Showing papers by "Karolinska Institutet published in 2021"
Daniel J. Klionsky1, Amal Kamal Abdel-Aziz2, Sara Abdelfatah3, Mahmoud Abdellatif4 +2980 more•Institutions (777)
TL;DR: In this article, the authors present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes.
Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
1,129 citations
TL;DR: In this article, a systematic review and meta-analysis aimed to identify studies assessing the long-term effects of COVID-19, which can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery.
Abstract: COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery. This systematic review and meta-analysis aims to identify studies assessing the long-term effects of COVID-19. LitCOVID and Embase were searched to identify articles with original data published before the 1st of January 2021, with a minimum of 100 patients. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. PRISMA guidelines were followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included (age 17–87 years). The included studies defined long-COVID as ranging from 14 to 110 days post-viral infection. It was estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.
969 citations
Erola Pairo-Castineira1, Erola Pairo-Castineira2, Sara Clohisey1, Lucija Klaric2 +1446 more•Institutions (27)
TL;DR: The GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2244 critically ill Covid-19 patients from 208 UK intensive care units is reported, finding evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease.
Abstract: Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice. A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.
941 citations
Harvard University1, State University of New York System2, French Institute of Health and Medical Research3, University of Toronto4, University of Texas Southwestern Medical Center5, Vanderbilt University6, Oregon Health & Science University7, University of Brescia8, Karolinska Institutet9, University of Paris10, Yale University11, Georgetown University12, Wrocław Medical University13, Duke University14, Lexicon Pharmaceuticals15, University of Michigan16
TL;DR: In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo.
Abstract: Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failu...
913 citations
King's College London1, University of Padua2, Karolinska Institutet3, University of Ferrara4, University of Pavia5, Hospital General Universitario Gregorio Marañón6, Yonsei University7, University College London8, University of Cambridge9, National Health Service10, Deakin University11, University of Toronto12
TL;DR: In this article, the authors conducted a systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015).
Abstract: Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes. However, the range and peak ages at onset for mental disorders are not fully established. To provide robust, global epidemiological estimates of age at onset for mental disorders, we conducted a PRISMA/MOOSE-compliant systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders, identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015). Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks. Median age at onset of specific disorders was additionally investigated. Across 192 studies (n = 708,561) included, the proportion of individuals with onset of any mental disorders before the ages of 14, 18, 25 were 34.6%, 48.4%, 62.5%, and peak age was 14.5 years (k = 14, median = 18, interquartile range (IQR) = 11-34). For diagnostic blocks, the proportion of individuals with onset of disorder before the age of 14, 18, 25 and peak age were as follows: neurodevelopmental disorders: 61.5%, 83.2%, 95.8%, 5.5 years (k = 21, median=12, IQR = 7-16), anxiety/fear-related disorders: 38.1%, 51.8%, 73.3%, 5.5 years (k = 73, median = 17, IQR = 9-25), obsessive-compulsive/related disorders: 24.6%, 45.1%, 64.0%, 14.5 years (k = 20, median = 19, IQR = 14-29), feeding/eating disorders/problems: 15.8%, 48.1%, 82.4%, 15.5 years (k = 11, median = 18, IQR = 15-23), conditions specifically associated with stress disorders: 16.9%, 27.6%, 43.1%, 15.5 years (k = 16, median = 30, IQR = 17-48), substance use disorders/addictive behaviours: 2.9%, 15.2%, 48.8%, 19.5 years (k = 58, median = 25, IQR = 20-41), schizophrenia-spectrum disorders/primary psychotic states: 3%, 12.3%, 47.8%, 20.5 years (k = 36, median = 25, IQR = 20-34), personality disorders/related traits: 1.9%, 9.6%, 47.7%, 20.5 years (k = 6, median = 25, IQR = 20-33), and mood disorders: 2.5%, 11.5%, 34.5%, 20.5 years (k = 79, median = 31, IQR = 21-46). No significant difference emerged by sex, or definition of age of onset. Median age at onset for specific mental disorders mapped on a time continuum, from phobias/separation anxiety/autism spectrum disorder/attention deficit hyperactivity disorder/social anxiety (8-13 years) to anorexia nervosa/bulimia nervosa/obsessive-compulsive/binge eating/cannabis use disorders (17-22 years), followed by schizophrenia, personality, panic and alcohol use disorders (25-27 years), and finally post-traumatic/depressive/generalized anxiety/bipolar/acute and transient psychotic disorders (30-35 years), with overlap among groups and no significant clustering. These results inform the timing of good mental health promotion/preventive/early intervention, updating the current mental health system structured around a child/adult service schism at age 18.
