodies of macrogametocytes and oocyst walls of E. maxima, Eimeria tenella and Eimeria acervulina. Homologous genes for two major gametocyte proteins - GAM56 and GAM82 - were found in E. maxima, E. tenella and E. acervulina. Alignment of the predicted protein sequences of these genes reveals that, as well as sharing regions of tyrosine richness, strong homology exists in their amino-terminal regions, where protective antibodies bind. This study confirms the conservation of the roles of GAM56 and GAM82 in oocyst wall formation and shows that antibodies to gametocyte antigens of E. maxima cross-react with homologous proteins in other species, helping to explain cross-species maternal immunity. 10.1016/j.ijpara.2009.05.004
BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1. Hogg Simon J,Vervoort Stephin J,Deswal Sumit,Ott Christopher J,Li Jason,Cluse Leonie A,Beavis Paul A,Darcy Phillip K,Martin Benjamin P,Spencer Andrew,Traunbauer Anna K,Sadovnik Irina,Bauer Karin,Valent Peter,Bradner James E,Zuber Johannes,Shortt Jake,Johnstone Ricky W Cell reports BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274. 10.1016/j.celrep.2017.02.011
Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor-Educated Platelets. Best Myron G,Sol Nik,In 't Veld Sjors G J G,Vancura Adrienne,Muller Mirte,Niemeijer Anna-Larissa N,Fejes Aniko V,Tjon Kon Fat Lee-Ann,Huis In 't Veld Anna E,Leurs Cyra,Le Large Tessa Y,Meijer Laura L,Kooi Irsan E,Rustenburg François,Schellen Pepijn,Verschueren Heleen,Post Edward,Wedekind Laurine E,Bracht Jillian,Esenkbrink Michelle,Wils Leon,Favaro Francesca,Schoonhoven Jilian D,Tannous Jihane,Meijers-Heijboer Hanne,Kazemier Geert,Giovannetti Elisa,Reijneveld Jaap C,Idema Sander,Killestein Joep,Heger Michal,de Jager Saskia C,Urbanus Rolf T,Hoefer Imo E,Pasterkamp Gerard,Mannhalter Christine,Gomez-Arroyo Jose,Bogaard Harm-Jan,Noske David P,Vandertop W Peter,van den Broek Daan,Ylstra Bauke,Nilsson R Jonas A,Wesseling Pieter,Karachaliou Niki,Rosell Rafael,Lee-Lewandrowski Elizabeth,Lewandrowski Kent B,Tannous Bakhos A,de Langen Adrianus J,Smit Egbert F,van den Heuvel Michel M,Wurdinger Thomas Cancer cell Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources. 10.1016/j.ccell.2017.07.004
Direct competition between hnRNP C and U2AF65 protects the transcriptome from the exonization of Alu elements. Cell There are ~650,000 Alu elements in transcribed regions of the human genome. These elements contain cryptic splice sites, so they are in constant danger of aberrant incorporation into mature transcripts. Despite posing a major threat to transcriptome integrity, little is known about the molecular mechanisms preventing their inclusion. Here, we present a mechanism for protecting the human transcriptome from the aberrant exonization of transposable elements. Quantitative iCLIP data show that the RNA-binding protein hnRNP C competes with the splicing factor U2AF65 at many genuine and cryptic splice sites. Loss of hnRNP C leads to formation of previously suppressed Alu exons, which severely disrupt transcript function. Minigene experiments explain disease-associated mutations in Alu elements that hamper hnRNP C binding. Thus, by preventing U2AF65 binding to Alu elements, hnRNP C plays a critical role as a genome-wide sentinel protecting the transcriptome. The findings have important implications for human evolution and disease. 10.1016/j.cell.2012.12.023
Tissue engineering-based therapeutic strategies for vocal fold repair and regeneration. Biomaterials Vocal folds are soft laryngeal connective tissues with distinct layered structures and complex multicomponent matrix compositions that endow phonatory and respiratory functions. This delicate tissue is easily damaged by various environmental factors and pathological conditions, altering vocal biomechanics and causing debilitating vocal disorders that detrimentally affect the daily lives of suffering individuals. Modern techniques and advanced knowledge of regenerative medicine have led to a deeper understanding of the microstructure, microphysiology, and micropathophysiology of vocal fold tissues. State-of-the-art materials ranging from extracecullar-matrix (ECM)-derived biomaterials to synthetic polymer scaffolds have been proposed for the prevention and treatment of voice disorders including vocal fold scarring and fibrosis. This review intends to provide a thorough overview of current achievements in the field of vocal fold tissue engineering, including the fabrication of injectable biomaterials to mimic in vitro cell microenvironments, novel designs of bioreactors that capture in vivo tissue biomechanics, and establishment of various animal models to characterize the in vivo biocompatibility of these materials. The combination of polymeric scaffolds, cell transplantation, biomechanical stimulation, and delivery of antifibrotic growth factors will lead to successful restoration of functional vocal folds and improved vocal recovery in animal models, facilitating the application of these materials and related methodologies in clinical practice. 10.1016/j.biomaterials.2016.08.054
TREM2 regulates microglial cell activation in response to demyelination in vivo. Cantoni Claudia,Bollman Bryan,Licastro Danilo,Xie Mingqiang,Mikesell Robert,Schmidt Robert,Yuede Carla M,Galimberti Daniela,Olivecrona Gunilla,Klein Robyn S,Cross Anne H,Otero Karel,Piccio Laura Acta neuropathologica Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. 10.1007/s00401-015-1388-1
The Benefits and Harms of Early Mobilization and Supervised Exercise Therapy after Non-surgically Treated Proximal Humerus or Distal Radius fracture: A systematic Review and Meta-analysis. Østergaard Helle K,Mechlenburg Inger,Launonen Antti P,Vestermark Marianne T,Mattila Ville M,Ponkilainen Ville T Current reviews in musculoskeletal medicine PURPOSE OF REVIEW:Fractures of the proximal humerus (PHF) and distal radius (DRF) are among the most common upper extremity fractures in the elderly. Recent randomized controlled trials support non-surgical treatment. Evidence behind the best non-surgical treatment strategy has been sparse and raises questions as to when and how to initiate exercises. The purpose of this systematic review and meta-analysis was to assess the benefits and harms of early mobilization versus late mobilization and supervised versus non-supervised exercises therapy after PHF and DRF. RECENT FINDINGS:15 published and 5 unpublished trials were included. Early mobilization after PHF resulted in better function with a mean difference (MD) of 4.55 (95% CI 0.00-9.10) on the Constant Shoulder Score. However, the MD was not found to be clinically relevant. No clear evidence showed that early mobilization after PHF had a positive effect on range of motion or pain. Neither did it lead to more complications. Furthermore, no eligible evidence was found supporting early mobilization to be superior to late mobilization after DRF, or that supervised exercise therapy was superior to non-supervised exercise therapy after PHF and DRF. The quality of evidence on all outcomes was found to be low or very low. Early mobilization after PHF may have a beneficial effect on function. Due to the lack of clear evidence, there is an urgent need for future studies to determine the effect of early mobilization and supervised exercise therapy after PHF and DRF. Prospero ID number: CRD42020167656, date of registration 28.04.2020. 10.1007/s12178-021-09697-5
Is Use of a Psychological Workbook Associated With Improved Disabilities of the Arm, Shoulder and Hand Scores in Patients With Distal Radius Fracture? Goudie Stuart,Dixon Diane,McMillan Gail,Ring David,McQueen Margaret Clinical orthopaedics and related research BACKGROUND:Symptom intensity and magnitude of limitations correlate with stress, distress, and less effective coping strategies. It is unclear if interventions to target these factors can be used to improve outcomes after distal radius fracture in either the short- or longer term. QUESTIONS/PURPOSES:(1) Are there any factors (including the use of a workbook aimed at optimizing psychological response to injury, demographic, radiographic, medical, or psychosocial) associated with improved Disabilities of the Arm, Shoulder and Hand (DASH) and Numerical Rating Scale pain (NRS pain) scores at 6 weeks after management of distal radius fracture? (2) Are any of these factors associated with improved DASH and NRS pain scores at 6 months after management of distal radius fracture? METHODS:We conducted a double-blind randomized controlled trial comparing a workbook designed to optimize rehabilitation by improving psychological response to injury using recognized psychological techniques (the LEARN technique and goal setting) versus a workbook containing details of stretching exercises in the otherwise routine management of distal radius fracture. Patients older than 18 years of age with an isolated distal radius fracture were recruited within 3 weeks of injury from a single academic teaching hospital between March and August 2016. During recruitment, 191 patients who met the inclusion criteria were approached; 52 (27%) declined participation and 139 were enrolled. Eight patients (6%) were lost to followup by 6 weeks. The remaining cohort of 129 patients was included in the analysis. DASH scores and NRS pain scores were recorded at 6 weeks and 6 months after injury. Multivariable regression analysis was used to identify factors associated with outcome scores. RESULTS:At 6 weeks after distal radius fracture, when compared with an information-only workbook, use of a psychologic workbook was not associated with improved DASH (workbook DASH: 38 [range, 21-48]; control DASH: 35 [range, 21-53]; difference of medians: 3; p = 0.949) nor NRS pain scores (workbook NRS: 3 [range, 1-5]; control NRS: 2 [range, 1-4]; difference of medians: 1; p = 0.128). Improved DASH scores were associated with less radial shortening (β = 0.2, p = 0.009), less dorsal tilt (β = 0.2, p = 0.035), and nonoperative treatment (β = 0.2, p = 0.027). Improved NRS pain scores were associated with nonoperative treatment (β = 0.2, p = 0.021) and no posttraumatic stress disorder (PTSD) (β = 0.2, p = 0.046). At 6 months, use of a psychologic workbook was not associated with improved DASH (workbook DASH: 11 [range, 5-28]; control DASH: 11 [range, 3-20]; difference of medians: 0; p = 0.367) nor NRS pain scores (workbook NRS: 1 [range, 0-2]; control NRS: 1 [range, 0-2]; difference of medians: 0; p = 0.704). Improved DASH score at 6 months was associated with having fewer medical comorbidities (β = 0.3, p < 0.001) and lower enrollment PTSD (β = 0.3, p < 0.011). Lower NRS pain scores at 6 months were associated with having fewer medical comorbidities (β = 0.2, p = 0.045), lower enrollment PTSD (β = 0.3, p = 0.008), and lower enrollment Tampa Scale for Kinesiophobia (β = 0.2, p = 0.042). CONCLUSIONS:Our study demonstrates that there is no benefit from the untargeted use of a psychological workbook based on the LEARN approach and goal-setting strategies in patients with distal radius fracture. Future research should investigate if there is a subgroup of patients with a negative psychological response to injury that benefits from psychological intervention and, if so, how best to identify these patients and intervene. LEVEL OF EVIDENCE:Level II, therapeutic study. 10.1007/s11999.0000000000000095
Stroke injury, cognitive impairment and vascular dementia. Kalaria Raj N,Akinyemi Rufus,Ihara Masafumi Biochimica et biophysica acta The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25-30% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood-brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. 10.1016/j.bbadis.2016.01.015
Surgical versus nonsurgical treatment of displaced intra-articular calcaneal fracture: a meta-analysis of current evidence base. Jiang Nan,Lin Qing-rong,Diao Xi-cai,Wu Liang,Yu Bin International orthopaedics PURPOSE:Controversy still surrounds the optimal treatment for patients with displaced intra-articular calcaneal fractures (DIACF). An up-to-date meta-analysis was performed to evaluate clinical effectiveness of surgical treatment for DIACF compared with nonsurgical treatment. METHODS:We systematically searched four electronic databases (Medline, BIOSIS, Cochrane library and Google Scholar) to identify randomised controlled trials (RCTs) and clinical controlled trials (CCTs) in which surgical treatment was compared with nonsurgical treatment of DIACF from 1980 to 2011. Trial quality was assessed using the modified Jadad scale and effective data were pooled for meta-analysis. RESULTS:Ten studies (six RCTs and four CCTs) with a total of 891 participants were screened. Results showed that surgical treatment was superior to nonsurgical treatment in better recovery of the Böhler angle (P < 0.0001), more stable calcaneal height (P = 0.0009) and width (P < 0.00001). Moreover, fewer surgically treated patients needed increased shoe size (P = 0.0004) and more were able to resume pre-injury work (P = 0.004) than the nonsurgical patients. No significant difference was identified between the two methods regarding the incidence of residual pain (P = 0.49). However, operative management was associated with a higher risk of complications (P = 0.008). CONCLUSIONS:Although surgical repair may increase the complication probability, it is the price that has to be paid for better reconstruction of the calcaneus and better functional results. Taken as a whole, surgery is probably the optimal choice in DIACF treatment. 10.1007/s00264-012-1563-0
Role of Flagella in the Pathogenesis of Helicobacter pylori. Gu Haiying Current microbiology This review aimed to investigate the role of Helicobacter pylori flagella on the pathogenicity of this bacterium in humans. Helicobacter pylori is a flagellated pathogen that colonizes the human gastroduodenal mucosa and produces inflammation, and is responsible for gastrointestinal disease. Its pathogenesis is attributed to colonization and virulence factors. The primary function of H. pylori flagella is to provide motility. We believe that H. pylori flagella play an important role in the colonization of the gastrointestinal mucosa. Therefore, we reviewed previous studies on flagellar morphology and motility in order to explore the relationship between H. pylori flagella and pathogenicity. Further investigation is required to confirm the association between flagella and pathogenicity in H. pylori. 10.1007/s00284-017-1256-4
A primary fish gill cell culture model to assess pharmaceutical uptake and efflux: evidence for passive and facilitated transport. Stott Lucy C,Schnell Sabine,Hogstrand Christer,Owen Stewart F,Bury Nic R Aquatic toxicology (Amsterdam, Netherlands) The gill is the principle site of xenobiotic transfer to and from the aqueous environment. To replace, refine or reduce (3Rs) the large numbers of fish used in in vivo uptake studies an effective in vitro screen is required that mimics the function of the teleost gill. This study uses a rainbow trout (Oncorhynchus mykiss) primary gill cell culture system grown on permeable inserts, which tolerates apical freshwater thus mimicking the intact organ, to assess the uptake and efflux of pharmaceuticals across the gill. Bidirectional transport studies in media of seven pharmaceuticals (propranolol, metoprolol, atenolol, formoterol, terbutaline, ranitidine and imipramine) showed they were transported transcellularly across the epithelium. However, studies conducted in water showed enhanced uptake of propranolol, ranitidine and imipramine. Concentration-equilibrated conditions without a concentration gradient suggested that a proportion of the uptake of propranolol and imipramine is via a carrier-mediated process. Further study using propranolol showed that its transport is pH-dependent and at very low environmentally relevant concentrations (ng L(-1)), transport deviated from linearity. At higher concentrations, passive uptake dominated. Known inhibitors of drug transport proteins; cimetidine, MK571, cyclosporine A and quinidine inhibited propranolol uptake, whilst amantadine and verapamil were without effect. Together this suggests the involvement of specific members of SLC and ABC drug transporter families in pharmaceutical transport. 10.1016/j.aquatox.2014.12.007
Cardiac biomarkers of acute coronary syndrome: from history to high-sensitivity cardiac troponin. Internal and emergency medicine The role of cardiac troponins as diagnostic biomarkers of myocardial injury in the context of acute coronary syndrome (ACS) is well established. Since the initial 1st-generation assays, 5th-generation high-sensitivity cardiac troponin (hs-cTn) assays have been developed, and are now widely used. However, its clinical adoption preceded guidelines and even best practice evidence. This review summarizes the history of cardiac biomarkers with particular emphasis on hs-cTn. We aim to provide insights into using hs-cTn as a quantitative marker of cardiomyocyte injury to help in the differential diagnosis of coronary versus non-coronary cardiac diseases. We also review the recent evidence and guidelines of using hs-cTn in suspected ACS. 10.1007/s11739-017-1612-1
Polymerase chain reaction in detection of porcine endogenous retrovirus (PERV) from porcine tissues. Prabha M Suji,Verghese Susan Indian journal of microbiology Pigs offer an unlimited source of xenografts for humans. The use of transplants from animal origin offers a potential solution to the limited supply of human organs and tissues. However, like many other mammalian species, pigs harbor porcine endogenous retrovirus (PERV), which are encoded in their genomic DNA and are assumed to have been integrated into the porcine germline. The ability of PERV to infect human cells in vitro has heightened safety concerns regarding the transmission of PERV to pig xenograft recipients. Porcine tissues were analyzed using validated assays specifi c for PERV: polymerase chain reaction (PCR) (for PERV DNA) and reverse transcriptase (RT)-PCR (for PERV RNA). PERV-specifi c gag sequences were found in the porcine heart tissue samples using DNA-PCR and RT-PCR. PCR is a rapid and specifi c test for the detection of PERV from xenografts. These fi ndings have demonstrated that the presence of both DNA and RNA forms of PERV in porcine tissues needs to be carefully considered when the infectious disease potential of xenotransplantation is being assessed. 10.1007/s12088-009-0002-4
BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity. Cellular and molecular neurobiology Brain-derived neurotrophic factor (BDNF) is one of the most widely distributed and extensively studied neurotrophins in the mammalian brain. Among its prominent functions, one can mention control of neuronal and glial development, neuroprotection, and modulation of both short- and long-lasting synaptic interactions, which are critical for cognition and memory. A wide spectrum of processes are controlled by BDNF, and the sometimes contradictory effects of its action can be explained based on its specific pattern of synthesis, comprising several intermediate biologically active isoforms that bind to different types of receptor, triggering several signaling pathways. The functions of BDNF must be discussed in close relation to the stage of brain development, the different cellular components of nervous tissue, as well as the molecular mechanisms of signal transduction activated under physiological and pathological conditions. In this review, we briefly summarize the current state of knowledge regarding the impact of BDNF on regulation of neurophysiological processes. The importance of BDNF for future studies aimed at disclosing mechanisms of activation of signaling pathways, neuro- and gliogenesis, as well as synaptic plasticity is highlighted. 10.1007/s10571-017-0510-4
Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis. Breast cancer research and treatment PURPOSE:In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC). METHODS:Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints. RESULTS:The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators. CONCLUSIONS:The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC. 10.1007/s10549-020-05577-7
Tissue regeneration of the vocal fold using bone marrow mesenchymal stem cells and synthetic extracellular matrix injections in rats. Johnson Beatriz Quinchia,Fox Ryan,Chen Xia,Thibeault Susan The Laryngoscope OBJECTIVES/HYPOTHESIS:To determine the effectiveness of bone marrow mesenchymal stem cell (BM-MSC) transplantation in isolation or within a synthetic extracellular matrix (sECM) for tissue regeneration of the scarred vocal fold lamina propria. METHODS:In vitro stability and compatibility of mouse BM-MSC embedded in sECM was assessed by flow cytometry detection of BM-MSC marker expression and proliferation. Eighteen rats were subjected to vocal fold injury bilaterally, followed by 1 month post-treatment with unilateral injections of saline or sECM hydrogel (Extracel; Glycosan BioSystems, Inc., Salt Lake City, UT), green fluorescence protein (GFP)-mouse BM-MSC, or BM-MSC suspended in sECM. Outcomes measured 1 month after treatment included procollagen-III, fibronectin, hyaluronan synthase-III (HAS3), hyaluronidase (HYAL3), smooth muscle actin (SMA), and transforming growth factor-beta 1(TGF-beta1) mRNA expression. The persistence of GFP BM-MSC, proliferation, apoptosis, and myofibroblast differentiation was assessed by immunofluorescence. RESULTS:BM-MSC grown in vitro within sECM express Sca-1, are positive for hyaluronan receptor CD44, and continue to proliferate. In the in vivo study, groups injected with BM-MSC had detectable GFP-labeled BM-MSC remaining and showed proliferation and low apoptotic or myofibroblast markers compared to the contralateral side. Embedded BM-MSC in the sECM group exhibited increased levels of procollagen III, fibronectin, and TGF-beta1. BM-MSC within sECM downregulated the expression of SMA compared to BM-MSC alone and exhibited upregulation of HYAL3 and no change in HAS3 compared to saline. CONCLUSIONS:Treatment of vocal fold scarring with BM-MSC injected in a sECM displayed the most favorable outcomes in ECM production, hyaluronan metabolism, myofibroblast differentiation, and production of TGF-beta1. Furthermore, the combined treatment had no detectable cytotoxicity and preserved local cell proliferation. 10.1002/lary.20782