537 citations
TL;DR: It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more symptoms, and there is a need for studies to stratify by sex, age, previous comorbidities, severity of COVID-19 (including asymptomatic), and duration of each symptom.
Abstract: Background: COVID-19, caused by SARS-CoV-2, can involve sequelae that last weeks to months after initial recovery. The objective of this systematic review and meta-analysis is to identify studies assessing the long-term effects of COVID-19 and estimate the prevalence of each symptom, sign, or laboratory parameters of patients at a post-COVID-19 stage.
Methods: In this systematic review and meta-analysis, LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. Studies published before 1st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using the I2 statistics. PRISMA guidelines were followed.
Findings: A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 15 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). In order to have a better understanding, there is a need for studies to stratify by sex, age, previous comorbidities, severity of COVID-19 (including asymptomatic), and duration of each symptom.
Interpretation: From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address after-COVID-19 care.
Funding: National Institute for Neurological Disorders and Stroke (NINDS), and Houston Methodist Research Institute, Houston, TX.
Declaration of Interests: SLL is an employee of Novartis Pharmaceutical Company; the statements presented in the paper do not necessarily represent the position of the company. The remaining authors have no competing interests to declare.
438 citations
Centre for Mental Health1, Swansea University2, University of Sydney3, University of Manchester4, University College Cork5, Griffith University6, Stellenbosch University7, Sao Paulo State University8, University of Zagreb9, University of Rochester Medical Center10, University of Udine11, National Taiwan University12, Innsbruck Medical University13, Yale University14, Australian National University15, Johns Hopkins University16, Brigham and Women's Hospital17, University of Auckland18, Hobart Corporation19, Columbia University Medical Center20, University of Oxford21, National Institute for Health Research22, Aga Khan University23, Katholieke Universiteit Leuven24, University of Bristol25, University of Peradeniya26, World Health Organization27, Karolinska Institutet28, First Pavlov State Medical University of St. Peterburg29, Medical University of Vienna30, University of Nottingham31, University of Glasgow32, University of Edinburgh33, Shanghai Jiao Tong University34, Columbia University35, University of Ulm36, University of Oslo37, Goethe University Frankfurt38, Saint Petersburg State University39, University of Toronto40, Sunnybrook Health Sciences Centre41, Waseda University42, Rajarata University of Sri Lanka43, Tel Aviv University44, University Hospitals Bristol NHS Foundation Trust45
TL;DR: In this article, the early effect of the COVID-19 pandemic on suicide rates around the world was assessed using real-time suicide data from countries or areas within countries through a systematic internet search and recourse to our networks and the published literature.
413 citations
TL;DR: In this article, the authors combined single-cell transcriptomics analysis with spatial antibody-based protein profiling to create a high-resolution singlecell type map of human tissues, which was used to explore the expression of human protein-coding genes in 192 individual cell type clusters.
Abstract: Advances in molecular profiling have opened up the possibility to map the expression of genes in cells, tissues, and organs in the human body. Here, we combined single-cell transcriptomics analysis with spatial antibody-based protein profiling to create a high-resolution single–cell type map of human tissues. An open access atlas has been launched to allow researchers to explore the expression of human protein-coding genes in 192 individual cell type clusters. An expression specificity classification was performed to determine the number of genes elevated in each cell type, allowing comparisons with bulk transcriptomics data. The analysis highlights distinct expression clusters corresponding to cell types sharing similar functions, both within the same organs and between organs.
384 citations
Niamh Mullins1, Andreas J. Forstner2, Andreas J. Forstner3, Andreas J. Forstner4 +396 more•Institutions (119)
TL;DR: The authors performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci, including genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics.
Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
378 citations
Lund University1, University of Gothenburg2, Karolinska Institutet3, Linköping University4, University of Southern Denmark5, University Hospital of Wales6, University Hospital of Lausanne7, University of Paris8, First Faculty of Medicine, Charles University in Prague9, Norwegian University of Science and Technology10
TL;DR: In this article, targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty, and an open-label trial with blinded asymptotics was conducted.