Cell-cell interaction between vocal fold fibroblasts and bone marrow mesenchymal stromal cells in three-dimensional hyaluronan hydrogel. Chen Xia,Thibeault Susan L Journal of tissue engineering and regenerative medicine Mesenchymal stromal cells (MSCs) are multipotential adult cells present in all tissues. Paracrine effects and differentiating ability make MSCs an ideal cell source for tissue regeneration. However, little is known about how interactions between implanted MSCs and native cells influence cellular growth, proliferation, and behaviour. By using an in vitro three-dimensional (3D) co-culture assay of normal or scarred human vocal fold fibroblasts (VFFs) and bone marrow-derived MSCs (BM-MSCs) in a uniquely suited hyaluronan hydrogel (HyStem-VF), we investigated cell morphology, survival rate, proliferation and protein and gene expression of VFFs and BM-MSCs. BM-MSCs inhibited cell proliferation of both normal and scarred VFFs without changes in VFF morphology or viability. BM-MSCs demonstrated decreased proliferation and survival rate after 7 days of co-culture with VFFs. Interactions between BM-MSCs and VFFs led to a significant increase in protein secretion of collagen I and hepatocyte growth factor (HGF) and a decrease of vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6). In particular, BM-MSCs significantly upregulated matrix metalloproteinase 1 (MMP1) and HGF gene expression for scarred VFFs compared to normal VFFs, indicating the potential for increases in extracellular matrix remodelling and tissue regeneration. Application of BM-MSCs-hydrogels may play a significant role in tissue regeneration, providing a therapeutic approach for vocal fold scarring. Copyright © 2013 John Wiley & Sons, Ltd. 10.1002/term.1757
Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Kovac Stjepana,Angelova Plamena R,Holmström Kira M,Zhang Ying,Dinkova-Kostova Albena T,Abramov Andrey Y Biochimica et biophysica acta BACKGROUND:Nuclear factor (erythroid-derived 2) factor 2 (Nrf2) is a crucial transcription factor mediating protection against oxidants. Nrf2 is negatively regulated by cytoplasmic Kelch-like ECH associated protein 1 (Keap1) thereby providing inducible antioxidant defence. Antioxidant properties of Nrf2 are thought to be mainly exerted by stimulating transcription of antioxidant proteins, whereas its effects on ROS production within the cell are uncertain. METHODS:Live cell imaging and qPCR in brain hippocampal glio-neuronal cultures and explants slice cultures with graded expression of Nrf2, i.e. Nrf2-knockout (Nrf2-KO), wild-type (WT), and Keap1-knockdown (Keap1-KD). RESULTS:We here show that ROS production in Nrf2-KO cells and tissues is increased compared to their WT counterparts. Mitochondrial ROS production is regulated by the Keap1-Nrf2 pathway by controlling mitochondrial bioenergetics. Surprisingly, Keap1-KD cells and tissues also showed higher rates of ROS production when compared to WT, although with a smaller magnitude. Analysis of the mRNA expression levels of the two NOX isoforms implicated in brain pathology showed, that NOX2 is dramatically upregulated under conditions of Nrf2 deficiency, whereas NOX4 is upregulated when Nrf2 is constitutively activated (Keap1-KD) to a degree which paralleled the increases in ROS production. CONCLUSIONS:These observations suggest that the Keap1-Nrf2 pathway regulates both mitochondrial and cytosolic ROS production through NADPH oxidase. GENERAL SIGNIFICANCE:Findings supports a key role of the Keap1-Nrf2 pathway in redox homeostasis within the cell. 10.1016/j.bbagen.2014.11.021
Mendelian Randomization and Type 2 Diabetes. Swerdlow Daniel I Cardiovascular drugs and therapy Type 2 diabetes (T2DM) is a common, complex disease that poses a substantial burden on individual and population health, but we have relatively limited understanding of its underlying pathophysiology. Observational studies have highlighted large numbers of risk factors for T2DM, some of which are modifiable through behavioural or pharmacological intervention. Determining which of these risk factors plays a causal role in the development of T2DM has been a challenge, but Mendelian randomisation (MR) studies are harnessing genetic data in population studies to offer new insights. Using evolving analytical methods, MR studies continue to address questions of causality related to T2DM, including exploring the roles of adiposity, blood lipids and inflammation. The causal roles of a number of important modifiable risk factors have been confirmed by MR studies, while the relevance of others has been called into question. As more MR studies are conducted, methods are developed and refined in order to make the most efficient and reliable use of available genetic and phenotypic data. In this review, the design and findings of some important MR studies related to T2DM are explored and their relevance for translation to clinical practice considered. 10.1007/s10557-016-6638-5
Modeling Avoidance in Mood and Anxiety Disorders Using Reinforcement Learning. Biological psychiatry BACKGROUND:Serious and debilitating symptoms of anxiety are the most common mental health problem worldwide, accounting for around 5% of all adult years lived with disability in the developed world. Avoidance behavior-avoiding social situations for fear of embarrassment, for instance-is a core feature of such anxiety. However, as for many other psychiatric symptoms the biological mechanisms underlying avoidance remain unclear. METHODS:Reinforcement learning models provide formal and testable characterizations of the mechanisms of decision making; here, we examine avoidance in these terms. A total of 101 healthy participants and individuals with mood and anxiety disorders completed an approach-avoidance go/no-go task under stress induced by threat of unpredictable shock. RESULTS:We show an increased reliance in the mood and anxiety group on a parameter of our reinforcement learning model that characterizes a prepotent (pavlovian) bias to withhold responding in the face of negative outcomes. This was particularly the case when the mood and anxiety group was under stress. CONCLUSIONS:This formal description of avoidance within the reinforcement learning framework provides a new means of linking clinical symptoms with biophysically plausible models of neural circuitry and, as such, takes us closer to a mechanistic understanding of mood and anxiety disorders. 10.1016/j.biopsych.2017.01.017
TNF-α blockers for the treatment of Kawasaki disease in children. The Cochrane database of systematic reviews BACKGROUND:Kawasaki disease (KD) is an acute inflammatory vasculitis (inflammation of the blood vessels) that mainly affects children between six months and five years of age. The vasculitis primarily impacts medium-sized blood vessels, especially in the coronary arteries. In most children, intravenous immunoglobulin (IVIG) and aspirin therapy rapidly reduce inflammatory markers, fever, and other clinical symptoms. However, approximately 15% to 20% of children receiving the initial IVIG infusion show persistent or recurrent fever and are classified as IVIG-resistant. Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that plays an important role in host defence against infections and in immune responses. Several studies have established that blocking TNF-α is critical for obtaining anti-inflammatory effects in children with KD, thus, there is a need to identify benefits and risks of TNF-α blockers for the treatment of KD. OBJECTIVES:To evaluate the efficacy and safety of using TNF-α blockers (i.e. infliximab and etanercept) to treat children with Kawasaki disease. SEARCH METHODS:The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 19 September 2018. We also undertook reference checking of grey literature. SELECTION CRITERIA:We included randomised controlled trials (RCTs) that compared TNF-α blockers (i.e. infliximab and etanercept) to placebo or other drugs (including retreatment with IVIG) in children with KD, reported in abstract or full-text. DATA COLLECTION AND ANALYSIS:Two review authors independently applied the study selection criteria, assessed risk of bias and extracted data. When necessary, we contacted study authors for additional information. We used GRADE to assess the certainty of the evidence. MAIN RESULTS:We included five trials from 14 reports, with a total of 494 participants. All included trials were individual RCTs that examined the effect of TNF-α blockers for KD.Five trials (with 494 participants) reported the incidence of treatment resistance. TNF-α blockers reduced the incidence of treatment resistance (TNF-α blocker intervention group 30/237, control group 58/257; risk ratio (RR) 0.57, 95% confidence interval (CI) 0.38 to 0.86; low-certainty evidence).Four trials reported the incidence of coronary artery abnormalities (CAAs). Three trials (with 270 participants) contributed data to the meta-analysis, since we could not get the data needed for the analysis from the fourth trial. There was no clear difference between groups in the incidence of CAAs (TNF-α blocker intervention group 8/125, control group 9/145; RR 1.18, 95% CI 0.45 to 3.12; low-certainty evidence).Three trials with 250 participants reported the adverse effect 'infusion reactions' after treatment initiation. The TNF-α blocker intervention decreased infusion reactions (TNF-α blocker intervention group 0/126, control group 15/124; RR 0.06, 95% CI 0.01 to 0.45; low-certainty evidence).Two trials with 227 participants reported the adverse effect 'infections' after treatment initiation. There was no clear difference between groups (TNF-α blocker intervention group 7/114, control group 10/113; RR 0.68, 95% CI 0.33 to 1.37; low-certainty evidence).One trial (with 31 participants) reported the adverse effect 'cutaneous reactions' (rash and contact dermatitis). There was no clear difference between the groups for incidence of rash (TNF-α blocker intervention group 2/16, control group 0/15; RR 4.71, 95% CI 0.24 to 90.69; very low-certainty evidence) or for incidence of contact dermatitis (TNF-α blocker intervention group 1/16, control group 3/15; RR 0.31, 95% CI 0.04 to 2.68; very low-certainty evidence).No trials reported other adverse effects such as injection site reactions, neutropenia, infections, demyelinating disease, heart failure, malignancy, and induction of autoimmunity. AUTHORS' CONCLUSIONS:We found a limited number of RCTs examining the effect of TNF-α blockers for KD. In summary, low-certainty evidence indicates that TNF-α blockers have beneficial effects on treatment resistance and the adverse effect 'infusion reaction' after treatment initiation for KD when compared with no treatment or additional treatment with IVIG. Further research will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution. Further large high quality trials with timing and type of TNF-α blockers used are needed to determine the effects of TNF-α blockers for KD. 10.1002/14651858.CD012448.pub2
Association of Maternal Use of Folic Acid and Multivitamin Supplements in the Periods Before and During Pregnancy With the Risk of Autism Spectrum Disorder in Offspring. Levine Stephen Z,Kodesh Arad,Viktorin Alexander,Smith Lauren,Uher Rudolf,Reichenberg Abraham,Sandin Sven JAMA psychiatry Importance:The association of maternal use of folic acid and multivitamin supplements before and during pregnancy with the risk of autism spectrum disorder (ASD) in offspring is unclear. Objective:To examine the associations between the use of maternal folic acid and multivitamin supplements before and during pregnancy and the risk of ASD in offspring. Design, Setting, and Participants:A case-control cohort study of 45 300 Israeli children born between January 1, 2003, and December 31, 2007, were followed up from birth to January 26, 2015, for the risk of ASD. The cases were all children diagnosed with ASD and the controls were a random sample of 33% of all live-born children. Exposures:Maternal vitamin supplements were classified for folic acid (vitamin B9), multivitamin supplements (Anatomical Therapeutic Chemical A11 codes vitamins A, B, C, and D), and any combination thereof exposed in the intervals before and during pregnancy. Main Outcomes and Measures:The association between maternal vitamin supplementation and the risk of ASD in offspring was quantified with relative risks (RRs) and their 95% CIs fitting Cox proportional hazards regression models adjusted for confounders. Sensitivity analyses were performed to test the robustness of the results. Results:Of the 45 300 children in the study (22 090 girls and 23 210 boys; mean [SD] age, 10.0 [1.4] years at the end of follow-up), 572 (1.3%) received a diagnosis of ASD. Maternal exposure to folic acid and/or multivitamin supplements before pregnancy was statistically significantly associated with a lower likelihood of ASD in the offspring compared with no exposure before pregnancy (RR, 0.39; 95% CI, 0.30-0.50; P < .001). Maternal exposure to folic acid and/or multivitamin supplements during pregnancy was statistically significantly associated with a lower likelihood of ASD in offspring compared with no exposure during pregnancy (RR, 0.27; 95% CI, 0.22-0.33; P < .001). Corresponding RRs were estimated for maternal exposure to folic acid before pregnancy (RR, 0.56; 95% CI, 0.42-0.74; P = .001), maternal exposure to folic acid during pregnancy (RR, 0.32; 95% CI, 0.26-0.41; P < .001), maternal exposure to multivitamin supplements before pregnancy (RR, 0.36; 95% CI, 0.24-0.52; P < .001), and maternal exposure to multivitamin supplements during pregnancy (RR, 0.35; 95% CI, 0.28-0.44; P < .001). The results generally remained statistically significant across sensitivity analyses. Conclusions and Relevance:Maternal exposure to folic acid and multivitamin supplements before and during pregnancy is associated with a reduced risk of ASD in the offspring compared with the offspring of mothers without such exposure. 10.1001/jamapsychiatry.2017.4050
Assessing Brain Metabolism With 7-T Proton Magnetic Resonance Spectroscopy in Patients With First-Episode Psychosis. Wang Anna M,Pradhan Subechhya,Coughlin Jennifer M,Trivedi Aditi,DuBois Samantha L,Crawford Jeffrey L,Sedlak Thomas W,Nucifora Fredrick C,Nestadt Gerald,Nucifora Leslie G,Schretlen David J,Sawa Akira,Barker Peter B JAMA psychiatry Importance:The use of high-field magnetic resonance spectroscopy (MRS) in multiple brain regions of a large population of human participants facilitates in vivo study of localized or diffusely altered brain metabolites in patients with first-episode psychosis (FEP) compared to healthy participants. Objective:To compare metabolite levels in 5 brain regions between patients with FEP (evaluated within 2 years of onset) and healthy controls, and to explore possible associations between targeted metabolite levels and neuropsychological test performance. Design, Setting, and Participants:Cross-sectional design used 7-T MRS at a research MR imaging facility in participants recruited from clinics at the Johns Hopkins Schizophrenia Center and the local population. Eighty-one patients who had received a DSM-IV diagnosis of FEP within the last 2 years and 91 healthy age-matched (but not sex-matched) volunteers participated. Main Outcomes and Measures:Brain metabolite levels including glutamate, glutamine, γ-aminobutyric acid (GABA), N-acetylaspartate, N-acetylaspartyl glutamate, and glutathione, as well as performance on neuropsychological tests. Results:The mean (SD) age of 81 patients with FEP was 22.3 (4.4) years and 57 were male, while the mean (SD) age of 91 healthy participants was 23.3 (3.9) years and 42 were male. Compared with healthy participants, patients with FEP had lower levels of glutamate (F1,162 = 8.63, P = .02), N-acetylaspartate (F1,161 = 5.93, P = .03), GABA (F1,163 = 6.38, P = .03), and glutathione (F1,162 = 4.79, P = .04) in the anterior cingulate (all P values are corrected for multiple comparisons); lower levels of N-acetylaspartate in the orbitofrontal region (F1,136 = 7.23, P = .05) and thalamus (F1,133 = 6.78, P = .03); and lower levels of glutathione in the thalamus (F1,135 = 7.57, P = .03). Among patients with FEP, N-acetylaspartate levels in the centrum semiovale white matter were significantly correlated with performance on neuropsychological tests, including processing speed (r = 0.48; P < .001), visual (r = 0.33; P = .04) and working (r = 0.38; P = .01) memory, and overall cognitive performance (r = 0.38; P = .01). Conclusions and Relevance:Seven-tesla MRS offers insights into biochemical changes associated with FEP and may be a useful tool for probing brain metabolism that ranges from neurotransmission to stress-associated pathways in participants with psychosis. 10.1001/jamapsychiatry.2018.3637
Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia: Systematic Overview and Quality Appraisal of the Meta-analytic Evidence. Correll Christoph U,Rubio Jose M,Inczedy-Farkas Gabriella,Birnbaum Michael L,Kane John M,Leucht Stefan JAMA psychiatry Importance:Limited treatment responses in schizophrenia prompted the testing of combining an antipsychotic drug treatment with a second psychotropic medication. A comprehensive evaluation of the efficacy of multiple medication combinations is missing. Objective:To summarize and compare the meta-analytically determined efficacy of pharmacologic combination strategies of antipsychotic drugs in adults with schizophrenia. Data Sources:Systematic search of PubMed and PsycInfo until May 13, 2016. Study Selection:Meta-analyses of randomized clinical trials comparing the efficacy of antipsychotic drugs combined with other antipsychotic or nonantipsychotic medications vs placebos or antipsychotic monotherapy among adults with schizophrenia. Data Extraction and Synthesis:Independent reviewers extracted the data and assessed the quality of the methods of the included meta-analyses using A Measurement Tool to Assess Systematic Reviews (AMSTAR), adding 6 new items to rate their quality. Effect sizes, expressed as standardized mean difference /Hedges g or risk ratio, were compared separately for combinations with any antipsychotic drug and for combinations with clozapine. Main Outcomes and Measures:The primary outcome was total symptom reduction. Secondary outcomes included positive and negative symptoms, treatment recommendations by authors, study-defined inefficacies, cognitive and depressive symptoms, discontinuation of treatment because of any cause, and inefficacies or intolerabilities. Results:Of 3397 publications, 29 meta-analyses testing 42 combination strategies in 381 individual trials and among 19 833 participants were included. For total symptom reductions, 32 strategies that augmented any antipsychotic drug and 5 strategies that augmented clozapine were examined. Fourteen combination treatments outperformed controls (standard mean difference/Hedges g, -1.27 [95% CI, -2.35 to -0.19] to -0.23 [95% CI, -0.44 to -0.02]; P = .05). No combination strategies with clozapine outperformed controls. The quality of the methods of the meta-analyses was generally high (mean score, 9 of a maximum score of 11) but the quality of the meta-analyzed studies was low (mean score, 2.8 of a maximum score of 8). Treatment recommendations correlated with the effect size (correlation coefficient, 0.22; 95% CI, 0.35-0.10; P < .001), yet effect sizes were inversely correlated with study quality (correlation coefficient, -0.06; 95% CI, 0.01 to -0.12; P = .02). Conclusions and Relevance:Meta-analyses of 21 interventions fully or partially recommended their use, with recommendations being positively correlated with the effect sizes of the pooled intervention. However, the effect sizes were inversely correlated with meta-analyzed study quality, reducing confidence in these recommendations. Higher-quality trials and patient-based meta-analyses are needed to determine whether subpopulations might benefit from combination treatment, as no single strategy can be recommended for patients with schizophrenia based on the current meta-analytic literature. 10.1001/jamapsychiatry.2017.0624
Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents: A Systematic Review and Meta-analysis. JAMA psychiatry Importance:Depressive disorders (DDs), anxiety disorders (ADs), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) are common mental disorders in children and adolescents. Objective:To examine the relative efficacy and safety of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and placebo for the treatment of DD, AD, OCD, and PTSD in children and adolescents. Data Sources:PubMed, EMBASE, PsycINFO, Web of Science, and Cochrane Database from inception through August 7, 2016. Study Selection:Published and unpublished randomized clinical trials of SSRIs or SNRIs in youths with DD, AD, OCD, or PTSD were included. Trials using other antidepressants (eg, tricyclic antidepressants, monoamine oxidase inhibitors) were excluded. Data Extraction and Synthesis:Effect sizes, calculated as standardized mean differences (Hedges g) and risk ratios (RRs) for adverse events, were assessed in a random-effects model. Main Outcomes and Measures:Primary outcomes, as defined by authors on preintervention and postintervention data, mean change data, and adverse event data, were extracted independently by multiple observers following PRISMA guidelines. Results:Thirty-six trials were eligible, including 6778 participants (3484 [51.4%] female; mean [SD] age, 12.9 [5.1] years); 17 studies for DD, 10 for AD, 8 for OCD, and 1 for PTSD. Analysis showed that SSRIs and SNRIs were significantly more beneficial compared with placebo, yielding a small effect size (g = 0.32; 95% CI, 0.25-0.40; P < .001). Anxiety disorder (g = 0.56; 95% CI, 0.40-0.72; P < .001) showed significantly larger between-group effect sizes than DD (g = 0.20; 95% CI, 0.13-0.27; P < .001). This difference was driven primarily by the placebo response: patients with DD exhibited significantly larger placebo responses (g = 1.57; 95% CI, 1.36-1.78; P < .001) compared with those with AD (g = 1.03; 95% CI, 0.84-1.21; P < .001). The SSRIs produced a relatively large effect size for ADs (g = 0.71; 95% CI, 0.45-0.97; P < .001). Compared with participants receiving placebo, patients receiving an antidepressant reported significantly more treatment-emergent adverse events (RR, 1.07; 95% CI, 1.01-1.12; P = .01 or RR, 1.49; 95% CI, 1.22-1.82; P < .001, depending on the reporting method), severe adverse events (RR, 1.76; 95% CI, 1.34-2.32; P < .001), and study discontinuation due to adverse events (RR, 1.79; 95% CI, 1.38-2.32; P < .001). Conclusions and Relevance:Compared with placebo, SSRIs and SNRIs are more beneficial than placebo in children and adolescents; however, the benefit is small and disorder specific, yielding a larger drug-placebo difference for AD than for other conditions. Response to placebo is large, especially in DD. Severe adverse events are significantly more common with SSRIs and SNRIs than placebo. 10.1001/jamapsychiatry.2017.2432