Abstract: Background Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. Methods In an open-label trial with blinded as...
371 citations
Liverpool School of Tropical Medicine1, Kenyatta University2, University of London3, University of Tübingen4, Karolinska Institutet5, Lusaka Apex Medical University6, Zambian Ministry of Health7, Muhimbili University of Health and Allied Sciences8, National Institute for Medical Research9, Indian Institute of Technology Delhi10, Stellenbosch University11, University of Maryland, Baltimore12, University of Cape Coast13, University of Pittsburgh14, Johns Hopkins University15, University of Cape Town16, Queen Mary University of London17, Barts Health NHS Trust18, University College London19
TL;DR: In 2019, TB remained the most common cause of death from a single infectious pathogen globally, and an estimated 10.0 million people developed TB disease in 2019, and there were an estimated 1.2 million TB deaths among HIV-negative people and an additional 208, 000 deaths among people living with HIV as discussed by the authors.
University of Michigan1, Cornell University2, University of Pennsylvania3, University of Massachusetts Medical School4, University of Naples Federico II5, Baylor College of Medicine6, Spanish National Research Council7, Complutense University of Madrid8, New York University9, University of Rome Tor Vergata10, Boston Children's Hospital11, NewYork–Presbyterian Hospital12, University of Pittsburgh13, University of Paris14, French Institute of Health and Medical Research15, National University of Cuyo16, Albert Einstein College of Medicine17, University of New Mexico18, Goethe University Frankfurt19, Weizmann Institute of Science20, University of Turku21, Sapienza University of Rome22, Virginia Commonwealth University23, St. Jude Children's Research Hospital24, Discovery Institute25, University of Copenhagen26, University of Tromsø27, Eötvös Loránd University28, Merck & Co.29, University of Freiburg30, Babraham Institute31, University of South Australia32, University of Adelaide33, University of Oviedo34, University of Chicago35, University of Graz36, National Institutes of Health37, Queens College38, City University of New York39, University of Tokyo40, University of Zurich41, Austrian Academy of Sciences42, University of British Columbia43, University of California, San Francisco44, Russian Academy of Sciences45, University Medical Center Groningen46, University of Cambridge47, University of Glasgow48, Rutgers University49, University of Padua50, University of Bern51, Kazan Federal University52, University of Oxford53, University of Oslo54, Oslo University Hospital55, Foundation for Research & Technology – Hellas56, University of Crete57, Francis Crick Institute58, Osaka University59, Harvard University60, Chinese Academy of Sciences61, Icahn School of Medicine at Mount Sinai62, Shanghai Jiao Tong University63, Karolinska Institutet64
TL;DR: In this paper, preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
Abstract: Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
University Medical Center Groningen1, European Bioinformatics Institute2, Netherlands Cancer Institute3, Georgia Institute of Technology4, Leipzig University5, Johns Hopkins University6, NHS Blood and Transplant7, University of Cambridge8, Garvan Institute of Medical Research9, University of Tartu10, Ontario Institute for Cancer Research11, University of Washington12, Public Health Research Institute13, University of Chicago14, Greifswald University Hospital15, Ludwig Maximilian University of Munich16, University of Bristol17, Erasmus University Rotterdam18, University of Westminster19, Luleå University of Technology20, Royal Devon and Exeter Hospital21, Swiss Institute of Bioinformatics22, University of Lausanne23, University of Dundee24, University of Geneva25, Agency for Science, Technology and Research26, University of Queensland27, Leiden University Medical Center28, Radboud University Nijmegen29, University of Liège30, University of Oxford31, Menzies Research Institute32, Icahn School of Medicine at Mount Sinai33, Ikerbasque34, VU University Amsterdam35, Stanford University36, Turku University Hospital37, University of Turku38, Maastricht University39, Karolinska Institutet40, Utrecht University41, University of Helsinki42, National Institutes of Health43, Technische Universität München44, Wellcome Trust Sanger Institute45, German Cancer Research Center46, Westlake University47, University of New South Wales48
TL;DR: In this article, the authors performed cis-and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium.
Abstract: Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
University of Utah1, University of Colorado Denver2, Oregon Health & Science University3, Harvard University4, University of California, San Diego5, University of Texas Health Science Center at Houston6, Medical College of Wisconsin7, Medical University of South Carolina8, Northwestern University9, Emory University10, University of Pennsylvania11, University of São Paulo12, Ghent University13, Sun Yat-sen University14, Karolinska Institutet15, University of Chicago16, Rush University Medical Center17, University of Barcelona18, University of California, Los Angeles19, Vanderbilt University20, University of Arizona21, University of Kansas22, Université de Montréal23, University of Auckland24, Rutgers University25, University of Amsterdam26, Columbia University27, Eastern Virginia Medical School28, University of New South Wales29, Katholieke Universiteit Leuven30, Guy's Hospital31, Stanford University32, University of British Columbia33, Mayo Clinic34, Johns Hopkins University35, Korea University36, Uniformed Services University of the Health Sciences37, Jikei University School of Medicine38, University of Washington39, University of Siena40, University of East Anglia41, University of Adelaide42, Pusan National University43, University of Calgary44, University of Cincinnati45, University of North Carolina at Chapel Hill46, Cleveland Clinic47, University of Winnipeg48, Chulalongkorn University49, Cornell University50, National University of Singapore51, University of Alabama at Birmingham52, University of Alberta53, Capital Medical University54
TL;DR: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in the understanding and treatment of rhinologic disease.
Abstract: I. Executive summary BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document. Methods ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided. Conclusion This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.
State University of New York Upstate Medical University1, Heidelberg University2, University of Melbourne3, Capital Medical University4, Harvard University5, Monash University, Clayton campus6, Icahn School of Medicine at Mount Sinai7, Montreal Children's Hospital8, Universidade Federal do Rio Grande do Sul9, Peking University10, University of Southampton11, University of Toronto12, University of Washington13, King Khalid University14, King's College London15, Aga Khan University16, Karolinska Institutet17, Radboud University Nijmegen18, Vrije Universiteit Brussel19, University of Nottingham20, Aarhus University21, University of Cologne22, Trinity College, Dublin23, University of Würzburg24, University of Bergen25, University Medical Center Groningen26, University of Wyoming27, University of California, Berkeley28, University of California, San Francisco29, Nottinghamshire Healthcare NHS Foundation Trust30, Duke University31, University of Amsterdam32, Örebro University33, Chongqing Medical University34, Tel Aviv University35, Washington University in St. Louis36, Federal University of Rio de Janeiro37, University College Cork38, University of British Columbia39, University of Pittsburgh40, Oregon Health & Science University41, University of Montpellier42, University of Ibadan43, University of São Paulo44, Hebrew University of Jerusalem45, University of Sydney46, Jawaharlal Institute of Postgraduate Medical Education and Research47, University of Canterbury48, Autonomous University of Barcelona49, Stellenbosch University50, University of California, Davis51, National Medical College52, Hofstra University53, University of Texas Health Science Center at Houston54, University of Southern Denmark55, University of California, Irvine56, Cardiff University57, Okinawa Institute of Science and Technology58, HU University of Applied Sciences Utrecht59, Katholieke Universiteit Leuven60, University of the Free State61, Johns Hopkins University62, University of Turin63, University of Zurich64
TL;DR: In this article, the authors presented 208 empirically supported statements about ADHD using meta-analysis, which allow for firm statements about the nature, course, outcome causes and treatments for disorders that are useful for reducing misconceptions and stigma.
University of Groningen1, Erasmus University Rotterdam2, Katholieke Universiteit Leuven3, Chinese Academy of Sciences4, University of Surrey5, King's College London6, University of Toronto7, Avera Health8, Karolinska Institutet9, University of Copenhagen10, University of Greifswald11, University of Kiel12, Yeshiva University13, Sungkyunkwan University14, University of Tartu15, Weizmann Institute of Science16, Copenhagen University Hospital17, University of Texas Health Science Center at Houston18, University of Alabama at Birmingham19, Stockholm University20, University of Michigan21, VU University Amsterdam22, University of Oxford23, University of Bristol24, University of Amsterdam25, Maastricht University26, University of California, San Diego27, University of Eastern Finland28, National Institutes of Health29, University of California, Los Angeles30, Linköping University31, Harvard University32, Radboud University Nijmegen33, University of North Carolina at Chapel Hill34, Ewha Womans University35, Fred Hutchinson Cancer Research Center36, National Research Council37
TL;DR: In this article, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts) and found high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples.