Effect of Digital Cognitive Behavioral Therapy for Insomnia on Health, Psychological Well-being, and Sleep-Related Quality of Life: A Randomized Clinical Trial. JAMA psychiatry Importance:Digital cognitive behavioral therapy (dCBT) is a scalable and effective intervention for treating insomnia. Most people with insomnia, however, seek help because of the daytime consequences of poor sleep, which adversely affects quality of life. Objectives:To investigate the effect of dCBT for insomnia on functional health, psychological well-being, and sleep-related quality of life and to determine whether a reduction in insomnia symptoms was a mediating factor. Design, Setting, and Participants:This online, 2-arm, parallel-group randomized trial comparing dCBT for insomnia with sleep hygiene education (SHE) evaluated 1711 participants with self-reported symptoms of insomnia. Participants were recruited between December 1, 2015, and December 1, 2016, and dCBT was delivered using web and/or mobile channels plus treatment as usual; SHE comprised a website and a downloadable booklet plus treatment as usual. Online assessments took place at 0 (baseline), 4 (midtreatment), 8 (posttreatment), and 24 (follow-up) weeks. Programs were completed within 12 weeks after inclusion. Main Outcomes and Measures:Primary outcomes were scores on self-reported measures of functional health (Patient-Reported Outcomes Measurement Information System: Global Health Scale; range, 10-50; higher scores indicate better health); psychological well-being (Warwick-Edinburgh Mental Well-being Scale; range, 14-70; higher scores indicate greater well-being); and sleep-related quality of life (Glasgow Sleep Impact Index; range, 1-100; higher scores indicate greater impairment). Secondary outcomes comprised mood, fatigue, sleepiness, cognitive failures, work productivity, and relationship satisfaction. Insomnia was assessed with the Sleep Condition Indicator (range: 0-32; higher scores indicate better sleep). Results:Of the 1711 participants included in the intention-to-treat analysis, 1329 (77.7%) were female, mean (SD) age was 48.0 (13.8) years, and 1558 (91.1%) were white. Use of dCBT was associated with a small improvement in functional health compared with SHE (adjusted difference [95% CI] at week 4, 0.90 [0.40-1.40]; week 8, 1.76 [1.24-2.28]; week 24, 1.76 [1.22-2.30]) and psychological well-being (adjusted difference [95% CI] at week 4, 1.04 [0.28-1.80]; week 8, 2.68 [1.89-3.47]; week 24, 2.95 [2.13-3.76]), and with a large improvement in sleep-related quality of life (at week 4, -8.76 [-11.83 to -5.69]; week 8, -17.60 [-20.81 to -14.39]; week 24, -18.72 [-22.04 to -15.41]) (all P < .01). A large improvement in insomnia mediated these outcomes (range mediated, 45.5%-84.0%). Conclusions and Relevance:Use of dCBT is effective in improving functional health, psychological well-being, and sleep-related quality of life in people reporting insomnia symptoms. A reduction in insomnia symptoms mediates these improvements. These results confirm that dCBT improves both daytime and nighttime aspects of insomnia, strengthening existing recommendations of CBT as the treatment of choice for insomnia. Trial Registration:isrctn.org identifier: ISRCTN60530898. 10.1001/jamapsychiatry.2018.2745
Functional Magnetic Resonance Imaging-Guided Personalization of Transcranial Magnetic Stimulation Treatment for Depression. Cash Robin F H,Cocchi Luca,Lv Jinglei,Fitzgerald Paul B,Zalesky Andrew JAMA psychiatry 10.1001/jamapsychiatry.2020.3794
Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk. JAMA psychiatry Importance:Between-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. Objectives:To compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and Participants:This case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and Measures:Mean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. Results:A comparison of 1151 patients with schizophrenia (mean [SD] age, 33.8 [10.6] years; 68.6% male [n = 790] and 31.4% female [n = 361]) with 2010 healthy controls (mean [SD] age, 32.6 [10.4] years; 56.0% male [n = 1126] and 44.0% female [n = 884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t = 3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age, 55.9 [7.5] years; 48.2% male [n = 6025] and 51.8% female [n = 6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t = -3.00) but was not significantly associated with dispersion. Conclusions and Relevance:This study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia. 10.1001/jamapsychiatry.2019.0257
Outcomes of Online Mindfulness-Based Cognitive Therapy for Patients With Residual Depressive Symptoms: A Randomized Clinical Trial. JAMA psychiatry Importance:Patients with residual depressive symptoms face a gap in care because few resources, to date, are available to manage the lingering effects of their illness. Objective:To evaluate the effectiveness for treating residual depressive symptoms with Mindful Mood Balance (MMB), a web-based application that delivers mindfulness-based cognitive therapy, plus usual depression care compared with usual depression care only. Design, Setting, and Participants:This randomized clinical trial was conducted in primary care and behavioral health clinics at Kaiser Permanente Colorado, Denver. Adults identified with residual depressive symptoms were recruited between March 2, 2015, and November 30, 2018. Outcomes were assessed for a 15-month period, comprising a 3-month intervention interval and a 12-month follow-up period. Interventions:Patients were randomized to receive usual depression care (UDC; n = 230) or MMB plus UDC (n = 230), which included 8 sessions delivered online for a 3-month interval plus minimal phone or email coaching support. Main Outcomes and Measures:Primary outcomes were reduction in residual depressive symptom severity, assessed using the Patient Health Questionaire-9 (PHQ-9); rates of depressive relapse (PHQ-9 scores ≥15); and rates of remission (PHQ-9 scores <5). Secondary outcomes included depression-free days, anxiety symptoms (General Anxiety Disorder-7 Item Scale), and functional status (12-Item Short Form Survey). Results:Among 460 randomized participants (mean [SD] age, 48.30 [14.89] years; 346 women [75.6%]), data were analyzed for the intent-to-treat sample, which included 362 participants (78.7%) at 3 months and 330 (71.7%) at 15 months. Participants who received MMB plus UDC had significantly greater reductions in residual depressive symptoms than did those receiving UDC only (mean [SE] PHQ-9 score, 0.95 [0.39], P < .02). A significantly greater proportion of patients achieved remission in the MMB plus UDC group compared with the UDC only group (PHQ-9 score, <5: β [SE], 0.38 [0.14], P = .008), and rates of depressive relapse were significantly lower in the MMB plus UDC group compared with the UDC only group (hazard ratio, 0.61; 95% CI, 0.39-0.95; P < .03). Compared with the UDC only group, the MMB plus UDC group had decreased depression-free days (mean [SD], 281.14 [164.99] days vs 247.54 [158.32] days; difference, -33.60 [154.14] days; t = -2.33; P = .02), decreased anxiety (mean [SE] General Anxiety Disorder-7 Item Scale score, 1.21 [0.42], P = .004), and improved mental functioning (mean [SE] 12-Item Short Form Survey score, -5.10 [1.37], P < .001), but there was no statistically significant difference in physical functioning. Conclusions and Relevance:Use of MMB plus UDC resulted in significant improvement in depression and functional outcomes compared with UDC only. The MMB web-based treatment may offer a scalable approach for the management of residual depressive symptoms. Trial Registration:ClinicalTrials.gov identifier: NCT02190968. 10.1001/jamapsychiatry.2019.4693
Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders. Chalkia Dimitra,Singh Larry N,Leipzig Jeremy,Lvova Maria,Derbeneva Olga,Lakatos Anita,Hadley Dexter,Hakonarson Hakon,Wallace Douglas C JAMA psychiatry Importance:Autism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and repetitive or restrictive behavior. Although multiple physiologic and biochemical studies have reported defects in mitochondrial oxidative phosphorylation in patients with ASD, the role of mitochondrial DNA (mtDNA) variation has remained relatively unexplored. Objective:To assess what impact mitochondrial lineages encompassing ancient mtDNA functional polymorphisms, termed haplogroups, have on ASD risk. Design, Setting, and Participants:In this cohort study, individuals with autism and their families were studied using the Autism Genetic Resource Exchange cohort genome-wide association studies data previously generated at the Children's Hospital of Philadelphia. From October 2010 to January 2017, we analyzed the data and used the mtDNA single-nucleotide polymorphisms interrogated by the Illumina HumanHap 550 chip to determine the mtDNA haplogroups of the individuals. Taking into account the familial structure of the Autism Genetic Resource Exchange data, we then determined whether the mtDNA haplogroups correlate with ASD risk. Main Outcomes and Measures:Odds ratios of mitochondrial haplogroup as predictors of ASD risk. Results:Of 1624 patients with autism included in this study, 1299 were boys (80%) and 325 were girls (20%). Families in the Autism Genetic Resource Exchange collection (933 families, encompassing 4041 individuals: 1624 patients with ASD and 2417 healthy parents and siblings) had been previously recruited in the United States with no restrictions on age, sex, race/ethnicity, or socioeconomic status. Relative to the most common European haplogroup HHV, European haplogroups I, J, K, O-X, T, and U were associated with increased risk of ASD, as were Asian and Native American haplogroups A and M, with odds ratios ranging from 1.55 (95% CI, 1.16-2.06) to 2.18 (95% CI, 1.59-3) (adjusted P < .04). Hence, mtDNA haplogroup variation is an important risk factor for ASD. Conclusions and Relevance:Because haplogroups I, J, K, O-X, T, and U encompass 55% of the European population, mtDNA lineages must make a significant contribution to overall ASD risk. 10.1001/jamapsychiatry.2017.2604
Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA psychiatry Importance:Anxiety is common among youth with autism spectrum disorder (ASD), often interfering with adaptive functioning. Psychological therapies are commonly used to treat school-aged youth with ASD; their efficacy has not been established. Objective:To compare the relative efficacy of 2 cognitive behavioral therapy (CBT) programs and treatment as usual (TAU) to assess treatment outcomes on maladaptive and interfering anxiety in children with ASD. The secondary objectives were to assess treatment outcomes on positive response, ASD symptom severity, and anxiety-associated adaptive functioning. Design, Setting, and Participants:This randomized clinical trial began recruitment in April 2014 at 3 universities in US cities. A volunteer sample of children (7-13 years) with ASD and maladaptive and interfering anxiety was randomized to standard-of-practice CBT, CBT adapted for ASD, or TAU. Independent evaluators were blinded to groupings. Data were collected through January 2017 and analyzed from December 2018 to February 2019. Interventions:The main features of standard-of-practice CBT were affect recognition, reappraisal, modeling/rehearsal, in vivo exposure tasks, and reinforcement. The CBT intervention adapted for ASD was similar but also addressed social communication and self-regulation challenges with perspective-taking training and behavior-analytic techniques. Main Outcomes and Measures:The primary outcome measure per a priori hypotheses was the Pediatric Anxiety Rating Scale. Secondary outcomes included treatment response on the Clinical Global Impressions-Improvement scale and checklist measures. Results:Of 214 children initially enrolled, 167 were randomized, 145 completed treatment, and 22 discontinued participation. Those who were not randomized failed to meet eligibility criteria (eg, confirmed ASD). There was no significant difference in discontinuation rates across conditions. Randomized children had a mean (SD) age of 9.9 (1.8) years; 34 were female (20.5%). The CBT program adapted for ASD outperformed standard-of-practice CBT (mean [SD] Pediatric Anxiety Rating Scale score, 2.13 [0.91] [95% CI, 1.91-2.36] vs 2.43 [0.70] [95% CI, 2.25-2.62]; P = .04) and TAU (2.93 [0.59] [95% CI, 2.63-3.22]; P < .001). The CBT adapted for ASD also outperformed standard-of-practice CBT and TAU on parent-reported scales of internalizing symptoms (estimated group mean differences: adapted vs standard-of-practice CBT, -0.097 [95% CI, -0.172 to -0.023], P = .01; adapted CBT vs TAU, -0.126 [95% CI, -0.243 to -0.010]; P = .04), ASD-associated social-communication symptoms (estimated group mean difference: adapted vs standard-of-practice CBT, -0.115 [95% CI, -0223 to -0.007]; P = .04; adapted CBT vs TAU: -0.235 [95% CI,-0.406 to -0.065]; P = .01); and anxiety-associated social functioning (estimated group mean difference: adapted vs standard-of-practice CBT, -0.160 [95% CI, -0.307 to -0.013]; P = .04; adapted CBT vs TAU: -0.284 [95% CI, -0.515 to -0.053]; P = .02). Both CBT conditions achieved higher rates of positive treatment response than TAU (BIACA, 61 of 66 [92.4%]; Coping Cat, 47 of 58 [81.0%]; TAU, 2 of 18 [11.1%]; P < .001 for each comparison). Conclusions and Relevance:In this study, CBT was efficacious for children with ASD and interfering anxiety, and an adapted CBT approach showed additional advantages. It is recommended that clinicians providing psychological treatments to school-aged children with ASD consider developing CBT expertise. Trial Registration:ClinicalTrials.gov identifier: NCT02028247. 10.1001/jamapsychiatry.2019.4160
Association of the Collagen Signature in the Tumor Microenvironment With Lymph Node Metastasis in Early Gastric Cancer. Chen Dexin,Chen Gang,Jiang Wei,Fu Meiting,Liu Wenju,Sui Jian,Xu Shuoyu,Liu Zhangyuanzhu,Zheng Xiaoling,Chi Liangjie,Lin Dajia,Li Kai,Chen Weisheng,Zuo Ning,Lu Jianping,Chen Jianxin,Li Guoxin,Zhuo Shuangmu,Yan Jun JAMA surgery Importance:Lymph node status is the primary determinant in treatment decision making in early gastric cancer (EGC). Current evaluation methods are not adequate for estimating lymph node metastasis (LNM) in EGC. Objective:To develop and validate a prediction model based on a fully quantitative collagen signature in the tumor microenvironment to estimate the individual risk of LNM in EGC. Design, Setting, and Participants:This retrospective study was conducted from August 1, 2016, to May 10, 2018, at 2 medical centers in China (Nanfang Hospital and Fujian Provincial Hospital). Participants included a primary cohort (n = 232) of consecutive patients with histologically confirmed gastric cancer who underwent radical gastrectomy and received a T1 gastric cancer diagnosis from January 1, 2008, to December 31, 2012. Patients with neoadjuvant radiotherapy, chemotherapy, or chemoradiotherapy were excluded. An additional consecutive cohort (n = 143) who received the same diagnosis from January 1, 2011, to December 31, 2013, was enrolled to provide validation. Baseline clinicopathologic data of each patient were collected. Collagen features were extracted in specimens using multiphoton imaging, and the collagen signature was constructed. An LNM prediction model based on the collagen signature was developed and was internally and externally validated. Main Outcomes and Measures:The area under the receiver operating characteristic curve (AUROC) of the prediction model and decision curve were analyzed for estimating LNM. Results:In total, 375 patients were included. The primary cohort comprised 232 consecutive patients, in whom the LNM rate was 16.4% (n = 38; 25 men [65.8%] with a mean [SD] age of 57.82 [10.17] years). The validation cohort consisted of 143 consecutive patients, in whom the LNM rate was 20.9% (n = 30; 20 men [66.7%] with a mean [SD] age of 54.10 [13.19] years). The collagen signature was statistically significantly associated with LNM (odds ratio, 5.470; 95% CI, 3.315-9.026; P < .001). Multivariate analysis revealed that the depth of tumor invasion, tumor differentiation, and the collagen signature were independent predictors of LNM. These 3 predictors were incorporated into the new prediction model, and a nomogram was established. The model showed good discrimination in the primary cohort (AUROC, 0.955; 95% CI, 0.919-0.991) and validation cohort (AUROC, 0.938; 95% CI, 0.897-0.981). An optimal cutoff value was selected in the primary cohort, which had a sensitivity of 86.8%, a specificity of 93.3%, an accuracy of 92.2%, a positive predictive value of 71.7%, and a negative predictive value of 97.3%. The validation cohort had a sensitivity of 90.0%, a specificity of 90.3%, an accuracy of 90.2%, a positive predictive value of 71.1%, and a negative predictive value of 97.1%. Among the 375 patients, a sensitivity of 87.3%, a specificity of 92.1%, an accuracy of 91.2%, a positive predictive value of 72.1%, and a negative predictive value of 96.9% were found. Conclusions and Relevance:This study's findings suggest that the collagen signature in the tumor microenvironment is an independent indicator of LNM in EGC, and the prediction model based on this collagen signature may be useful in treatment decision making for patients with EGC. 10.1001/jamasurg.2018.5249
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. Daly Ella J,Trivedi Madhukar H,Janik Adam,Li Honglan,Zhang Yun,Li Xiang,Lane Rosanne,Lim Pilar,Duca Anna R,Hough David,Thase Michael E,Zajecka John,Winokur Andrew,Divacka Ilona,Fagiolini Andrea,Cubala Wieslaw J,Bitter István,Blier Pierre,Shelton Richard C,Molero Patricio,Manji Husseini,Drevets Wayne C,Singh Jaskaran B JAMA psychiatry Importance:Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. Objective:To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. Design, Setting, and Participants:In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. Interventions:Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Main Outcomes and Measures:Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. Results:Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo. Conclusions and Relevance:For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo. Trial Registration:ClinicalTrials.gov identifier: NCT02493868. 10.1001/jamapsychiatry.2019.1189
Quantification of Exosomes. Koritzinsky Erik H,Street Jonathan M,Star Robert A,Yuen Peter S T Journal of cellular physiology Exosomes are released by cells as self-contained vesicles with an intact lipid bilayer that encapsulates a small portion of the parent cell. Exosomes have been studied widely as information-rich sources of potential biomarkers that can reveal cellular physiology. We suggest that quantification is essential to understand basic biological relationships between exosomes and their parent cells and hence the underlying interpretation of exosome signals. The number of methods for quantifying exosomes has expanded as interest in exosomes has increased. However, a consensus on proper quantification has not developed, making each study difficult to compare to another. Overcoming this ad hoc approach will require widely available standards that have been adequately characterized, and multiple comparative studies across platforms. We outline the current status of these technical approaches and our view of how they can become more coherent. J. Cell. Physiol. 232: 1587-1590, 2017. © 2016 Wiley Periodicals, Inc. 10.1002/jcp.25387
Risk Factors, Patterns, and Outcomes of Late Recurrence After Liver Resection for Hepatocellular Carcinoma: A Multicenter Study From China. Xu Xin-Fei,Xing Hao,Han Jun,Li Zhen-Li,Lau Wan-Yee,Zhou Ya-Hao,Gu Wei-Min,Wang Hong,Chen Ting-Hao,Zeng Yong-Yi,Li Chao,Wu Meng-Chao,Shen Feng,Yang Tian JAMA surgery Importance:Late recurrence (more than 2 years) after liver resection for hepatocellular carcinoma (HCC) is generally considered as a multicentric tumor or a de novo cancer. Objective:To investigate the risk factors, patterns, and outcomes of late recurrence after curative liver resection for HCC. Design, Setting, and Participants:This study was a multicenter retrospective analysis of patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. Among 734 patients who were alive and free of recurrence at 2 years after resection, 303 patients developed late recurrence. Data were analyzed from June 2017 to February 2018. Interventions:Liver resection for HCC. Main Outcomes and Measures:Risk factors of late recurrence as well as patterns, treatments, and long-term outcomes of patients with late recurrence. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors of late recurrence. Results:Of the included 734 patients, 652 (88.8%) were male, and the mean (SD) age was 51.0 (10.3) years. At a median (interquartile range) follow-up of 78.0 (52.8-112.5) months, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. Of the 303 patients with late recurrence, 273 (90.1%) had only intrahepatic recurrence, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had only extrahepatic recurrence. Potentially curative treatments were given to 165 of 303 patients (54.5%) with late recurrence, which included reresection, transplant, and local ablation. Multivariate Cox regression analysis showed that regular surveillance for postoperative recurrence (hazard ratio [HR], 0.470; 95% CI, 0.310-0.713; P = .001), cirrhosis (HR, 1.381; 95% CI, 1.049-1.854; P = .02), portal hypertension (HR, 2.424; 95% CI, 1.644-3.574; P < .001), Child-Pugh grade of B or C (HR, 1.376; 95% CI, 1.153-1.674; P < .001), Barcelona Clinic Liver Cancer stage B (HR, 1.304; 95% CI, 1.007-1.708; P = .04) and stage C (HR, 2.037; 95% CI, 1.583-2.842; P < .001), and potentially curative treatment (HR, 0.443; 95% CI, 0.297-0.661; P < .001) were independent predictors of overall survival for patients with late recurrence. Conclusions and Relevance:Late recurrence after HCC resection was associated with sex, cirrhosis, and several aggressive tumor characteristics of the initial HCC. The patterns of late recurrence suggested surveillance for recurrence after 2 years of surgery should be targeted to the liver. Postoperative surveillance improved the chance of potentially curative treatments, with improved survival outcomes in patients with late recurrence. 10.1001/jamasurg.2018.4334
Inflammatory Biomarkers and Risk of Schizophrenia: A 2-Sample Mendelian Randomization Study. Hartwig Fernando Pires,Borges Maria Carolina,Horta Bernardo Lessa,Bowden Jack,Davey Smith George JAMA psychiatry Importance:Positive associations between inflammatory biomarkers and risk of psychiatric disorders, including schizophrenia, have been reported in observational studies. However, conventional observational studies are prone to bias, such as reverse causation and residual confounding, thus limiting our understanding of the effect (if any) of inflammatory biomarkers on schizophrenia risk. Objective:To evaluate whether inflammatory biomarkers have an effect on the risk of developing schizophrenia. Design, Setting, and Participants:Two-sample mendelian randomization study using genetic variants associated with inflammatory biomarkers as instrumental variables to improve inference. Summary association results from large consortia of candidate gene or genome-wide association studies, including several epidemiologic studies with different designs, were used. Gene-inflammatory biomarker associations were estimated in pooled samples ranging from 1645 to more than 80 000 individuals, while gene-schizophrenia associations were estimated in more than 30 000 cases and more than 45 000 ancestry-matched controls. In most studies included in the consortia, participants were of European ancestry, and the prevalence of men was approximately 50%. All studies were conducted in adults, with a wide age range (18 to 80 years). Exposures:Genetically elevated circulating levels of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R). Main Outcomes and Measures:Risk of developing schizophrenia. Individuals with schizophrenia or schizoaffective disorders were included as cases. Given that many studies contributed to the analyses, different diagnostic procedures were used. Results:The pooled odds ratio estimate using 18 CRP genetic instruments was 0.90 (random effects 95% CI, 0.84-0.97; P = .005) per 2-fold increment in CRP levels; consistent results were obtained using different mendelian randomization methods and a more conservative set of instruments. The odds ratio for sIL-6R was 1.06 (95% CI, 1.01-1.12; P = .02) per 2-fold increment. Estimates for IL-1Ra were inconsistent among instruments, and pooled estimates were imprecise and centered on the null. Conclusions and Relevance:Under mendelian randomization assumptions, our findings suggest a protective effect of CRP and a risk-increasing effect of sIL-6R (potentially mediated at least in part by CRP) on schizophrenia risk. It is possible that such effects are a result of increased susceptibility to early life infection. 10.1001/jamapsychiatry.2017.3191
Association of Atopic Dermatitis With Sleep Quality in Children. JAMA pediatrics Importance:Pruritus, a hallmark of atopic dermatitis (AD), is thought to disrupt sleep, yet little is known about how variations in disease activity and severity of this common childhood condition may be associated with sleep patterns over time. Objective:To determine whether children with active AD have impaired sleep duration and quality at multiple time points throughout childhood and whether disease severity affects sleep outcomes. Design, Setting, and Participants:This longitudinal cohort study used data of children enrolled in the Avon Longitudinal Study of Parents and Children, a population-based birth cohort in Avon, United Kingdom. Participants were children (N = 13 988) alive at 1 year and followed up with repeated measures of self-reported AD and sleep through 16 years of age. This study was based on data collected from 1990 to 2008. Data analysis was performed from September 2017 to September 2018. Main Outcomes and Measures:Standardized measure of sleep duration and composite measure of sleep quality, including nighttime awakenings, early morning awakenings, difficulty falling asleep, and nightmares, were repeated at multiple time points between 2 and 16 years of age. Results:The study sample comprised 13 988 children (7220 male [51.6%]) followed up for a median (interquartile range [IQR]) duration of 11 (5-14) years. Of this total, 4938 children (35.3%) met the definition of having atopic dermatitis between 2 and 16 years of age. Total sleep duration was similar between children with active AD and without AD at all ages, and the average estimated difference across childhood was a clinically negligible difference of 2 minutes less per day for children with AD (95% CI, -4 to 0 minutes). In contrast, children with active AD were more likely to report worse sleep quality at all time points, with a nearly 50% higher odds of experiencing more sleep-quality disturbances (adjusted odds ratio [aOR], 1.48; 95% CI, 1.33 to 1.66). Children with more severe active disease (quite bad or very bad AD: aOR, 1.68; 95% CI, 1.42 to 1.98) and with comorbid asthma or allergic rhinitis (aOR, 1.79; 95% CI, 1.54 to 2.09) had worse sleep quality. However, even children with mild AD (OR, 1.40; 95% CI, 1.27 to 1.54) or inactive AD (OR, 1.41; 95% CI, 1.28 to 1.55) had statistically significantly increased odds of impaired sleep quality. Conclusions and Relevance:Atopic dermatitis appeared to be associated with impaired sleep quality throughout childhood; thus, it is suggested that clinicians should consider sleep quality among all children with AD, especially those with comorbid asthma or allergic rhinitis and severe disease, and that interventions to improve sleep quality are needed. 10.1001/jamapediatrics.2019.0025
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA psychiatry Importance:Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective:To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants:This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. Interventions:In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. Main Outcomes and Measures:The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Results:Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). Conclusions and Relevance:In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. Trial Registration:clinicaltrials.gov identifier: NCT01998958. 10.1001/jamapsychiatry.2017.3739
Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China. JAMA ophthalmology IMPORTANCE:While the outbreak of coronavirus disease 2019 (COVID-19) has resulted in more than 100 000 infected individuals in China and worldwide, there are few reports on the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with ocular abnormalities. Understanding ocular manifestations of patients with COVID-19 by ophthalmologists and others may facilitate the diagnosis and prevention of transmission of the disease. OBJECTIVE:To investigate ocular manifestations and viral prevalence in the conjunctiva of patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS:In this case series, patients with COVID-19 treated from February 9 to 15, 2020, at a hospital center in Hubei province, China, were retrospectively reviewed for ocular manifestations. During the period of treatment, the ocular signs and symptoms as well as results of blood tests and reverse transcriptase-polymerase chain reaction (RT-PCR) from nasopharyngeal and conjunctival swabs for SARS-CoV-2 were noted and analyzed. MAIN OUTCOMES AND MEASURES:Ocular signs and symptoms as well as results of blood tests and RT-PCR for SARS-CoV-2. RESULTS:Of the 38 included patients with clinically confirmed COVID-19, 25 (65.8%) were male, and the mean (SD) age was 65.8 (16.6) years. Among them, 28 patients (73.7%) had positive findings for COVID-19 on RT-PCR from nasopharyngeal swabs, and of these, 2 patients (5.2%) yielded positive findings for SARS-CoV-2 in their conjunctival as well as nasopharyngeal specimens. A total of 12 of 38 patients (31.6%; 95% CI, 17.5-48.7) had ocular manifestations consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions. By univariate analysis, patients with ocular symptoms were more likely to have higher white blood cell and neutrophil counts and higher levels of procalcitonin, C-reactive protein, and lactate dehydrogenase than patients without ocular symptoms. In addition, 11 of 12 patients with ocular abnormalities (91.7%; 95% CI, 61.5-99.8) had positive results for SARS-CoV-2 on RT-PCR from nasopharyngeal swabs. Of these, 2 (16.7%) had positive results for SARS-CoV-2 on RT-PCR from both conjunctival and nasopharyngeal swabs. CONCLUSIONS AND RELEVANCE:In this study, one-third of patients with COVID-19 had ocular abnormalities, which frequently occurred in patients with more severe COVID-19. Although there is a low prevalence of SARS-CoV-2 in tears, it is possible to transmit via the eyes. 10.1001/jamaophthalmol.2020.1291
Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial. JAMA psychiatry Importance:Individuals living with schizophrenia are affected by cardiometabolic, endocrine, and motor adverse effects of current antipsychotic medications. Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects. Objective:To examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia. Design, Setting, and Participants:This randomized, double-blind, placebo-controlled, phase 3 clinical trial was conducted from November 13, 2014, to July 20, 2015, with data analyses performed from August 13 to September 15, 2015. Patients with schizophrenia who were aged 18 to 60 years and were experiencing an acute exacerbation of psychosis were enrolled from 12 clinical sites in the United States. Interventions:Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg; lumateperone tosylate, 40 mg (equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone); or placebo once daily for 4 weeks. Main Outcomes and Measures:The prespecified primary efficacy end point was mean change from baseline to day 28 in the Positive and Negative Syndrome Scale (PANSS) total score vs placebo. The key secondary efficacy measure was the Clinical Global Impression-Severity of Illness (CGI-S) score. The PANSS subscale scores, social function, safety, and tolerability were also assessed. Results:The study comprised 450 patients (mean [SD] age, 42.4 [10.2] years; 346 [77.1%] male; mean [SD] baseline PANSS score, 89.8 [10.3]; mean [SD] baseline CGI-S score, 4.8 [0.6]). In the prespecified modified intent-to-treat efficacy analysis (n = 435), 42 mg of lumateperone met the primary and key secondary efficacy objectives, demonstrating a statistically significant improvement vs placebo from baseline to day 28 on the PANSS total score (least-squares mean difference [LSMD], -4.2; 95% CI, -7.8 to -0.6; P = .02; effect size [ES], -0.3) and the CGI-S (LSMD, -0.3; 95% CI, -0.5 to -0.1; P = .003; ES, -0.4). For 28 mg of lumateperone, the LSMD from baseline to day 28 was -2.6 (95% CI, -6.2 to 1.1; P = .16; ES, -0.2) on the PANSS total score and -0.2 (95% CI, -0.5 to 0.0; P = .02; ES, -0.3) on the CGI-S. Both lumateperone doses were well tolerated without clinically significant treatment-emergent motor adverse effects or changes in cardiometabolic or endocrine factors vs placebo. Conclusions and Relevance:Lumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile. Trial Registration:ClinicalTrials.gov identifier: NCT02282761. 10.1001/jamapsychiatry.2019.4379
Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. Rizvi Naiyer A,Cho Byoung Chul,Reinmuth Niels,Lee Ki Hyeong,Luft Alexander,Ahn Myung-Ju,van den Heuvel Michel M,Cobo Manuel,Vicente David,Smolin Alexey,Moiseyenko Vladimir,Antonia Scott J,Le Moulec Sylvestre,Robinet Gilles,Natale Ronald,Schneider Jeffrey,Shepherd Frances A,Geater Sarayut Lucien,Garon Edward B,Kim Edward S,Goldberg Sarah B,Nakagawa Kazuhiko,Raja Rajiv,Higgs Brandon W,Boothman Anne-Marie,Zhao Luping,Scheuring Urban,Stockman Paul K,Chand Vikram K,Peters Solange, JAMA oncology Importance:Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer. Objective:To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. Design, Setting, and Participants:This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018. Interventions:Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. Main Outcomes and Measures:The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory. Results:Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively. Conclusions and Relevance:The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab. Trial Registration:ClinicalT rials.gov Identifier: NCT02453282. 10.1001/jamaoncol.2020.0237
Clinical Evidence for Association of Acupuncture and Acupressure With Improved Cancer Pain: A Systematic Review and Meta-Analysis. He Yihan,Guo Xinfeng,May Brian H,Zhang Anthony Lin,Liu Yihong,Lu Chuanjian,Mao Jun J,Xue Charlie Changli,Zhang Haibo JAMA oncology Importance:Research into acupuncture and acupressure and their application for cancer pain has been growing, but the findings have been inconsistent. Objective:To evaluate the existing randomized clinical trials (RCTs) for evidence of the association of acupuncture and acupressure with reduction in cancer pain. Data Sources:Three English-language databases (PubMed, Embase, and CINAHL) and 4 Chinese-language biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from database inception through March 31, 2019. Study Selection:Randomized clinical trials that compared acupuncture and acupressure with a sham control, analgesic therapy, or usual care for managing cancer pain were included. Data Extraction and Synthesis:Data were screened and extracted independently using predesigned forms. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. Random-effects modeling was used to calculate the effect sizes of included RCTs. The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. Main Outcomes and Measures:The primary outcome was pain intensity measured by the Brief Pain Inventory, Numerical Rating Scale, Visual Analog Scale, or Verbal Rating Scale. Results:A total of 17 RCTs (with 1111 patients) were included in the systematic review, and data from 14 RCTs (with 920 patients) were used in the meta-analysis. Seven sham-controlled RCTs (35%) were notable for their high quality, being judged to have a low risk of bias for all of their domains, and showed that real (compared with sham) acupuncture was associated with reduced pain intensity (mean difference [MD], -1.38 points; 95% CI, -2.13 to -0.64 points; I2 = 81%). A favorable association was also seen when acupuncture and acupressure were combined with analgesic therapy in 6 RCTs for reducing pain intensity (MD, -1.44 points; 95% CI, -1.98 to -0.89; I2 = 92%) and in 2 RCTs for reducing opioid dose (MD, -30.00 mg morphine equivalent daily dose; 95% CI, -37.5 mg to -22.5 mg). The evidence grade was moderate because of the substantial heterogeneity among studies. Conclusions and Relevance:This systematic review and meta-analysis found that acupuncture and/or acupressure was significantly associated with reduced cancer pain and decreased use of analgesics, although the evidence level was moderate. This finding suggests that more rigorous trials are needed to identify the association of acupuncture and acupressure with specific types of cancer pain and to integrate such evidence into clinical care to reduce opioid use. 10.1001/jamaoncol.2019.5233
Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study. JAMA oncology Importance:Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H). Objective:To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC. Design, Setting, and Participants:A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease. Interventions:We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio. Main Outcomes and Measures:The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB). Results:Of 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004). Conclusions and Relevance:This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted. Trial Registration:ClinicalTrials.gov Identifier: NCT02870920. 10.1001/jamaoncol.2020.0910
Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. Shen Shuhong,Chen Xiaojuan,Cai Jiaoyang,Yu Jie,Gao Ju,Hu Shaoyan,Zhai Xiaowen,Liang Changda,Ju Xiuli,Jiang Hua,Jin Runming,Wu Xuedong,Wang Ningling,Tian Xin,Pan Kaili,Jiang Hui,Sun Lirong,Fang Yongjun,Li Chi-Kong,Hu Qun,Yang Minghua,Zhu Yiping,Zhang Hui,Li Chunfu,Pei Deqing,Jeha Sima,Yang Jun J,Cheng Cheng,Tang Jingyan,Zhu Xiaofan,Pui Ching-Hon JAMA oncology Importance:A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Objective:To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. Design, Setting, and Participants:This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. Interventions:Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. Main Outcomes and Measures:The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. Results:Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Conclusions and Relevance:Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation. Trial Registration:Chinese Clinical Trial Registry: ChiCTR-IPR-14005706. 10.1001/jamaoncol.2019.5868
Morbidity and Mortality of Laparoscopic vs Open Total Gastrectomy for Clinical Stage I Gastric Cancer: The CLASS02 Multicenter Randomized Clinical Trial. Liu Fenglin,Huang Changming,Xu Zekuan,Su Xiangqian,Zhao Gang,Ye Jianxin,Du Xiaohui,Huang Hua,Hu Jiankun,Li Guoxin,Yu Peiwu,Li Yong,Suo Jian,Zhao Naiqing,Zhang Wei,Li Haojie,He Hongyong,Sun Yihong, JAMA oncology Importance:The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains uncertain given the lack of high-level clinical evidence. Objective:To compare the safety of LTG for clinical stage I gastric cancer with that of conventional open total gastrectomy (OTG). Design, Setting, and Participants:The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group CLASS02 study was a prospective, multicenter, open-label, noninferiority, randomized clinical trial that compared the safety of LTG vs OTG with lymphadenectomy for patients with clinical stage I gastric cancer. From January 2017 to September 2018, a total of 227 patients were enrolled. Final follow-up was in October 2018. Interventions:Eligible patients were randomized to LTG (n = 113) or OTG (n = 114) by an interactive web response system. Main Outcomes and Measures:The primary outcome was the morbidity and mortality within 30 days following surgeries between LTG and OTG with a noninferiority margin of 10%. The secondary outcomes were recovery courses and postoperative hospital stays. Results:A total of 214 patients were analyzed for morbidity and mortality (105 patients in the LTG group and 109 patients in the OTG group). The mean (SD) age was 59.8 (9.4) years in the LTG group and 59.4 (9.2) years in the OTG group, and most were male (LTG group, 75 of 105 [71.4%]; OTG group, 80 of 109 [73.4%]). The overall morbidity and mortality rates were not significantly different between the groups (rate difference, -1.1%; 95% CI, -11.8% to 9.6%). Intraoperative complications occurred in 3 patients (2.9%) in the LTG group and 4 patients (3.7%) in the OTG group (rate difference, -0.8%; 95% CI, -6.5% to 4.9%). In addition, there was no significant difference in the overall postoperative complication rate of 18.1% in the LTG group and 17.4% in the OTG group (rate difference, 0.7%; 95% CI, -9.6% to 11.0%). One patient in the LTG group died from intra-abdominal bleeding secondary to splenic artery hemorrhage. However, there was no significant difference in mortality between the LTG group and the OTG group (rate difference, 1.0%; 95% CI, -2.5% to 5.2%), and the distribution of complication severity was similar between the 2 groups. Conclusions and Relevance:The results of the CLASS02 trial showed that the safety of LTG with lymphadenectomy by experienced surgeons for clinical stage I gastric cancer was comparable to that of OTG. Trial Registration:ClinicalTrials.gov Identifier: NCT03007550. 10.1001/jamaoncol.2020.3152
Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial. Klein Oliver,Kee Damien,Nagrial Adnan,Markman Ben,Underhill Craig,Michael Michael,Jackett Louise,Lum Caroline,Behren Andreas,Palmer Jodie,Tebbutt Niall C,Carlino Matteo S,Cebon Jonathan JAMA oncology Importance:Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies. Objective:To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers. Design, Setting, and Participants:The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research. Interventions:Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events. Main Outcomes and Measures:The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1. Results:Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events. Conclusions and Relevance:This subgroup analysis of a phase 2 clinical trial found that combination immunotherapy with nivolumab and ipilimumab was associated with substantial positive outcomes patients with advanced biliary tract cancers. This treatment compares favorably to single-agent anti-programmed cell death protein 1 (anti-PD-1) therapy and warrants further investigation. Ongoing translational research is focused on identifying biomarkers that can predict treatment response. Trial Registration:ClinicalTrials.gov Identifier: NCT02923934. 10.1001/jamaoncol.2020.2814