Abstract: To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10−10 < P < 5 × 10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
TL;DR: Soehnlein et al. as discussed by the authors consider a gamut of attractive possibilities for modifying inflammation in atherosclerosis, including targeting pivotal inflammatory pathways such as the inflammasomes, inhibiting cytokines, manipulating adaptive immunity and promoting pro-resolution mechanisms.
Abstract: Atherosclerosis, a dominant and growing cause of death and disability worldwide, involves inflammation from its inception to the emergence of complications. Targeting inflammatory pathways could therefore provide a promising new avenue to prevent and treat atherosclerosis. Indeed, clinical studies have now demonstrated unequivocally that modulation of inflammation can forestall the clinical complications of atherosclerosis. This progress pinpoints the need for preclinical investigations to refine strategies for combatting inflammation in the human disease. In this Review, we consider a gamut of attractive possibilities for modifying inflammation in atherosclerosis, including targeting pivotal inflammatory pathways such as the inflammasomes, inhibiting cytokines, manipulating adaptive immunity and promoting pro-resolution mechanisms. Along with lifestyle measures, pharmacological interventions to mute inflammation could complement traditional targets, such as lipids and hypertension, to make new inroads into the management of atherosclerotic risk. The contribution of inflammation to atherosclerosis is substantial, and is just beginning to be understood. In this Review, Soehnlein and Libby discuss how inflammation promotes atherosclerosis and its consequences, and how such processes could be targeted therapeutically. The potential pitfalls of targeting immune processes — namely the increased potential for infections — are also discussed, along with ways to modulate cardiovascular therapies in time and space to make them more effective.
University of Bern1, Harvard University2, VU University Amsterdam3, University of Oxford4, Public Health Research Institute5, University of Wuppertal6, Kyoto University7, University of Amsterdam8, University of New South Wales9, University of Melbourne10, City University London11, University of Gothenburg12, Free University of Berlin13, University of Texas at Austin14, James I University15, Carlos III Health Institute16, Ohio State University17, Northwestern University18, University of Erlangen-Nuremberg19, University Hospitals Bristol NHS Foundation Trust20, University of Bristol21, Trinity College, Dublin22, University of York23, Karolinska Institutet24, Peking Union Medical College25, Linköping University26, University of Regina27, University of Sydney28, McLean Hospital29, University of Lübeck30, University of Zaragoza31, Imperial College London32, University of Nottingham33, University of Hamburg34, Oregon Research Institute35, Australian National University36, The Ohio State University Wexner Medical Center37, Hofstra University38, Stockholm University39, Hull York Medical School40, Tilburg University41, Linnaeus University42
TL;DR: In this article, the authors conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD-network meta-regression, and found that both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-9 scores than control treatments over the short term and the long term.
Abstract: Importance Personalized treatment choices would increase the effectiveness of internet-based cognitive behavioral therapy (iCBT) for depression to the extent that patients differ in interventions that better suit them. Objective To provide personalized estimates of short-term and long-term relative efficacy of guided and unguided iCBT for depression using patient-level information. Data Sources We searched PubMed, Embase, PsycInfo, and Cochrane Library to identify randomized clinical trials (RCTs) published up to January 1, 2019. Study Selection Eligible RCTs were those comparing guided or unguided iCBT against each other or against any control intervention in individuals with depression. Available individual patient data (IPD) was collected from all eligible studies. Depression symptom severity was assessed after treatment, 6 months, and 12 months after randomization. Data Extraction and Synthesis We conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD network meta-regression. Main Outcomes and Measures Patient Health Questionnaire–9 (PHQ-9) scores. Results Of 42 eligible RCTs, 39 studies comprising 9751 participants with depression contributed IPD to the IPD network meta-analysis, of which 8107 IPD were synthesized. Overall, both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-9 scores than control treatments over the short term and the long term. Guided iCBT was associated with more effectiveness than unguided iCBT (mean difference [MD] in posttreatment PHQ-9 scores, −0.8; 95% CI, −1.4 to −0.2), but we found no evidence of a difference at 6 or 12 months following randomization. Baseline depression was found to be the most important modifier of the relative association for efficacy of guided vs unguided iCBT. Differences between unguided and guided iCBT in people with baseline symptoms of subthreshold depression (PHQ-9 scores 5-9) were small, while guided iCBT was associated with overall better outcomes in patients with baseline PHQ-9 greater than 9. Conclusions and Relevance In this network meta-analysis with IPD, guided iCBT was associated with more effectiveness than unguided iCBT for individuals with depression, benefits were more substantial in individuals with moderate to severe depression. Unguided iCBT was associated with similar effectiveness among individuals with symptoms of mild/subthreshold depression. Personalized treatment selection is entirely possible and necessary to ensure the best allocation of treatment resources for depression.