Effect of Collaborative Dementia Care via Telephone and Internet on Quality of Life, Caregiver Well-being, and Health Care Use: The Care Ecosystem Randomized Clinical Trial. Possin Katherine L,Merrilees Jennifer J,Dulaney Sarah,Bonasera Stephen J,Chiong Winston,Lee Kirby,Hooper Sarah M,Allen Isabel Elaine,Braley Tamara,Bernstein Alissa,Rosa Talita D,Harrison Krista,Begert-Hellings Hailey,Kornak John,Kahn James G,Naasan Georges,Lanata Serggio,Clark Amy M,Chodos Anna,Gearhart Rosalie,Ritchie Christine,Miller Bruce L JAMA internal medicine Importance:Few health systems have adopted effective dementia care management programs. The Care Ecosystem is a model for delivering care from centralized hubs across broad geographic areas to caregivers and persons with dementia (PWDs) independently of their health system affiliations. Objective:To determine whether the Care Ecosystem is effective in improving outcomes important to PWDs, their caregivers, and payers beyond those achieved with usual care. Design, Setting, and Participants:A single-blind, randomized clinical trial with a pragmatic design was conducted among PWDs and their caregivers. Each PWD-caregiver dyad was enrolled for 12 months between March 20, 2015, and February 28, 2017. Data were collected until March 5, 2018. Study interventions and assessments were administered over the telephone and internet by clinical and research teams in San Francisco, California, and Omaha, Nebraska. Of 2585 referred or volunteer PWD-caregiver dyads in California, Iowa, or Nebraska, 780 met eligibility criteria and were enrolled. A total of 512 PWD-caregiver dyads were randomized to receive care through the Care Ecosystem and 268 dyads to receive usual care. All eligible PWDs had a dementia diagnosis; were enrolled or eligible for enrollment in Medicare or Medicaid; and spoke English, Spanish, or Cantonese. Analyses were intention-to-treat. Intervention:Telephone-based collaborative dementia care was delivered by a trained care team navigator, who provided education, support and care coordination with a team of dementia specialists (advanced practice nurse, social worker, and pharmacist). Main Outcomes and Measures:Primary outcome measure: Quality of Life in Alzheimer's Disease based on caregiver's rating of 13 aspects of PWD's well-being (including physical health, energy level, mood, living situation, memory, relationships, and finances) on a 4-point scale (poor to excellent). Secondary outcomes: frequencies of PWDs' use of emergency department, hospitalization, and ambulance services; caregiver depression (score on 9-Item Patient Health Questionnaire; higher scores indicate more severe depression); and caregiver burden (score on 12-Item Zarit Burden Interview; higher scores indicate more severe caregiver burden). Results:The 780 PWDs (56.3% female; mean [SD] age, 78.1 [9.9] years) and 780 caregivers (70.9% female; mean [SD] age, 64.7 [12.0] years) lived in California (n = 452), Nebraska (n = 284), or Iowa (n = 44). Of 780 dyads, 655 were still active at 12 months, and 571 completed the 12-month survey. Compared with usual care, the Care Ecosystem improved PWD quality of life (B, 0.53; 95% CI, 0.25-1.30; P = .04), reduced emergency department visits (B, -0.14; 95% CI, -0.29 to -0.01; P = .04), and decreased caregiver depression (B, -1.14; 95% CI, -2.15 to -0.13; P = .03) and caregiver burden (B, -1.90; 95% CI, -3.89 to -0.08; P = .046). Conclusions and Relevance:Effective care management for dementia can be delivered from centralized hubs to supplement usual care and mitigate the growing societal and economic burdens of dementia. Trial Registration:ClinicalTrials.gov identifier: NCT02213458. 10.1001/jamainternmed.2019.4101
Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. Rosenberg Russell,Murphy Patricia,Zammit Gary,Mayleben David,Kumar Dinesh,Dhadda Shobha,Filippov Gleb,LoPresti Antonia,Moline Margaret JAMA network open Importance:Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population. Objective:To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder. Design, Setting, and Participants:The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties. Interventions:Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime. Main Outcomes and Measures:Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy. Results:Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P < .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P < .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P < .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P < .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, -24.0 min; 95% CI, -30.0 to -18.0 min; P < .001 and for lemborexant 10 mg, -25.4 min; 95% CI, -31.4 to -19.3 min; P < .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, -6.7 min; 95% CI, -11.2 to -2.2 min; P = .004 and for lemborexant 10 mg, -8.0 min; 95% CI, -12.5 to -3.5 min; P < .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity. Conclusions and Relevance:In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated. Trial Registrations:ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39. 10.1001/jamanetworkopen.2019.18254
Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. Grasselli Giacomo,Greco Massimiliano,Zanella Alberto,Albano Giovanni,Antonelli Massimo,Bellani Giacomo,Bonanomi Ezio,Cabrini Luca,Carlesso Eleonora,Castelli Gianpaolo,Cattaneo Sergio,Cereda Danilo,Colombo Sergio,Coluccello Antonio,Crescini Giuseppe,Forastieri Molinari Andrea,Foti Giuseppe,Fumagalli Roberto,Iotti Giorgio Antonio,Langer Thomas,Latronico Nicola,Lorini Ferdinando Luca,Mojoli Francesco,Natalini Giuseppe,Pessina Carla Maria,Ranieri Vito Marco,Rech Roberto,Scudeller Luigia,Rosano Antonio,Storti Enrico,Thompson B Taylor,Tirani Marcello,Villani Pier Giorgio,Pesenti Antonio,Cecconi Maurizio, JAMA internal medicine Importance:Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU). Objective:To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy. Design, Setting, and Participants:This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020. Exposures:Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission. Main Outcomes and Measures:Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression. Results:Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (Fio2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29). Conclusions and Relevance:In this retrospective cohort study of critically ill patients admitted to ICUs in Lombardy, Italy, with laboratory-confirmed COVID-19, most patients required IMV. The mortality rate and absolute mortality were high. 10.1001/jamainternmed.2020.3539
Association of Metformin With Pregnancy Outcomes in Women With Polycystic Ovarian Syndrome Undergoing In Vitro Fertilization: A Systematic Review and Meta-analysis. Wu Yiqing,Tu Mixue,Huang Yun,Liu Yifeng,Zhang Dan JAMA network open Importance:Metformin is widely used among women with polycystic ovary syndrome (PCOS). However, its associations with outcomes of in vitro fertilization or intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) in women with PCOS remain controversial. Objective:To assess whether metformin is associated with improved outcomes of IVF/ICSI-ET in women with PCOS. Data Sources:PubMed, Embase, and Cochrane were searched from database inception to January 31, 2020. Study Selection:Only randomized clinical trials (RCTs) were included. Eligible studies enrolled women with PCOS undergoing infertility treatment with IVF/ICSI-ET and reported at least 1 outcome of IVF/ICSI-ET. Data Extraction and Synthesis:This study followed the Preferred Reporting Items for Systematic Reviews and Meta analyses guidelines. Two authors independently extracted the data. Study quality was evaluated using the GRADE system. Treatment effect was quantified using odds ratios (ORs) with 95% CIs using random-effect models with the Mantel-Haenszel method. Main Outcomes and Measures:Ovarian hyperstimulation syndrome (OHSS), clinical pregnancy rate, and live birth rate. Results:A total of 12 RCTs, which collectively included 1123 women with PCOS undergoing infertility treatment with IVF/ICSI-ET, were identified. The risk of OHSS in women randomized to metformin was lower than in women not randomized to metformin (OR, 0.43; 95% CI, 0.24-0.78), although this difference was not significant for women with PCOS with a body mass index of less than 26 (OR, 0.67; 95% CI, 0.30-1.51). There was no significant difference in clinical pregnancy rate (OR, 1.24; 95% CI, 0.82-1.86) or live birth rate (OR, 1.23; 95% CI, 0.74-2.04) in the total population studied. However, in a post hoc analysis among women with a body mass index of 26 or greater, metformin treatment was associated with increased clinical pregnancy rates (OR, 1.71; 95% CI, 1.12-2.60). Conclusions and Relevance:In this study, metformin treatment was associated with a decreased risk of OHSS but had no association with the overall clinical pregnancy rate or live birth rate among women with PCOS undergoing IVF/ICSI-ET. Metformin treatment should be carefully considered for women with PCOS undergoing IVF/ICSI-ET and may be more preferred for women with a body mass index greater than 26. 10.1001/jamanetworkopen.2020.11995
Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer: A Phase 1 Study. Emens Leisha A,Cruz Cristina,Eder Joseph Paul,Braiteh Fadi,Chung Cathie,Tolaney Sara M,Kuter Irene,Nanda Rita,Cassier Philippe A,Delord Jean-Pierre,Gordon Michael S,ElGabry Ehab,Chang Ching-Wei,Sarkar Indrani,Grossman William,O'Hear Carol,Fassò Marcella,Molinero Luciana,Schmid Peter JAMA oncology Importance:Atezolizumab (anti-programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported. Objective:To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC. Design, Setting, and Participants:Women with mTNBC (defined by investigator assessment) were enrolled between January 2013 and February 2016 in a multicohort open-label, phase 1 study at US and European academic medical centers. Median follow-up was 25.3 months (range, 0.4-45.6 months). Eligible patients regardless of line of therapy had measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1; Eastern Cooperative Oncology Group performance status of 0 to 1; and a representative tumor sample for assessment of immune cell (IC) PD-L1 expression. Interventions:Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects or loss of clinical benefit. Main Outcomes and Measures:Primary outcome was safety and tolerability. Activity and exploratory outcomes included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Outcomes were assessed in all patients and in key patient subgroups. Results:Among 116 evaluable patients (median age, 53 years [range, 29-82 years]), treatment-related adverse events occurred in 73 (63%); 58 (79%) were grade 1 to 2. Most adverse events occurred within the first treatment year. The ORRs were numerically higher in first-line (5 of 21 [24%]) than in second-line or greater patients (6 of 94 [6%]). Median duration of response was 21 months (range, 3 to ≥38 months). Median PFS was 1.4 (95% CI, 1.3-1.6) months by RECIST and 1.9 (95% CI, 1.4-2.5) months by irRC. In first-line patients, median OS was 17.6 months (95% CI, 10.2 months to not estimable). Patients with PD-L1 expression of at least 1% tumor-infiltrating ICs had higher ORRs and longer OS (12% [11 of 91]; 10.1 [95% CI, 7.0-13.8] months, respectively) than those with less than 1% ICs (0 of 21; 6.0 [95% CI, 2.6-12.6] months, respectively). High levels of ICs (>10%) were independently associated with higher ORRs and longer OS. Conclusions and Relevance:Single-agent atezolizumab was well tolerated and provided durable clinical benefit in patients with mTNBC with stable or responding disease and in earlier lines of treatment. Trial Registration:ClinicalTrials.gov identifier: NCT01375842. 10.1001/jamaoncol.2018.4224
Development of a Novel Risk Prediction Model for Sudden Cardiac Death in Childhood Hypertrophic Cardiomyopathy (HCM Risk-Kids). JAMA cardiology Importance:Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM), but there is no validated algorithm to identify those at highest risk. Objective:To develop and validate an SCD risk prediction model that provides individualized risk estimates. Design, Setting, and Participants:A prognostic model was developed from a retrospective, multicenter, longitudinal cohort study of 1024 consecutively evaluated patients aged 16 years or younger with HCM. The study was conducted from January 1, 1970, to December 31, 2017. Exposures:The model was developed using preselected predictor variables (unexplained syncope, maximal left-ventricular wall thickness, left atrial diameter, left-ventricular outflow tract gradient, and nonsustained ventricular tachycardia) identified from the literature and internally validated using bootstrapping. Main Outcomes and Measures:A composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia associated with hemodynamic compromise). Results:Of the 1024 patients included in the study, 699 were boys (68.3%); mean (interquartile range [IQR]) age was 11 (7-14) years. Over a median follow-up of 5.3 years (IQR, 2.6-8.3; total patient years, 5984), 89 patients (8.7%) died suddenly or had an equivalent event (annual event rate, 1.49; 95% CI, 1.15-1.92). The pediatric model was developed using preselected variables to predict the risk of SCD. The model's ability to predict risk at 5 years was validated; the C statistic was 0.69 (95% CI, 0.66-0.72), and the calibration slope was 0.98 (95% CI, 0.59-1.38). For every 10 implantable cardioverter defibrillators implanted in patients with 6% or more of a 5-year SCD risk, 1 patient may potentially be saved from SCD at 5 years. Conclusions and Relevance:This new, validated risk stratification model for SCD in childhood HCM may provide individualized estimates of risk at 5 years using readily obtained clinical risk factors. External validation studies are required to demonstrate the accuracy of this model's predictions in diverse patient populations. 10.1001/jamacardio.2019.2861
Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. O'Reilly Eileen M,Oh Do-Youn,Dhani Neesha,Renouf Daniel J,Lee Myung Ah,Sun Weijing,Fisher George,Hezel Aram,Chang Shao-Chun,Vlahovic Gordana,Takahashi Osamu,Yang Yin,Fitts David,Philip Philip Agop JAMA oncology Importance:New therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC. Objective:To evaluate the safety and efficacy of the anti-PD-L1 (programmed death-ligand 1) antibody using either durvalumab monotherapy or in combination with the anticytotoxic T-lymphocyte antigen 4 antibody using durvalumab plus tremelimumab therapy in patients with mPDAC. Design, Setting, and Participants:Part A of this multicenter, 2-part, phase 2 randomized clinical trial was a lead-in safety, open-label study with planned expansion to part B pending an efficacy signal from part A. Between November 26, 2015, and March 23, 2017, 65 patients with mPDAC who had previously received only 1 first-line fluorouracil-based or gemcitabine-based treatment were enrolled at 21 sites in 6 countries. Efficacy analysis included the intent-to-treat population; safety analysis included patients who received at least 1 dose of study treatment and for whom any postdose data were available. Interventions:Patients received durvalumab (1500 mg every 4 weeks) plus tremelimumab (75 mg every 4 weeks) combination therapy for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until the onset of progressive disease or unacceptable toxic effects. Main Outcomes and Measures:Safety and efficacy were measured by objective response rate, which was used to determine study expansion to part B. The threshold for expansion was an objective response rate of 10% for either treatment arm. Results:Among 65 randomized patients, 34 (52%) were men and median age was 61 (95% CI, 37-81) years. Grade 3 or higher treatment-related adverse events occurred in 7 of 32 patients (22%) receiving combination therapy and in 2 of 32 patients (6%) receiving monotherapy; 1 patient randomized to the monotherapy arm did not receive treatment owing to worsened disease. Fatigue, diarrhea, and pruritus were the most common adverse events in both arms. Overall, 4 of 64 patients (6%) discontinued treatment owing to treatment-related adverse events. Objective response rate was 3.1% (95% CI, 0.08-16.22) for patients receiving combination therapy and 0% (95% CI, 0.00-10.58) for patients receiving monotherapy. Low patient numbers limited observation of the associations between treatment response and PD-L1 expression or microsatellite instability status. Conclusion and Relevance:Treatment was well tolerated, and the efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease. Patients were not enrolled in part B because the threshold for efficacy was not met in part A. Trial Registration:ClinicalTrials.gov identifier: NCT02558894. 10.1001/jamaoncol.2019.1588
The Role of Maintenance Strategies in Metastatic Colorectal Cancer: A Systematic Review and Network Meta-analysis of Randomized Clinical Trials. Sonbol Mohamad Bassam,Mountjoy Luke J,Firwana Belal,Liu Alex J,Almader-Douglas Diana,Mody Kabir,Hubbard Joleen,Borad Mitesh,Ahn Daniel H,Murad M Hassan,Bekaii-Saab Tanios JAMA oncology Importance:In metastatic colorectal cancer, induction combination chemotherapy with a targeted agent is considered the mainstay of treatment. Multiple randomized clinical trials have examined different strategies of continuing cytotoxic therapy until progression compared with a period of either observation or the use of various maintenance agents. However, those randomized clinical trials have shown inconsistent efficacy results that make it challenging to draw any conclusion on which strategy is preferred. Therefore, a network meta-analysis is helpful to compare different agents across randomized clinical trials. Objective:To evaluate the comparative effectiveness of different treatment strategies for patients with metastatic colorectal cancer. Evidence Review:MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for randomized clinical trials evaluating different strategies for patients with previously untreated metastatic colorectal cancer. Trials of interest included those including patients with metastatic colorectal cancer who were treated with an initial period of cytotoxic chemotherapy (with or without a biologic) and then switched to one of the following strategies: observation; maintenance with bevacizumab (Bev), fluoropyrimidine (FP), or both (FP + Bev); or continuing the induction regimen until progression. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian and Laird random-effects model. Network meta-analysis was conducted using a random-effects consistency model to pool evidence from direct and indirect comparisons. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores correspond to greater efficacy. Initial analysis was performed on December 18, 2018. An updated search was performed in April 2019, and no additional studies were added. Findings:Twelve trials at low risk of bias (5540 patients; age range, 23-85 years; 64.4 % male) were included. Network meta-analysis showed no benefit of continuing full cytotoxic chemotherapy until progression vs observation in terms of PFS (hazard ratio, 0.71; 95% CI, 0.46-1.09) and OS (hazard ratio, 0.95; 95% CI, 0.85-1.07). Compared with observation, maintenance therapy showed a PFS benefit (hazard ratio, 0.58; 95% CI, 0.43-0.77) but not an OS benefit (hazard ratio, 0.91; 95% CI, 0.83-1.01). All maintenance strategies (FP, FP + Bev, and Bev) showed significant improvement in PFS vs observation. On SUCRA analysis, maintenance treatment (FP or FP + Bev) had the highest likelihood of achieving improved PFS (67.1% for FP, 99.8% for FP + Bev, and 36.5% for Bev) and OS (81.3% for FP, 73.2% for FP + Bev, and 32.6% for Bev). Conclusions and Relevance:For patients with metastatic colorectal cancer, there is no benefit to continuing the full induction regimen until progression, without a period of either observation or maintenance treatment. A maintenance strategy with a fluoropyrimidine, with or without the addition of bevacizumab, is preferred. However, given the lack of a clear OS benefit, shared decision-making should include observation as an acceptable alternative. 10.1001/jamaoncol.2019.4489