VU University Amsterdam1, University of Oslo2, Oslo University Hospital3, University of California, San Diego4, University of Bergen5, Norwegian University of Science and Technology6, University of Michigan7, Namsos Hospital8, Statens Serum Institut9, Harvard University10, King's College London11, Vanderbilt University Medical Center12, Karolinska Institutet13, University of California, Riverside14, Jönköping University15, deCODE genetics16, University of Iceland17, University of Gothenburg18, Sahlgrenska University Hospital19, Akershus University Hospital20, Stavanger University Hospital21, Charité22, Broad Institute23, University of Amsterdam24
TL;DR: This paper identified microglia, immune cells and protein catabolism as relevant genes for late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest.
Abstract: Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.
TL;DR: All NAFLD histological stages were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLd histology, while the contributions of cardiovascular disease and HCC were modest.
Abstract: Objective Population-based data are lacking regarding the risk of overall and cause-specific mortality across the complete histological spectrum of non-alcoholic fatty liver disease (NAFLD). Design This nationwide, matched cohort study included all individuals in Sweden with biopsy-confirmed NAFLD (1966 to 2017; n=10 568). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden’s 28 pathology departments, after excluding other etiologies of liver disease, and further categorised as, simple steatosis, non-fibrotic steatohepatitis (NASH), non-cirrhotic fibrosis and cirrhosis. NAFLD cases were matched to ≤5 general population comparators by age, sex, calendar year and county (n=49 925). Using Cox regression, we estimated multivariable-adjusted HRs (aHRs) and 95% CIs. Results Over a median of 14.2 years, 4,338 NAFLD patients died. Compared with controls, NAFLD patients had significantly increased overall mortality (16.9 vs 28.6/1000 PY; difference=11.7/1000 PY; aHR=1.93, 95% CI=1.86 to 2.00). Compared with controls, significant excess mortality risk was observed with simple steatosis (8.3/1000 PY, aHR=1.71, 95% CI=1.64 to 1.79), non-fibrotic NASH (13.4/1000 PY, aHR=2.14, 95% CI=1.93 to 2.38), non-cirrhotic fibrosis (18.4/1000 PY, aHR=2.44, 95% CI=2.22 to 2.69) and cirrhosis (53.6/1000 PY, aHR=3.79, 95% CI=3.34 to 4.30)(ptrend Conclusion All NAFLD histological stages were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLD histology. Most of this excess mortality was from extrahepatic cancer and cirrhosis, while in contrast, the contributions of cardiovascular disease and HCC were modest.
Queen Mary University of London1, Harvard University2, University of Auckland3, St. Michael's Hospital4, Winthrop-University Hospital5, Karolinska Institutet6, University of Zurich7, Pontifical Catholic University of Chile8, University of Copenhagen9, Boston Children's Hospital10, University of Parma11, University of London12, University of Colorado Denver13, Ben-Gurion University of the Negev14, McMaster University15, Case Western Reserve University16, Katholieke Universiteit Leuven17, University of Tampere18, Columbia University Medical Center19, Medical University of Łódź20, Pennsylvania State University21, University of Birmingham22, University of Otago23, Jikei University School of Medicine24, QIMR Berghofer Medical Research Institute25, Dartmouth College26, University of Helsinki27, University College of Medical Sciences28, University of Melbourne29, Menzies Research Institute30, University of Delhi31
TL;DR: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention as discussed by the authors.
TL;DR: This cohort study describes COVID-19–related symptoms persisting 8 months after SARS-CoV-2 infection among Swedish health care workers and self-reported effects of the residual symptoms on respondents' home, work, and social function.