Assessment of the Predictive Validity of Etiologic Stroke Classification. Arsava E Murat,Helenius Johanna,Avery Ross,Sorgun Mine H,Kim Gyeong-Moon,Pontes-Neto Octavio M,Park Kwang Yeol,Rosand Jonathan,Vangel Mark,Ay Hakan JAMA neurology Importance:The ability of present-day etiologic stroke classification systems to generate subtypes with discrete stroke characteristics is not known. Objective:To test the hypothesis that etiologic stroke subtyping identifies different disease processes that can be recognized through their different clinical courses. Design, Setting, and Participants:We performed a head-to-head evaluation of the ability of the Causative Classification of Stroke (CCS), Trial of Org 10172 in Acute Stroke Treatment (TOAST), and ASCO (A for atherosclerosis, S for small-vessel disease, C for cardiac source, and O for other cause) classification systems to generate etiologic subtypes with different clinical, imaging, and prognostic characteristics in 1816 patients with ischemic stroke. This study included 2 cohorts recruited at separate periods; the first cohort was recruited between April 2003 and June 2006 and the second between June 2009 and December 2011. Data analysis was performed between June 2014 and May 2016. Main Outcomes and Measures:Separate teams of stroke-trained neurologists performed CCS, TOAST, and ASCO classifications based on information available at the time of hospital discharge. We assessed the association between etiologic subtypes and stroke characteristics by computing receiver operating characteristic curves for binary variables (90-day stroke recurrence and 90-day mortality) and by calculating the ratio of between-category to within-category variability from the analysis of variance for continuous variables (admission National Institutes of Health Stroke Scale score and acute infarct volume). Results:Among the 1816 patients included, the median age was 70 years (interquartile range, 58-80 years) (830 women [46%]). The classification systems differed in their ability to assign stroke etiologies into known subtypes; the size of the undetermined category was 33% by CCS, 53% by TOAST, and 42% by ASCO (P < .001 for all binary comparisons). All systems provided significant discrimination for the validation variables tested. For the primary validation variable (90-day recurrence), the area under the receiver operating characteristic curve was 0.71 (95% CI, 0.66-0.75) for CCS, 0.61 (95% CI, 0.56-0.67) for TOAST, and 0.66 (95% CI, 0.60-0.71) for ASCO (P = .01 for CCS vs ASCO; P < .001 for CCS vs TOAST; P = .13 for ASCO vs TOAST). The classification systems exhibited similar discrimination for 90-day mortality. For admission National Institutes of Health Stroke Scale score and acute infarct volume, CCS generated more distinct subtypes with higher between-category to within-category variability than TOAST and ASCO. Conclusions and Relevance:Our findings suggest that the major etiologic stroke subtypes are distinct categories with different stroke characteristics irrespective of the classification system used to identify them. We further show that CCS generates discrete etiologic categories with more diverse clinical, imaging, and prognostic characteristics than either TOAST or ASCO. 10.1001/jamaneurol.2016.5815
Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA oncology IMPORTANCE:Patterns-of-failure studies suggest that in metastatic non-small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited. OBJECTIVE:To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non-progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS). DESIGN, SETTING, AND PARTICIPANTS:This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy. INTERVENTIONS:Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy. MAIN OUTCOMES AND MEASURES:The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival. RESULTS:A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy-alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy-alone arm (P = .01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly. CONCLUSIONS AND RELEVANCE:Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT02045446. 10.1001/jamaoncol.2017.3501
Efficacy and Safety of Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma With Macroscopic Vascular Invasion: A Randomized Clinical Trial. Yoon Sang Min,Ryoo Baek-Yeol,Lee So Jung,Kim Jong Hoon,Shin Ji Hoon,An Ji Hyun,Lee Han Chu,Lim Young-Suk JAMA oncology Importance:Patients with hepatocellular carcinoma showing macroscopic vascular invasion have a poor prognosis. Sorafenib is the sole treatment option for these patients, with unsatisfactory response and survival benefit. Combined treatment with transarterial chemoembolization (TACE) plus external beam radiotherapy (RT) has shown promising results for these patients in observational studies. Objective:To evaluate the efficacy and safety of TACE plus RT compared with sorafenib for patients with hepatocellular carcinoma and macroscopic vascular invasion. Design, Setting, and Participants:In this randomized, open-label clinical trial conducted at an academic tertiary care center between July 1, 2013, and October 31, 2016, 90 treatment-naive patients with liver-confined hepatocellular carcinoma showing macroscopic vascular invasion were randomly assigned to receive sorafenib (400 mg twice daily; 45 participants [the sorafenib group]) or TACE (every 6 weeks) plus RT (within 3 weeks after the first TACE, maximum 45 Gy with the fraction size of 2.5 to 3 Gy; 45 participants [the TACE-RT group]). Main Outcomes and Measures:The primary end point was the 12-week progression-free survival rate by intention-to-treat analysis. Radiologic response was assessed by independent review according to the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Treatment crossover was permitted after confirming disease progression. Results:Of the 90 patients (median age, 55 years; range, 33-82 years), 77 were men and 13 were women. All patients had portal vein invasion of hepatocellular carcinoma and Child-Pugh class A liver function. The median maximal tumor diameter was 9.7 cm. Most patients (71 [78.9%]) had multiple lesions. At week 12, the progression-free survival rate was significantly higher in the TACE-RT group than the sorafenib group (86.7% vs 34.3%; P < .001). The TACE-RT group showed a significantly higher radiologic response rate than the sorafenib group at 24 weeks (15 [33.3%] vs 1 [2.2%]; P < .001), a significantly longer median time to progression (31.0 vs 11.7 weeks; P < .001), and significantly longer overall survival (55.0 vs 43.0 weeks; P = .04). Curative surgical resection was conducted for 5 patients (11.1%) in the TACE-RT group owing to downstaging. No patients in the TACE-RT group discontinued treatment owing to hepatic decompensation. Conclusions and Relevance:For patients with advanced hepatocellular carcinoma showing macroscopic vascular invasion, first-line treatment with TACE plus RT was well tolerated and provided an improved progression-free survival, objective response rate, time to progression, and overall survival compared with sorafenib treatment. Trial Registration:clinicaltrials.gov Identifier: NCT01901692. 10.1001/jamaoncol.2017.5847
Development and Validation of a Prognostic Model of Swallowing Recovery and Enteral Tube Feeding After Ischemic Stroke. Galovic Marian,Stauber Anne Julia,Leisi Natascha,Krammer Werner,Brugger Florian,Vehoff Jochen,Balcerak Philipp,Müller Anna,Müller Marlise,Rosenfeld Jochen,Polymeris Alexandros,Thilemann Sebastian,De Marchis Gian Marco,Niemann Thorsten,Leifke Maren,Lyrer Philippe,Saladin Petra,Kahles Timo,Nedeltchev Krassen,Sarikaya Hakan,Jung Simon,Fischer Urs,Manno Concetta,Cereda Carlo W,Sander Josemir W,Tettenborn Barbara,Weder Bruno J,Stoeckli Sandro J,Arnold Marcel,Kägi Georg JAMA neurology Importance:Predicting the duration of poststroke dysphagia is important to guide therapeutic decisions. Guidelines recommend nasogastric tube (NGT) feeding if swallowing impairment persists for 7 days or longer and percutaneous endoscopic gastrostomy (PEG) placement if dysphagia does not recover within 30 days, but, to our knowledge, a systematic prediction method does not exist. Objective:To develop and validate a prognostic model predicting swallowing recovery and the need for enteral tube feeding. Design, Setting, and Participants:We enrolled participants with consecutive admissions for acute ischemic stroke and initially severe dysphagia in a prospective single-center derivation (2011-2014) and a multicenter validation (July 2015-March 2018) cohort study in 5 tertiary stroke referral centers in Switzerland. Exposures:Severely impaired oral intake at admission (Functional Oral Intake Scale score <5). Main Outcomes and Measures:Recovery of oral intake (primary end point, Functional Oral Intake Scale ≥5) or return to prestroke diet (secondary end point) measured 7 (indication for NGT feeding) and 30 (indication for PEG feeding) days after stroke. Results:In total, 279 participants (131 women [47.0%]; median age, 77 years [interquartile range, 67-84 years]) were enrolled (153 [54.8%] in the derivation study; 126 [45.2%] in the validation cohort). Overall, 64% (95% CI, 59-71) participants failed to recover functional oral intake within 7 days and 30% (95% CI, 24-37) within 30 days. Prolonged swallowing recovery was independently associated with poor outcomes after stroke. The final prognostic model, the Predictive Swallowing Score, included 5 variables: age, stroke severity on admission, lesion location, initial risk of aspiration, and initial impairment of oral intake. Predictive Swallowing Score prediction estimates ranged from 5% (score, 0) to 96% (score, 10) for a persistent impairment of oral intake on day 7 and from 2% to 62% on day 30. Model performance in the validation cohort showed a discrimination (C statistic) of 0.84 (95% CI, 0.76-0.91; P < .001) for predicting the recovery of oral intake on day 7 and 0.77 (95% CI, 0.67-0.87; P < .001) on day 30, and a discrimination for a return to prestroke diet of 0.94 (day 7; 95% CI, 0.87-1.00; P < .001) and 0.71 (day 30; 95% CI, 0.61-0.82; P < .001). Calibration plots showed high agreement between the predicted and observed outcomes. Conclusions and Relevance:The Predictive Swallowing Score, available as a smartphone application, is an easily applied prognostic instrument that reliably predicts swallowing recovery. It will support decision making for NGT or PEG insertion after ischemic stroke and is a step toward personalized medicine. 10.1001/jamaneurol.2018.4858
Association of Influenza-like Illness Activity With Hospitalizations for Heart Failure: The Atherosclerosis Risk in Communities Study. Kytömaa Sonja,Hegde Sheila,Claggett Brian,Udell Jacob A,Rosamond Wayne,Temte Jonathan,Nichol Kristin,Wright Jacqueline D,Solomon Scott D,Vardeny Orly JAMA cardiology Importance:Influenza is associated with an increased risk of cardiovascular events, but to our knowledge, few studies have explored the temporal association between influenza activity and hospitalizations, especially those caused by heart failure (HF). Objective:To explore the temporal association between influenza activity and hospitalizations due to HF and myocardial infarction (MI). We hypothesized that increased influenza activity would be associated with an increase in hospitalizations for HF and MI among adults in the community. Design, Setting, and Participants:As part of the community surveillance component of the Atherosclerosis Risk in Communities (ARIC) study, a population-based study with hospitalizations sampled from 4 US communities, data were collected from 451 588 adults aged 35 to 84 years residing in the ARIC communities from annual cross-sectional stratified random samples of hospitalizations during October 2010 to September 2014. Exposures:Monthly influenza activity, defined as the percentage of patient visits to sentinel clinicians for influenza-like illness by state, as reported by the Centers for Disease Control and Prevention Surveillance Network. Main Outcomes and Measures:The monthly frequency of MI hospitalizations (n = 3541) and HF hospitalizations (n = 4321), collected through community surveillance and adjudicated as part of the ARIC Study. Results:Between October 2010 and September 2014, 2042 (47.3%) and 1599 (45.1%) of the sampled patients who were hospitalized for HF and MI, respectively, were women and 2391 (53.3%) and 2013 (57.4%) were white, respectively. A 5% monthly absolute increase in influenza activity was associated with a 24% increase in HF hospitalization rates, standardized to the total population in each community, within the same month after adjusting for region, season, race/ethnicity, sex, age, and number of MI/HF hospitalizations from the month before (incidence rate ratio, 1.24; 95% CI, 1.11-1.38; P < .001), while overall influenza activity was not significantly associated with MI hospitalizations (incidence rate ratio, 1.02; 95% CI, 0.90-1.17; P = .72). Influenza activity in the months before hospitalization was not associated with either outcome. Our model suggests that in a month with high influenza activity, approximately 19% of HF hospitalizations (95% CI, 10%-28%) could be attributable to influenza. Conclusions and Relevance:Influenza activity was temporally associated with an increase in HF hospitalizations across 4 influenza seasons. These data suggest that influenza may contribute to the risk of HF hospitalization in the general population. 10.1001/jamacardio.2019.0549
Sildenafil Treatment in Heart Failure With Preserved Ejection Fraction: Targeted Metabolomic Profiling in the RELAX Trial. Wang Hanghang,Anstrom Kevin,Ilkayeva Olga,Muehlbauer Michael J,Bain James R,McNulty Steven,Newgard Christopher B,Kraus William E,Hernandez Adrian,Felker G Michael,Redfield Margaret,Shah Svati H JAMA cardiology Importance:Phosphodiesterase-5 inhibition with sildenafil compared with a placebo had no effect on the exercise capacity or clinical status of patients with heart failure with preserved ejection fraction (HFpEF) in the PhosphodiesteRasE-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure with Preserved Ejection Fraction (RELAX) clinical trial. Metabolic impairments may explain the neutral results. Objective:To test the hypothesis that profiling metabolites in the RELAX trial would clarify the mechanisms of sildenafil effects and identify metabolites associated with clinical outcomes in HFpEF. Design, Setting, and Participants:Paired baseline and 24-week plasma samples of 160 stable outpatient individuals with HFpEF enrolled in the RELAX clinical trial were analyzed using flow injection tandem mass spectrometry (60 metabolites) and conventional assays (5 metabolites). Interventions:Sildenafil (n = 79) or a placebo (n = 81) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Main Outcomes and Measures:The primary measure was metabolite level changes between baseline and 24 weeks stratified by treatments. Secondary measures included correlations between metabolite level changes and clinical biomarkers and associations between baseline metabolite levels and the composite clinical score. Results:No metabolites changed between baseline and 24 weeks in the group treated with a placebo; however, 7 metabolites changed in the group treated with sildenafil, including decreased amino acids (alanine and proline; median change [25th-75th], -38.26 [-100.3 to 28.19] and -28.24 [-56.29 to 12.08], respectively; false discovery rate-adjusted P = .01 and .03, respectively), and increased short-chain dicarboxylacylcarnitines glutaryl carnitine, octenedioyl carnitine, and adipoyl carnitine (median change, 6.19 [-3.37 to 14.18], 2.72 [-3 to 12.57], and 10.72 [-11.23 to 29.57], respectively; false discovery rate-adjusted P = .01, .04, and .05, respectively), and 1 long-chain acylcarnitine metabolite (palmitoyl carnitine; median change, 7.83 [-5.64 to 26.99]; false discovery rate-adjusted P = .03). The increases in long-chain acylarnitine metabolites and short-chain dicarboxylacylcarnitines correlated with increases in endothelin-1 and creatinine/cystatin C, respectively. Higher baseline levels of short-chain dicarboxylacylcarnitine metabolite 3-hydroxyisovalerylcarnitine/malonylcarnitine and asparagine/aspartic acid were associated with worse clinical rank scores in both treatment groups (β, -96.60, P = .001 and β, -0.02, P = .01; after renal adjustment, P = .09 and .02, respectively). Conclusions and Relevance:Our study provides a potential mechanism for the effects of sildenafil that, through adverse effects on mitochondrial function and endoplasmic reticulum stress, could have contributed to the neutral trial results in RELAX. Short-chain dicarboxylacylcarnitine metabolites and asparagine/aspartic acid could serve as biomarkers associated with adverse clinical outcomes in HFpEF. 10.1001/jamacardio.2017.1239
Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas: A Phase 2 Clinical Trial. JAMA oncology IMPORTANCE:There is a strong rationale for treating sarcomas with immunotherapy. OBJECTIVE:To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. DESIGN, SETTING, AND PARTICIPANTS:This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST). All patients received 50 mg twice daily cyclophosphamide 1 week on and 1 week off and 200 mg of intravenous pembrolizumab every 3 weeks. INTERVENTION OR EXPOSURE:Pembrolizumab in combination with metronomic cyclophosphamide. MAIN OUTCOMES AND MEASURES:There was a dual primary end point, encompassing both the nonprogression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for LMS, UPS, and others and 6-month nonprogression for GIST. An objective response rate of 20% and/or a 6-month nonprogression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from patient tumor and plasma samples. RESULTS:Between June 2015 and July 2016, 57 patients were included (median [range] age, 59.5 [18.5-84.0] years; 24 women [42%]); 50 patients were assessable for the efficacy end point. Three patients experienced tumor shrinkage, resulting in a partial response in a single solitary fibrous tumor. The 6-month nonprogression rates were 0%, 0%, 14.3% (95% CI, 1.8%-42.8%) for LMS, UPS, and others, respectively, and 11.1% (95% CI, 2.8%-48.3%) for GIST. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, and anemia. The only patient who experienced partial response was the only one with strong programmed cell death 1 ligand 1-positive staining in immune cell. Strong infiltration by macrophage expressing the inhibitory enzyme indoleamine 2,3-dioxygenase 1 (IDO1) was observed in the majority of cases. Moreover, a significant increase in the kynurenine to tryptophan ratio was observed in patient plasma samples during the study treatment. CONCLUSIONS AND RELEVANCE:We found that PD-1 inhibition has limited activity in selected STS and GIST. This may be explained by an immunosuppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT02406781. 10.1001/jamaoncol.2017.1617
Association of Ipilimumab With Safety and Antitumor Activity in Women With Metastatic or Recurrent Human Papillomavirus-Related Cervical Carcinoma. Lheureux Stephanie,Butler Marcus O,Clarke Blaise,Cristea Mihaela C,Martin Lainie P,Tonkin Katia,Fleming Gini F,Tinker Anna V,Hirte Hal W,Tsoref Daliah,Mackay Helen,Dhani Neesha C,Ghatage Prafull,Weberpals Johanne,Welch Stephen,Pham Nhu-An,Motta Vinicius,Sotov Valentin,Wang Lisa,Karakasis Katherine,Udagani Smitha,Kamel-Reid Suzanne,Streicher Howard Z,Shaw Patricia,Oza Amit M JAMA oncology Importance:Based on evidence of human papillomavirus (HPV)-induced immune evasion, immunotherapy may be an attractive strategy in cervical cancer. Ipilimumab is a fully humanized monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), which acts to downregulate the T-cell immune response. Objective:To assess the safety and antitumor activity of ipilimumab in recurrent cervical cancer. Design, Setting, and Participants:A multicenter trial was designed for patients with metastatic cervical cancer (squamous cell carcinoma or adenocarcinoma) with measurable disease and progression after at least 1 line of platinum chemotherapy. A run-in safety cohort using ipilimumab, 3 mg/kg, every 21 days for 4 cycles in 6 patients was followed by a phase II cohort of ipilimumab, 10 mg/kg, every 21 days for 4 cycles and then 4 cycles of maintenance therapy every 12 weeks for patients demonstrating radiologic response or stabilization. Immune correlative studies were performed on peripheral blood before and after therapy on archival tissue and fresh tumor obtained prior to registration and 7 days after cycle 2. The study was conducted from December 3, 2012, to September 15, 2014. The data were analyzed from April 2016 to June 2016 and in July 2017. Main Outcomes and Measures:The primary end points were safety and objective response rate. Immune analyses were performed on blood and tumor tissue. Results:A total of 42 women (median age, 49 years; range, 23-78 years) were enrolled (29 [69%] squamous cell cervical cancer and 13 [31%] adenocarcinoma; 37 [93%] of 40 patients with tissue available for analysis had HPV-positive confirmation; there was no archival tissue for 2 women). Grade 3 toxic effects included diarrhea in 4 patients, 3 of whom had colitis. Of 34 patients evaluated for best response (Response Evaluation Criteria in Solid Tumors, version 1.1), 1 patient had partial response and 10 had stable disease. The median progression-free survival and overall survival were 2.5 months (95% CI, 2.1-3.2 months) and 8.5 months (95% CI, 3.6-not reached; 1 patient was still alive), respectively. Intratumoral pretreatment CD3, CD4, CD8, FoxP3, indoleamine 2,3-dioxygenase, and programmed cell death ligand 1 (PD-L1) expression was not predictive of benefit and did not significantly change with treatment. Multicolor flow cytometry on peripheral lymphocytes revealed a treatment-dependent increase of inducible T-cell costimulator, human leukocyte antigen-antigen D related, and PD-1 during initial treatment, which returned to baseline during maintenance. Conclusions and Relevance:Ipilimumab was tolerable in this population but did not show significant single-agent activity. Immune changes were induced by anti-CTLA-4 therapy but did not correlate with clinical activity. Changes in these markers may guide further treatment strategies. 10.1001/jamaoncol.2017.3776
Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis. JAMA cardiology Importance:Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. Objective:To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. Design, Setting, and Participants:Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. Exposures:Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Main Outcomes and Measures:The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. Results:Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28). Conclusions and Relevance:The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA. 10.1001/jamacardio.2017.4293
Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial. Han Baohui,Li Kai,Wang Qiming,Zhang Li,Shi Jianhua,Wang Zhehai,Cheng Ying,He Jianxing,Shi Yuankai,Zhao Yizhuo,Yu Hao,Zhao Yang,Chen Weiqiang,Luo Yi,Wu Lin,Wang Xiuwen,Pirker Robert,Nan Kejun,Jin Faguang,Dong Jian,Li Baolan,Sun Yan JAMA oncology Importance:Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival, leading to the phase 3 trial to confirm the drug's efficacy in advanced non-small cell lung cancer (NSCLC). Objective:To investigate the efficacy of anlotinib on overall survival of patients with advanced NSCLC progressing after second-line or further treatment. Design, Setting, and Participants:The ALTER 0303 trial was a multicenter, double-blind, phase 3 randomized clinical trial designed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC. Patients from 31 grade-A tertiary hospitals in China were enrolled between March 1, 2015, and August 31, 2016. Those aged 18 to 75 years who had histologically or cytologically confirmed NSCLC were eligible (n = 606), and those who had centrally located squamous cell carcinoma with cavitary features or brain metastases that were uncontrolled or controlled for less than 2 months were excluded. Patients (n = 440) were randomly assigned in a 2-to-1 ratio to receive either 12 mg/d of anlotinib or a matched placebo. All cases were treated with study drugs at least once in accordance with the intention-to-treat principle. Main Outcomes and Measures:The primary end point was overall survival. The secondary end points were progression-free survival, objective response rate, disease control rate, quality of life, and safety. Results:In total, 439 patients were randomized, 296 to the anlotinib group (106 [36.1%] were female and 188 [64.0%] were male, with a mean [SD] age of 57.9 [9.1] years) and 143 to the placebo group (46 [32.2%] were female and 97 [67.8%] were male, with a mean [SD] age of 56.8 [9.1] years). Overall survival was significantly longer in the anlotinib group (median, 9.6 months; 95% CI, 8.2-10.6) than the placebo group (median, 6.3 months; 95% CI, 5.0-8.1), with a hazard ratio (HR) of 0.68 (95% CI, 0.54-0.87; P = .002). A substantial increase in progression-free survival was noted in the anlotinib group compared with the placebo group (median, 5.4 months [95% CI, 4.4-5.6] vs 1.4 months [95% CI, 1.1-1.5]; HR, 0.25 [95% CI, 0.19-0.31]; P < .001). Considerable improvement in objective response rate and disease control rate was observed in the anlotinib group over the placebo group. The most common grade 3 or higher adverse events in the anlotinib arm were hypertension and hyponatremia. Conclusions and Relevance:Among the Chinese patients in this trial, anlotinib appears to lead to prolonged overall survival and progression-free survival. This finding suggests that anlotinib is well tolerated and is a potential third-line or further therapy for patients with advanced NSCLC. Trial Registration:ClinicalTrials.gov identifier: NCT02388919. 10.1001/jamaoncol.2018.3039
Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer. Tie Jeanne,Cohen Joshua D,Wang Yuxuan,Christie Michael,Simons Koen,Lee Margaret,Wong Rachel,Kosmider Suzanne,Ananda Sumitra,McKendrick Joseph,Lee Belinda,Cho Jin Hee,Faragher Ian,Jones Ian T,Ptak Janine,Schaeffer Mary J,Silliman Natalie,Dobbyn Lisa,Li Lu,Tomasetti Cristian,Papadopoulos Nicholas,Kinzler Kenneth W,Vogelstein Bert,Gibbs Peter JAMA oncology Importance:Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers. Objective:To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer. Design, Setting, and Participants:This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019. Exposures:Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA. Main Outcomes and Measures:Detection of ctDNA and recurrence-free interval (RFI). Results:After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001). Conclusions and Relevance:Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches. 10.1001/jamaoncol.2019.3616
A Bibliometric Analysis of Top-Cited Journal Articles in Obstetrics and Gynecology. Brandt Justin S,Hadaya Ola,Schuster Meike,Rosen Todd,Sauer Mark V,Ananth Cande V JAMA network open Importance:Citation analysis is a bibliometric method that uses citation rates to evaluate research performance. This type of analysis can identify the articles that have shaped the modern history of obstetrics and gynecology (OBGYN). Objectives:To identify and characterize top-cited OBGYN articles in the Institute for Scientific Information Web of Science's Science Citation Index Expanded and to compare top-cited OBGYN articles published in specialty OBGYN journals with those published in nonspecialty journals. Design, Setting, and Participants:Cross-sectional bibliometric analysis of top-cited articles that were indexed in the Science Citation Index Expanded from 1980 to 2018. The Science Citation Index Expanded was queried using search terms from the American Board of Obstetrics and Gynecology's 2018 certifying examination topics list. The top 100 articles from all journals and the top 100 articles from OBGYN journals were evaluated for specific characteristics. Data were analyzed in March 2019. Main Outcomes and Measures:The articles were characterized by citation number, publication year, topic, study design, and authorship. After excluding articles that featured on both lists, top-cited articles were compared. Results:The query identified 3 767 874 articles, of which 278 846 (7.4%) were published in OBGYN journals. The top-cited article was published by Rossouw and colleagues in JAMA (2002). Top-cited articles published in nonspecialty journals were more frequently cited than those in OBGYN journals (median [interquartile range], 1738 [1490-2077] citations vs 666 [580-843] citations, respectively; P < .001) and were more likely to be randomized trials (25.0% vs 2.2%, respectively; difference, 22.8%; 95% CI, 13.5%-32.2%; P < .001). Whereas articles from nonspecialty journals focused on broad topics like osteoporosis, articles from OBGYN journal focused on topics like preeclampsia and endometriosis. Conclusions and Relevance:This study found substantial differences between top-cited OBGYN articles published in nonspecialty vs OBGYN journals. These differences may reflect the different goals of the journals, which work together to ensure optimal dissemination of impactful articles. 10.1001/jamanetworkopen.2019.18007
Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA Importance:There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). Objective:To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and Participants:Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). Exposures:Plasma P-tau217. Main Outcomes and Measures:Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). Results:Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22). Conclusions and Relevance:Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care. 10.1001/jama.2020.12134
Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. Wang Dawei,Hu Bo,Hu Chang,Zhu Fangfang,Liu Xing,Zhang Jing,Wang Binbin,Xiang Hui,Cheng Zhenshun,Xiong Yong,Zhao Yan,Li Yirong,Wang Xinghuan,Peng Zhiyong JAMA Importance:In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited. Objective:To describe the epidemiological and clinical characteristics of NCIP. Design, Setting, and Participants:Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020. Exposures:Documented NCIP. Main Outcomes and Measures:Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked. Results:Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 109/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0). Conclusions and Relevance:In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%. 10.1001/jama.2020.1585
Effect of C-Reactive Protein-Guided Antibiotic Treatment Duration, 7-Day Treatment, or 14-Day Treatment on 30-Day Clinical Failure Rate in Patients With Uncomplicated Gram-Negative Bacteremia: A Randomized Clinical Trial. von Dach Elodie,Albrich Werner C,Brunel Anne-Sophie,Prendki Virginie,Cuvelier Clémence,Flury Domenica,Gayet-Ageron Angèle,Huttner Benedikt,Kohler Philipp,Lemmenmeier Eva,McCallin Shawna,Rossel Anne,Harbarth Stephan,Kaiser Laurent,Bochud Pierre-Yves,Huttner Angela JAMA Importance:Antibiotic overuse drives antibiotic resistance. Gram-negative bacteremia is a common infection that results in substantial antibiotic use. Objective:To compare the clinical effectiveness of C-reactive protein (CRP)-guided, 7-day, and 14-day antibiotic durations 30, 60, and 90 days after treatment initiation. Design, Setting, and Participants:Multicenter, noninferiority, point-of-care randomized clinical trial including adults hospitalized with gram-negative bacteremia conducted in 3 Swiss tertiary care hospitals between April 2017 and May 2019, with follow-up until August 2019. Patients and physicians were blinded between randomization and antibiotic discontinuation. Adults (aged ≥18 years) were eligible for randomization on day 5 (±1 d) of microbiologically efficacious therapy for fermenting, gram-negative bacteria in blood culture(s) if they were afebrile for 24 hours without evidence for complicated infection (eg, abscess) or severe immunosuppression. Intervention:Randomization in a 1:1:1 ratio to an individualized CRP-guided antibiotic treatment duration (discontinuation once CRP declined by 75% from peak; n = 170), fixed 7-day treatment duration (n = 169), or fixed 14-day treatment duration (n = 165). Main Outcomes and Measures:The primary outcome was the clinical failure rate at day 30, defined as the presence of at least 1 of the following, with a non-inferiority margin of 10%: recurrent bacteremia, local suppurative complication, distant complication (growth of the same organism causing the initial bacteremia), restarting gram-negative-directed antibiotic therapy due to clinical worsening suspected to be due to the initial organism, or death due to any cause. Secondary outcomes included the clinical failure rate on day 90 of follow-up. Results:Among 504 patients randomized (median [interquartile range] age, 79 [68-86] years; 306 of 503 [61%] were women), 493 (98%) completed 30-day follow-up and 448 (89%) completed 90-day follow-up. Median antibiotic duration in the CRP group was 7 (interquartile range, 6-10; range, 5-28) days; 34 of the 164 patients (21%) who completed the 30-day follow-up had protocol violations related to treatment assignment. The primary outcome occurred in 4 of 164 (2.4%) patients in the CRP group, 11 of 166 (6.6%) in the 7-day group, and 9 of 163 (5.5%) in the 14-day group (difference in CRP vs 14-day group, -3.1% [1-sided 97.5% CI, -∞ to 1.1]; P < .001; difference in 7-day vs 14-day group, 1.1% [1-sided 97.5% CI, -∞ to 6.3]; P < .001). By day 90, clinical failure occurred in 10 of 143 patients (7.0%) in the CRP group, 16 of 151 (10.6%) in the 7-day group, and 16 of 153 (10.5%) in the 14-day group. Conclusions and Relevance:Among adults with uncomplicated gram-negative bacteremia, 30-day rates of clinical failure for CRP-guided antibiotic treatment duration and fixed 7-day treatment were noninferior to fixed 14-day treatment. However, interpretation is limited by the large noninferiority margin compared with the low observed event rate, as well as low adherence and wide range of treatment durations in the CRP-guided group. Trial Registration:ClinicalTrials.gov Identifier: NCT03101072. 10.1001/jama.2020.6348
Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA Importance:Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials. Objective:To test the effects of vitamin D3 supplementation on late-life depression risk and mood scores. Design, Setting, and Participants:There were 18 353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25 871 adults in the US. There were 16 657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up. Intervention:Randomized assignment in a 2 × 2 factorial design to vitamin D3 (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D3 and 9172 were randomized to matching placebo. Main Outcomes and Measures:The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points). Results:Among the 18 353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years) (hazard ratio, 0.97 [95% CI, 0.87 to 1.09]; P = .62); there were no significant differences between groups in depression incidence or recurrence. No significant differences were observed between treatment groups for change in mood scores over time; mean change in PHQ-8 score was not significantly different from zero (mean difference for change in mood scores, 0.01 points [95% CI, -0.04 to 0.05 points]). Conclusions and Relevance:Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D3 compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D3 in adults to prevent depression. Trial Registration:ClinicalTrials.gov Identifiers: NCT01169259 and NCT01696435. 10.1001/jama.2020.10224
Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial. JAMA Importance:Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds. Objective:To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability. Design, Setting, and Participants:Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018. Interventions:Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants' postnatal age and current health state. Main Outcome and Measures:The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth. Results:Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, -4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of -0.7% (95% CI, -4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, -3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of -1.3% (95% CI, -4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups. Conclusions and Relevance:Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age. Trial Registration:ClinicalTrials.gov Identifier: NCT01393496. 10.1001/jama.2020.10690
Effect of High Add Power, Medium Add Power, or Single-Vision Contact Lenses on Myopia Progression in Children: The BLINK Randomized Clinical Trial. Walline Jeffrey J,Walker Maria K,Mutti Donald O,Jones-Jordan Lisa A,Sinnott Loraine T,Giannoni Amber Gaume,Bickle Katherine M,Schulle Krystal L,Nixon Alex,Pierce Gilbert E,Berntsen David A, JAMA Importance:Slowing myopia progression could decrease the risk of sight-threatening complications. Objective:To determine whether soft multifocal contact lenses slow myopia progression in children, and whether high add power (+2.50 D) slows myopia progression more than medium (+1.50 D) add power lenses. Design, Setting, and Participants:A double-masked randomized clinical trial that took place at 2 optometry schools located in Columbus, Ohio, and Houston, Texas. A total of 294 consecutive eligible children aged 7 to 11 years with -0.75 D to -5.00 D of spherical component myopia and less than 1.00 D astigmatism were enrolled between September 22, 2014, and June 20, 2016. Follow-up was completed June 24, 2019. Interventions:Participants were randomly assigned to wear high add power (n = 98), medium add power (n = 98), or single-vision (n = 98) contact lenses. Main Outcomes and Measures:The primary outcome was the 3-year change in cycloplegic spherical equivalent autorefraction, as measured by the mean of 10 autorefraction readings. There were 11 secondary end points, 4 of which were analyzed for this study, including 3-year eye growth. Results:Among 294 randomized participants, 292 (99%) were included in the analyses (mean [SD] age, 10.3 [1.2] years; 177 [60.2%] were female; mean [SD] spherical equivalent refractive error, -2.39 [1.00] D). Adjusted 3-year myopia progression was -0.60 D for high add power, -0.89 D for medium add power, and -1.05 D for single-vision contact lenses. The difference in progression was 0.46 D (95% CI, 0.29-0.63) for high add power vs single vision, 0.30 D (95% CI, 0.13-0.47) for high add vs medium add power, and 0.16 D (95% CI, -0.01 to 0.33) for medium add power vs single vision. Of the 4 secondary end points, there were no statistically significant differences between the groups for 3 of the end points. Adjusted mean eye growth was 0.42 mm for high add power, 0.58 mm for medium add power, and 0.66 mm for single vision. The difference in eye growth was -0.23 mm (95% CI, -0.30 to -0.17) for high add power vs single vision, -0.16 mm (95% CI, -0.23 to -0.09) for high add vs medium add power, and -0.07 mm (95% CI, -0.14 to -0.01) for medium add power vs single vision. Conclusions and Relevance:Among children with myopia, treatment with high add power multifocal contact lenses significantly reduced the rate of myopia progression over 3 years compared with medium add power multifocal and single-vision contact lenses. However, further research is needed to understand the clinical importance of the observed differences. Trial Registration:ClinicalTrials.gov Identifier: NCT02255474. 10.1001/jama.2020.10834
Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial. Devereux Graham,Cotton Seonaidh,Fielding Shona,McMeekin Nicola,Barnes Peter J,Briggs Andrew,Burns Graham,Chaudhuri Rekha,Chrystyn Henry,Davies Lisa,De Soyza Anthony,Gompertz Simon,Haughney John,Innes Karen,Kaniewska Joanna,Lee Amanda,Morice Alyn,Norrie John,Sullivan Anita,Wilson Andrew,Price David JAMA Importance:Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective:To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants:The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions:Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures:The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results:Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance:Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration:isrctn.org Identifier: ISRCTN27066620. 10.1001/jama.2018.14432
Effect of Probiotic Use on Antibiotic Administration Among Care Home Residents: A Randomized Clinical Trial. Butler Christopher C,Lau Mandy,Gillespie David,Owen-Jones Eleri,Lown Mark,Wootton Mandy,Calder Philip C,Bayer Antony J,Moore Michael,Little Paul,Davies Jane,Edwards Alison,Shepherd Victoria,Hood Kerenza,Hobbs F D Richard,Davoudianfar Mina,Rutter Heather,Stanton Helen,Lowe Rachel,Fuller Richard,Francis Nick A JAMA Importance:Probiotics are frequently used by residents in care homes (residential homes or nursing homes that provide residents with 24-hour support for personal care or nursing care), although the evidence on whether probiotics prevent infections and reduce antibiotic use in these settings is limited. Objective:To determine whether a daily oral probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12 compared with placebo reduces antibiotic administration in care home residents. Design, Setting, and Participants:Placebo-controlled randomized clinical trial of 310 care home residents, aged 65 years and older, recruited from 23 care homes in the United Kingdom between December 2016 and May 2018, with last follow-up on October 31, 2018. Interventions:Study participants were randomized to receive a daily capsule containing a probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12 (total cell count per capsule, 1.3 × 1010 to 1.6 × 1010) (n = 155), or daily matched placebo (n = 155), for up to 1 year. Main Outcomes and Measures:The primary outcome was cumulative antibiotic administration days for all-cause infections measured from randomization for up to 1 year. Results:Among 310 randomized care home residents (mean age, 85.3 years; 66.8% women), 195 (62.9%) remained alive and completed the trial. Participant diary data (daily data including study product use, antibiotic administration, and signs of infection) were available for 98.7% randomized to the probiotic group and 97.4% randomized to placebo. Care home residents randomized to the probiotic group had a mean of 12.9 cumulative systemic antibiotic administration days (95% CI, 0 to 18.05), and residents randomized to placebo had a mean of 12.0 days (95% CI, 0 to 16.95) (absolute difference, 0.9 days [95% CI, -3.25 to 5.05]; adjusted incidence rate ratio, 1.13 [95% CI, 0.79 to 1.63]; P = .50). A total of 120 care home residents experienced 283 adverse events (150 adverse events in the probiotic group and 133 in the placebo group). Hospitalizations accounted for 94 of the events in probiotic group and 78 events in the placebo group, and deaths accounted for 33 of the events in the probiotic group and 32 of the events in the placebo group. Conclusions and Relevance:Among care home residents in the United Kingdom, a daily dose of a probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12 did not significantly reduce antibiotic administration for all-cause infections. These findings do not support the use of probiotics in this setting. Trial Registration:ISRCTN Identifier:16392920. 10.1001/jama.2020.8556
Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial. Gage Brian F,Bass Anne R,Lin Hannah,Woller Scott C,Stevens Scott M,Al-Hammadi Noor,Li Juan,Rodríguez Tomás,Miller J Philip,McMillin Gwendolyn A,Pendleton Robert C,Jaffer Amir K,King Cristi R,Whipple Brandi DeVore,Porche-Sorbet Rhonda,Napoli Lynnae,Merritt Kerri,Thompson Anna M,Hyun Gina,Anderson Jeffrey L,Hollomon Wesley,Barrack Robert L,Nunley Ryan M,Moskowitz Gerard,Dávila-Román Victor,Eby Charles S JAMA Importance:Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. Objective:To determine whether genotype-guided dosing improves the safety of warfarin initiation. Design, Setting, and Patients:The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions:Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. Main Outcomes and Measures:The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. Results:Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths. Conclusions and Relevance:Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing. Trial Registration:clinicaltrials.gov Identifier: NCT01006733. 10.1001/jama.2017.11469