Abstract: This cohort study describes COVID-19–related symptoms persisting 8 months after SARS-CoV-2 infection among Swedish health care workers and self-reported effects of the residual symptoms on respondents’ home, work, and social function.
TL;DR: In this paper, the authors used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes of the SARS-CoV-2 spike protein.
Abstract: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structures, we engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.
University of Groningen1, Sapienza University of Rome2, Tel Aviv University3, Boston Children's Hospital4, Karolinska Institutet5, University of Glasgow6, University of Toronto7, University of Edinburgh8, University of Warmia and Mazury in Olsztyn9, University of Helsinki10, Wolfson Medical Center11, Hospital Sant Joan de Déu Barcelona12, Royal Hospital for Sick Children13, Sheba Medical Center14, Humanitas University15, Hebrew University of Jerusalem16, University of Alberta17, Necker-Enfants Malades Hospital18, Paris Descartes University19
TL;DR: An evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn's disease is provided, establishing that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity to reduce bowel damage.
Stephen P.H. Alexander1, Arthur Christopoulos2, Anthony P. Davenport3, Eamonn Kelly4 +151 more•Institutions (85)
TL;DR: The Concise Guide to PHARMACOLOGY 2021/22 as mentioned in this paper provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands.
Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Allen Institute for Brain Science1, Harvard University2, University of California, San Diego3, Salk Institute for Biological Studies4, University of Washington5, Cold Spring Harbor Laboratory6, Leiden University Medical Center7, J. Craig Venter Institute8, United States Department of Veterans Affairs9, University of Maryland, Baltimore10, University of Maryland, College Park11, Ludwig Institute for Cancer Research12, Discovery Institute13, University of Connecticut14, Karolinska Institutet15, Washington University in St. Louis16, Icahn School of Medicine at Mount Sinai17, Delft University of Technology18, Harborview Medical Center19, University of California, Los Angeles20, Broad Institute21, La Jolla Institute for Allergy and Immunology22, McGovern Institute for Brain Research23, Massachusetts Institute of Technology24
TL;DR: The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals using high-throughput transcriptomic and epigenomic profiling of more than 450k single nuclei in humans, marmoset monkeys and mice as mentioned in this paper.
Abstract: The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.
Broad Institute1, Harvard University2, Duke University3, Massachusetts Institute of Technology4, University of California, San Diego5, Icahn School of Medicine at Mount Sinai6, Brigham and Women's Hospital7, Yale University8, Ragon Institute of MGH, MIT and Harvard9, Royal Institute of Technology10, University of Bonn11, Centre national de la recherche scientifique12, Wellcome Trust Sanger Institute13, Karolinska Institutet14, Translational Genomics Research Institute15, Boston University16, Hannover Medical School17, European Bioinformatics Institute18, Boston Medical Center19, Technische Universität München20, University of Cambridge21, Stanford University22
TL;DR: In this paper, cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues was assessed.
Abstract: Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.
University of Oxford1, Trinity College, Dublin2, RWTH Aachen University3, Public Health England4, Beaumont Hospital5, Manchester Royal Infirmary6, China-Japan Friendship Hospital7, University of Bern8, New Generation University College9, Centre for Health Protection10, University of Würzburg11, Temple University12, Royal College of Surgeons in Ireland13, Cardiff University14, Statens Serum Institut15, National Health Laboratory Service16, Pasteur Institute17, Public Health Agency of Canada18, Katholieke Universiteit Leuven19, Karolinska Institutet20, The Chinese University of Hong Kong21, Örebro University22, National Institute for Health and Welfare23, University of Mons24, Public Health Agency of Sweden25, Hospital Sant Joan de Déu Barcelona26, University of Otago27, Israel Ministry of Health28, Korea University29, University of Amsterdam30
TL;DR: In this article, the authors investigated the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic and found that containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in lifethreatening invasive diseases in many countries worldwide.
Abstract: Summary Background Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. Methods In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. Findings 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 434 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27–0·37]) and 82% at 8 weeks (0·18 [0·14–0·23]) following the week in which significant changes in population movements were recorded. Interpretation The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. Funding Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Publica de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).
TL;DR: This paper conducted a meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants.
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
TL;DR: This article showed that a lack of bifidobacteria, and in particular depletion of genes required for human milk oligosaccharide utilization from the metagenome, is associated with systemic inflammation and immune dysregulation early in life.