Trends in Dietary Carbohydrate, Protein, and Fat Intake and Diet Quality Among US Adults, 1999-2016. JAMA Importance:Changes in the economy, nutrition policies, and food processing methods can affect dietary macronutrient intake and diet quality. It is essential to evaluate trends in dietary intake, food sources, and diet quality to inform policy makers. Objective:To investigate trends in dietary macronutrient intake, food sources, and diet quality among US adults. Design, Setting, and Participants:Serial cross-sectional analysis of the US nationally representative 24-hour dietary recall data from 9 National Health and Nutrition Examination Survey cycles (1999-2016) among adults aged 20 years or older. Exposure:Survey cycle. Main Outcomes and Measures:Dietary intake of macronutrients and their subtypes, food sources, and the Healthy Eating Index 2015 (range, 0-100; higher scores indicate better diet quality; a minimal clinically important difference has not been defined). Results:There were 43 996 respondents (weighted mean age, 46.9 years; 51.9% women). From 1999 to 2016, the estimated energy from total carbohydrates declined from 52.5% to 50.5% (difference, -2.02%; 95% CI, -2.41% to -1.63%), whereas that of total protein and total fat increased from 15.5% to 16.4% (difference, 0.82%; 95% CI, 0.67%-0.97%) and from 32.0% to 33.2% (difference, 1.20%; 95% CI, 0.84%-1.55%), respectively (all P < .001 for trend). Estimated energy from low-quality carbohydrates decreased by 3.25% (95% CI, 2.74%-3.75%; P < .001 for trend) from 45.1% to 41.8%. Increases were observed in estimated energy from high-quality carbohydrates (by 1.23% [95% CI, 0.84%-1.61%] from 7.42% to 8.65%), plant protein (by 0.38% [95% CI, 0.28%-0.49%] from 5.38% to 5.76%), saturated fatty acids (by 0.36% [95% CI, 0.20%-0.51%] from 11.5% to 11.9%), and polyunsaturated fatty acids (by 0.65% [95% CI, 0.56%-0.74%] from 7.58% to 8.23%) (all P < .001 for trend). The estimated overall Healthy Eating Index 2015 increased from 55.7 to 57.7 (difference, 2.01; 95% CI, 0.86-3.16; P < .001 for trend). Trends in high- and low-quality carbohydrates primarily reflected higher estimated energy from whole grains (0.65%) and reduced estimated energy from added sugars (-2.00%), respectively. Trends in plant protein were predominantly due to higher estimated intake of whole grains (0.12%) and nuts (0.09%). Conclusions and Relevance:From 1999 to 2016, US adults experienced a significant decrease in percentage of energy intake from low-quality carbohydrates and significant increases in percentage of energy intake from high-quality carbohydrates, plant protein, and polyunsaturated fat. Despite improvements in macronutrient composition and diet quality, continued high intake of low-quality carbohydrates and saturated fat remained. 10.1001/jama.2019.13771
Effect of Postextubation High-Flow Nasal Oxygen With Noninvasive Ventilation vs High-Flow Nasal Oxygen Alone on Reintubation Among Patients at High Risk of Extubation Failure: A Randomized Clinical Trial. Thille Arnaud W,Muller Grégoire,Gacouin Arnaud,Coudroy Rémi,Decavèle Maxens,Sonneville Romain,Beloncle François,Girault Christophe,Dangers Laurence,Lautrette Alexandre,Cabasson Séverin,Rouzé Anahita,Vivier Emmanuel,Le Meur Anthony,Ricard Jean-Damien,Razazi Keyvan,Barberet Guillaume,Lebert Christine,Ehrmann Stephan,Sabatier Caroline,Bourenne Jeremy,Pradel Gael,Bailly Pierre,Terzi Nicolas,Dellamonica Jean,Lacave Guillaume,Danin Pierre-Éric,Nanadoumgar Hodanou,Gibelin Aude,Zanre Lassane,Deye Nicolas,Demoule Alexandre,Maamar Adel,Nay Mai-Anh,Robert René,Ragot Stéphanie,Frat Jean-Pierre, JAMA Importance:High-flow nasal oxygen may prevent postextubation respiratory failure in the intensive care unit (ICU). The combination of high-flow nasal oxygen with noninvasive ventilation (NIV) may be an optimal strategy of ventilation to avoid reintubation. Objective:To determine whether high-flow nasal oxygen with prophylactic NIV applied immediately after extubation could reduce the rate of reintubation, compared with high-flow nasal oxygen alone, in patients at high risk of extubation failure in the ICU. Design, Setting, and Participants:Multicenter randomized clinical trial conducted from April 2017 to January 2018 among 641 patients at high risk of extubation failure (ie, older than 65 years or with an underlying cardiac or respiratory disease) at 30 ICUs in France; follow-up was until April 2018. Interventions:Patients were randomly assigned to high-flow nasal oxygen alone (n = 306) or high-flow nasal oxygen alternating with NIV (n = 342) immediately after extubation. Main Outcomes and Measures:The primary outcome was the proportion of patients reintubated at day 7; secondary outcomes included postextubation respiratory failure at day 7, reintubation rates up until ICU discharge, and ICU mortality. Results:Among 648 patients who were randomized (mean [SD] age, 70 [10] years; 219 women [34%]), 641 patients completed the trial. The reintubation rate at day 7 was 11.8% (95% CI, 8.4%-15.2%) (40/339) with high-flow nasal oxygen and NIV and 18.2% (95% CI, 13.9%-22.6%) (55/302) with high-flow nasal oxygen alone (difference, -6.4% [95% CI, -12.0% to -0.9%]; P = .02). Among the 11 prespecified secondary outcomes, 6 showed no significant difference. The proportion of patients with postextubation respiratory failure at day 7 (21% vs 29%; difference, -8.7% [95% CI, -15.2% to -1.8%]; P = .01) and reintubation rates up until ICU discharge (12% vs 20%, difference -7.4% [95% CI, -13.2% to -1.8%]; P = .009) were significantly lower with high-flow nasal oxygen and NIV than with high-flow nasal oxygen alone. ICU mortality rates were not significantly different: 6% with high-flow nasal oxygen and NIV and 9% with high-flow nasal oxygen alone (difference, -2.4% [95% CI, -6.7% to 1.7%]; P = .25). Conclusions and Relevance:In mechanically ventilated patients at high risk of extubation failure, the use of high-flow nasal oxygen with NIV immediately after extubation significantly decreased the risk of reintubation compared with high-flow nasal oxygen alone. Trial Registration:ClinicalTrials.gov Identifier: NCT03121482. 10.1001/jama.2019.14901
Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial. Schisterman Enrique F,Sjaarda Lindsey A,Clemons Traci,Carrell Douglas T,Perkins Neil J,Johnstone Erica,Lamb Denise,Chaney Kayla,Van Voorhis Bradley J,Ryan Ginny,Summers Karen,Hotaling Jim,Robins Jared,Mills James L,Mendola Pauline,Chen Zhen,DeVilbiss Elizabeth A,Peterson C Matthew,Mumford Sunni L JAMA Importance:Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. Objective:To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth. Design, Setting, and Participants:The Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019. Interventions:Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months. Main Outcomes and Measures:The co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. Results:Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, -0.9% [95% CI, -4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]). Conclusions and Relevance:Among a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples' live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility. Trial Registration:ClinicalTrials.gov Identifier: NCT01857310. 10.1001/jama.2019.18714
Effect of Home Noninvasive Ventilation With Oxygen Therapy vs Oxygen Therapy Alone on Hospital Readmission or Death After an Acute COPD Exacerbation: A Randomized Clinical Trial. Murphy Patrick B,Rehal Sunita,Arbane Gill,Bourke Stephen,Calverley Peter M A,Crook Angela M,Dowson Lee,Duffy Nicholas,Gibson G John,Hughes Philip D,Hurst John R,Lewis Keir E,Mukherjee Rahul,Nickol Annabel,Oscroft Nicholas,Patout Maxime,Pepperell Justin,Smith Ian,Stradling John R,Wedzicha Jadwiga A,Polkey Michael I,Elliott Mark W,Hart Nicholas JAMA Importance:Outcomes after exacerbations of chronic obstructive pulmonary disease (COPD) requiring acute noninvasive ventilation (NIV) are poor and there are few treatments to prevent hospital readmission and death. Objective:To investigate the effect of home NIV plus oxygen on time to readmission or death in patients with persistent hypercapnia after an acute COPD exacerbation. Design, Setting, and Participants:A randomized clinical trial of patients with persistent hypercapnia (Paco2 >53 mm Hg) 2 weeks to 4 weeks after resolution of respiratory acidemia, who were recruited from 13 UK centers between 2010 and 2015. Exclusion criteria included obesity (body mass index [BMI] >35), obstructive sleep apnea syndrome, or other causes of respiratory failure. Of 2021 patients screened, 124 were eligible. Interventions:There were 59 patients randomized to home oxygen alone (median oxygen flow rate, 1.0 L/min [interquartile range {IQR}, 0.5-2.0 L/min]) and 57 patients to home oxygen plus home NIV (median oxygen flow rate, 1.0 L/min [IQR, 0.5-1.5 L/min]). The median home ventilator settings were an inspiratory positive airway pressure of 24 (IQR, 22-26) cm H2O, an expiratory positive airway pressure of 4 (IQR, 4-5) cm H2O, and a backup rate of 14 (IQR, 14-16) breaths/minute. Main Outcomes and Measures:Time to readmission or death within 12 months adjusted for the number of previous COPD admissions, previous use of long-term oxygen, age, and BMI. Results:A total of 116 patients (mean [SD] age of 67 [10] years, 53% female, mean BMI of 21.6 [IQR, 18.2-26.1], mean [SD] forced expiratory volume in the first second of expiration of 0.6 L [0.2 L], and mean [SD] Paco2 while breathing room air of 59 [7] mm Hg) were randomized. Sixty-four patients (28 in home oxygen alone and 36 in home oxygen plus home NIV) completed the 12-month study period. The median time to readmission or death was 4.3 months (IQR, 1.3-13.8 months) in the home oxygen plus home NIV group vs 1.4 months (IQR, 0.5-3.9 months) in the home oxygen alone group, adjusted hazard ratio of 0.49 (95% CI, 0.31-0.77; P = .002). The 12-month risk of readmission or death was 63.4% in the home oxygen plus home NIV group vs 80.4% in the home oxygen alone group, absolute risk reduction of 17.0% (95% CI, 0.1%-34.0%). At 12 months, 16 patients had died in the home oxygen plus home NIV group vs 19 in the home oxygen alone group. Conclusions and Relevance:Among patients with persistent hypercapnia following an acute exacerbation of COPD, adding home noninvasive ventilation to home oxygen therapy prolonged the time to readmission or death within 12 months. Trial Registration:clinicaltrials.gov Identifier: NCT00990132. 10.1001/jama.2017.4451
Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial. JAMA Importance:Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. Objective:To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. Design, Setting, and Participants:This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). Interventions:Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. Main Outcomes and Measures:The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. Results:The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Conclusions and Relevance:Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. Trial Registration:ClinicalTrials.gov Identifier: NCT01307579. 10.1001/jama.2019.15702
Effect of Vericiguat vs Placebo on Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The VITALITY-HFpEF Randomized Clinical Trial. Armstrong Paul W,Lam Carolyn S P,Anstrom Kevin J,Ezekowitz Justin,Hernandez Adrian F,O'Connor Christopher M,Pieske Burkert,Ponikowski Piotr,Shah Sanjiv J,Solomon Scott D,Voors Adriaan A,She Lilin,Vlajnic Vanja,Carvalho Francine,Bamber Luke,Blaustein Robert O,Roessig Lothar,Butler Javed, JAMA Importance:Patients with heart failure and preserved ejection fraction (HFpEF) are at high risk of mortality, hospitalizations, and reduced functional capacity and quality of life. Objective:To assess the efficacy of the oral soluble guanylate cyclase stimulator vericiguat on the physical limitation score (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ). Design, Setting, and Participants:Phase 2b randomized, double-blind, placebo-controlled, multicenter trial of 789 patients with chronic HFpEF and left ventricular ejection fraction 45% or higher with New York Heart Association class II-III symptoms, within 6 months of a recent decompensation (HF hospitalization or intravenous diuretics for HF without hospitalization), and with elevated natriuretic peptides, enrolled at 167 sites in 21 countries from June 15, 2018, through March 27, 2019; follow-up was completed on November 4, 2019. Interventions:Patients were randomized to receive vericiguat, up-titrated to 15-mg (n = 264) or 10-mg (n = 263) daily oral dosages, compared with placebo (n = 262) and randomized 1:1:1. Main Outcomes and Measures:The primary outcome was change in the KCCQ PLS (range, 0-100; higher values indicate better functioning) after 24 weeks of treatment. The secondary outcome was 6-minute walking distance from baseline to 24 weeks. Results:Among 789 randomized patients, the mean age was 72.7 (SD, 9.4) years; 385 (49%) were female; mean EF was 56%; and median N-terminal pro-brain natriuretic peptide level was 1403 pg/mL; 761 (96.5%) completed the trial. The baseline and 24-week KCCQ PLS means for the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 60.0 and 68.3, 57.3 and 69.0, and 59.0 and 67.1, respectively, and the least-squares mean changes were 5.5, 6.4, and 6.9, respectively. The least-squares mean difference in scores between the 15-mg/d vericiguat and placebo groups was -1.5 (95% CI, -5.5 to 2.5; P = .47) and between the 10-mg/d vericiguat and placebo groups was -0.5 (95% CI, -4.6 to 3.5; P = .80). The baseline and 24-week 6-minute walking distance mean scores in the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 295.0 m and 311.8m , 292.1 m and 318.3 m, and 295.8 m and 311.4 m, and the least-squares mean changes were 5.0 m, 8.7 m, and 10.5 m, respectively. The least-squares mean difference between the 15-mg/d vericiguat and placebo groups was -5.5 m (95% CI, -19.7 m to 8.8 m; P = .45) and between the 10-mg/d vericiguat and placebo groups was -1.8 m (95% CI, -16.2 m to 12.6 m; P = .81), respectively. The proportions of patients who experienced symptomatic hypotension were 6.4% in the 15-mg/d vericiguat group, 4.2% in the 10-mg/d vericiguat group, and 3.4% in the placebo group; those with syncope were 1.5%, 0.8%, and 0.4%, respectively. Conclusions and Relevance:Among patients with HFpEF and recent decompensation, 24-week treatment with vericiguat at either 15-mg/d or 10-mg/d dosages compared with placebo did not improve the physical limitation score of the KCCQ. Trial Registration:ClinicalTrials.gov Identifier: NCT03547583. 10.1001/jama.2020.15922
Derivation and External Validation of Prediction Models for Advanced Chronic Kidney Disease Following Acute Kidney Injury. James Matthew T,Pannu Neesh,Hemmelgarn Brenda R,Austin Peter C,Tan Zhi,McArthur Eric,Manns Braden J,Tonelli Marcello,Wald Ron,Quinn Robert R,Ravani Pietro,Garg Amit X JAMA Importance:Some patients will develop chronic kidney disease after a hospitalization with acute kidney injury; however, no risk-prediction tools have been developed to identify high-risk patients requiring follow-up. Objective:To derive and validate predictive models for progression of acute kidney injury to advanced chronic kidney disease. Design, Setting, and Participants:Data from 2 population-based cohorts of patients with a prehospitalization estimated glomerular filtration rate (eGFR) of more than 45 mL/min/1.73 m2 and who had survived hospitalization with acute kidney injury (defined by a serum creatinine increase during hospitalization > 0.3 mg/dL or > 50% of their prehospitalization baseline), were used to derive and validate multivariable prediction models. The risk models were derived from 9973 patients hospitalized in Alberta, Canada (April 2004-March 2014, with follow-up to March 2015). The risk models were externally validated with data from a cohort of 2761 patients hospitalized in Ontario, Canada (June 2004-March 2012, with follow-up to March 2013). Exposures:Demographic, laboratory, and comorbidity variables measured prior to discharge. Main Outcomes and Measures:Advanced chronic kidney disease was defined by a sustained reduction in eGFR less than 30 mL/min/1.73 m2 for at least 3 months during the year after discharge. All participants were followed up for up to 1 year. Results:The participants (mean [SD] age, 66 [15] years in the derivation and internal validation cohorts and 69 [11] years in the external validation cohort; 40%-43% women per cohort) had a mean (SD) baseline serum creatinine level of 1.0 (0.2) mg/dL and more than 20% had stage 2 or 3 acute kidney injury. Advanced chronic kidney disease developed in 408 (2.7%) of 9973 patients in the derivation cohort and 62 (2.2%) of 2761 patients in the external validation cohort. In the derivation cohort, 6 variables were independently associated with the outcome: older age, female sex, higher baseline serum creatinine value, albuminuria, greater severity of acute kidney injury, and higher serum creatinine value at discharge. In the external validation cohort, a multivariable model including these 6 variables had a C statistic of 0.81 (95% CI, 0.75-0.86) and improved discrimination and reclassification compared with reduced models that included age, sex, and discharge serum creatinine value alone (integrated discrimination improvement, 2.6%; 95% CI, 1.1%-4.0%; categorical net reclassification index, 13.5%; 95% CI, 1.9%-25.1%) or included age, sex, and acute kidney injury stage alone (integrated discrimination improvement, 8.0%; 95% CI, 5.1%-11.0%; categorical net reclassification index, 79.9%; 95% CI, 60.9%-98.9%). Conclusions and Relevance:A multivariable model using routine laboratory data was able to predict advanced chronic kidney disease following hospitalization with acute kidney injury. The utility of this model in clinical care requires further research. 10.1001/jama.2017.16326
Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. Fowler Alpha A,Truwit Jonathon D,Hite R Duncan,Morris Peter E,DeWilde Christine,Priday Anna,Fisher Bernard,Thacker Leroy R,Natarajan Ramesh,Brophy Donald F,Sculthorpe Robin,Nanchal Rahul,Syed Aamer,Sturgill Jamie,Martin Greg S,Sevransky Jonathan,Kashiouris Markos,Hamman Stella,Egan Katherine F,Hastings Andrei,Spencer Wendy,Tench Shawnda,Mehkri Omar,Bindas James,Duggal Abhijit,Graf Jeanette,Zellner Stephanie,Yanny Lynda,McPolin Catherine,Hollrith Tonya,Kramer David,Ojielo Charles,Damm Tessa,Cassity Evan,Wieliczko Aleksandra,Halquist Matthew JAMA Importance:Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective:To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants:The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions:Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures:The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results:Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours. Conclusions and Relevance:In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration:ClinicalTrials.gov Identifier: NCT02106975. 10.1001/jama.2019.11825
Effect of Vitamin D and Omega-3 Fatty Acid Supplementation on Kidney Function in Patients With Type 2 Diabetes: A Randomized Clinical Trial. de Boer Ian H,Zelnick Leila R,Ruzinski John,Friedenberg Georgina,Duszlak Julie,Bubes Vadim Y,Hoofnagle Andrew N,Thadhani Ravi,Glynn Robert J,Buring Julie E,Sesso Howard D,Manson JoAnn E JAMA Importance:Chronic kidney disease (CKD) is a common complication of type 2 diabetes that can lead to end-stage kidney disease and is associated with high cardiovascular risk. Few treatments are available to prevent CKD in type 2 diabetes. Objective:To test whether supplementation with vitamin D3 or omega-3 fatty acids prevents development or progression of CKD in type 2 diabetes. Design, Setting, and Participants:Randomized clinical trial with a 2 × 2 factorial design conducted among 1312 adults with type 2 diabetes recruited between November 2011 and March 2014 from all 50 US states as an ancillary study to the Vitamin D and Omega-3 Trial (VITAL), coordinated by a single center in Massachusetts. Follow-up was completed in December 2017. Interventions:Participants were randomized to receive vitamin D3 (2000 IU/d) and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; 1 g/d) (n = 370), vitamin D3 and placebo (n = 333), placebo and omega-3 fatty acids (n = 289), or 2 placebos (n = 320) for 5 years. Main Outcomes and Measures:The primary outcome was change in glomerular filtration rate estimated from serum creatinine and cystatin C (eGFR) from baseline to year 5. Results:Among 1312 participants randomized (mean age, 67.6 years; 46% women; 31% of racial or ethnic minority), 934 (71%) completed the study. Baseline mean eGFR was 85.8 (SD, 22.1) mL/min/1.73 m2. Mean change in eGFR from baseline to year 5 was -12.3 (95% CI, -13.4 to -11.2) mL/min/1.73 m2 with vitamin D3 vs -13.1 (95% CI, -14.2 to -11.9) mL/min/1.73 m2 with placebo (difference, 0.9 [95% CI, -0.7 to 2.5] mL/min/1.73 m2). Mean change in eGFR was -12.2 (95% CI, -13.3 to -11.1) mL/min/1.73 m2 with omega-3 fatty acids vs -13.1 (95% CI, -14.2 to -12.0) mL/min/1.73 m2 with placebo (difference, 0.9 [95% CI, -0.7 to 2.6] mL/min/1.73 m2). There was no significant interaction between the 2 interventions. Kidney stones occurred among 58 participants (n = 32 receiving vitamin D3 and n = 26 receiving placebo) and gastrointestinal bleeding among 45 (n = 28 receiving omega-3 fatty acids and n = 17 receiving placebo). Conclusions and Relevance:Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years. The findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes. Trial Registration:ClinicalTrials.gov Identifier: NCT01684722. 10.1001/jama.2019.17380
Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels: The VDKA Randomized Clinical Trial. Forno Erick,Bacharier Leonard B,Phipatanakul Wanda,Guilbert Theresa W,Cabana Michael D,Ross Kristie,Covar Ronina,Gern James E,Rosser Franziska J,Blatter Joshua,Durrani Sandy,Han Yueh-Ying,Wisniewski Stephen R,Celedón Juan C JAMA Importance:Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3 supplementation reduces severe childhood asthma exacerbations is unclear. Objective:To determine whether vitamin D3 supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels. Design, Setting, and Participants:The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019. Interventions:Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old). Main Outcomes and Measures:The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial. Results:Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3 group vs 253 days in the placebo group (mean group difference, -13.1 days [95% CI, -42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85]; P = .63). Vitamin D3 supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group, n = 11; placebo group, n = 9). Conclusions and Relevance:Among children with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3 supplementation to prevent severe asthma exacerbations in this group of patients. Trial Registration:ClinicalTrials.gov Identifier: NCT02687815. 10.1001/jama.2020.12384