Showing papers by "Paris Descartes University published in 2019"
University of Bristol1, University Hospitals Bristol NHS Foundation Trust2, Monash University3, French Institute of Health and Medical Research4, Paris Descartes University5, Cochrane Collaboration6, St George's, University of London7, University of York8, Queen Mary University of London9, Clinical Trial Service Unit10, Harvard University11, University of Oxford12, Odense University Hospital13, University of Southern Denmark14, University of Alberta15, University of Toronto16, University of Manchester17, Johns Hopkins University18, McGill University19, University College London20
TL;DR: The Cochrane risk-of-bias tool has been updated to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
Abstract: Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
9,228 citations
TL;DR: A panel of therapeutic strategies to use, combine and develop to treat hot, altered and cold tumours is provided and the impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.
Abstract: Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In this Review, we focus on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and we describe approaches to treat such tumours with combination immunotherapies, including checkpoint inhibitors. In the upcoming era of combination immunotherapy, it is becoming critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity. The impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.
1,680 citations
Heidelberg University1, University of Marburg2, Queen Mary University of London3, University of Leeds4, Rutgers University5, University of New South Wales6, University of Münster7, Aarhus University8, Columbia University9, University of Chieti-Pescara10, University of Oslo11, Karolinska Institutet12, Université catholique de Louvain13, University of Sydney14, Paris Descartes University15, Royal Perth Hospital16, University of Western Australia17, University of Dundee18, Maastricht University19, Katholieke Universiteit Leuven20, National Yang-Ming University21, Taipei Veterans General Hospital22
TL;DR: In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in this proposal, this subgroup is called “chronic primary pain,” and in 6 other subgroups, pain is secondary to an underlying disease.
Abstract: Chronic pain is a major source of suffering. It interferes with daily functioning and often is accompanied by distress. Yet, in the International Classification of Diseases, chronic pain diagnoses are not represented systematically. The lack of appropriate codes renders accurate epidemiological investigations difficult and impedes health policy decisions regarding chronic pain such as adequate financing of access to multimodal pain management. In cooperation with the WHO, an IASP Working Group has developed a classification system that is applicable in a wide range of contexts, including pain medicine, primary care, and low-resource environments. Chronic pain is defined as pain that persists or recurs for more than 3 months. In chronic pain syndromes, pain can be the sole or a leading complaint and requires special treatment and care. In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in our proposal, we call this subgroup "chronic primary pain." In 6 other subgroups, pain is secondary to an underlying disease: chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. These conditions are summarized as "chronic secondary pain" where pain may at least initially be conceived as a symptom. Implementation of these codes in the upcoming 11th edition of International Classification of Diseases will lead to improved classification and diagnostic coding, thereby advancing the recognition of chronic pain as a health condition in its own right.
1,311 citations
University of Manchester1, University of Barcelona2, University of Texas Health Science Center at San Antonio3, National Institutes of Health4, McGill University Health Centre5, Brigham and Women's Hospital6, Temple University7, Flinders University8, Royal Devon and Exeter Hospital9, University of Michigan10, University of the Republic11, NewYork–Presbyterian Hospital12, Central University of Venezuela13, University of Ferrara14, Paris Descartes University15, University of British Columbia16, University of Birmingham17, University of Marburg18
TL;DR: Blood eosinophils are recommended as a biomarker to support clinical decisions regarding the use of inhaled corticosteroids in chronic obstructive pulmonary disease patients, based on recent evidence from clinical trials.
Abstract: Precision medicine is a patient-specific approach that integrates all relevant clinical, genetic and biological information in order to optimise the therapeutic benefit relative to the possibility of side-effects for each individual. Recent clinical trials have shown that higher blood eosinophil counts are associated with a greater efficacy of inhaled corticosteroids (ICSs) in chronic obstructive pulmonary disease (COPD) patients. Blood eosinophil counts are a biomarker with potential to be used in clinical practice, to help target ICS treatment with more precision in COPD patients with a history of exacerbations despite appropriate bronchodilator treatment. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 pharmacological treatment algorithms, based on the ABCD assessment, can be applied relatively easily to treatment-naive individuals at initial presentation. However, their use is more problematic during follow-up in patients who are already on maintenance treatment. There is a need for a different system to guide COPD pharmacological management during follow-up. Recent large randomised controlled trials have provided important new information concerning the therapeutic effects of ICSs and long-acting bronchodilators on exacerbations. The new evidence regarding blood eosinophils and inhaled treatments, and the need to distinguish between initial and follow-up pharmacological management, led to changes in the GOLD pharmacological treatment recommendations. This article explains the evidence and rationale for the GOLD 2019 pharmacological treatment recommendations.
1,122 citations
TL;DR: The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.
Abstract: Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.
1,071 citations
New York University1, Lunenfeld-Tanenbaum Research Institute2, Northwood University3, Ghent University Hospital4, Johns Hopkins University School of Medicine5, Brigham and Women's Hospital6, Paris Descartes University7, Cornell University8, University of Fribourg9, University of Cincinnati Academic Health Center10, Yale University11
TL;DR: The PI-RADS Steering Committee, using a consensus-based process, has recommended several modifications to PI- RADS v2, maintaining the framework of assigning scores to individual sequences and using these scores to derive an overall assessment category.
1,053 citations
Carlos III Health Institute1, University of Cologne2, University of Sydney3, Paris Descartes University4, Pontifícia Universidade Católica do Rio Grande do Sul5, Universidade Federal de Ciências da Saúde de Porto Alegre6, Medical University of Graz7, University of California, San Diego8, University of Copenhagen9, Katholieke Universiteit Leuven10, University of Bologna11, University of the Witwatersrand12, RMIT University13, McGill University14, Hacettepe University15, University of Paris16, Utrecht University17, Mazandaran University of Medical Sciences18, Tel Aviv University19, Hospital General de México20, Istituto Giannina Gaslini21, Mahidol University22, Federal University of São Paulo23, King's College, Aberdeen24, Comenius University in Bratislava25, Boston Children's Hospital26, Complutense University of Madrid27, Hospital General Universitario Gregorio Marañón28, University Hospital Heidelberg29, University of California, Los Angeles30, American University of Beirut31, Innsbruck Medical University32, University of Lausanne33, Catholic University of Korea34, Goethe University Frankfurt35, Erasmus University Rotterdam36, National and Kapodistrian University of Athens37, Monash University38, Federal University of Rio de Janeiro39, Catholic University of the Sacred Heart40, University of Health Sciences Antigua41, National Institutes of Health42, Amrita Institute of Medical Sciences and Research Centre43, University of Pittsburgh44, Peter MacCallum Cancer Centre45, University of Melbourne46, P. D. Hinduja Hospital and Medical Research Centre47, University of Southern California48, Duke University49, Singapore General Hospital50, NewYork–Presbyterian Hospital51, Cardiff University52, University of Texas Health Science Center at San Antonio53, Children's Hospital of Philadelphia54, Post Graduate Institute of Medical Education and Research55
TL;DR: Management of mucormycosis depends on recognising disease patterns and on early diagnosis, and limited availability of contemporary treatments burdens patients in low and middle income settings.
Abstract: Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the "One World One Guideline" initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.
842 citations
TL;DR: Obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer but does not seem to avoid the need for systematic biopsy.
Abstract: Summary Background Whether multiparametric MRI improves the detection of clinically significant prostate cancer and avoids the need for systematic biopsy in biopsy-naive patients remains controversial. We aimed to investigate whether using this approach before biopsy would improve detection of clinically significant prostate cancer in biopsy-naive patients. Methods In this prospective, multicentre, paired diagnostic study, done at 16 centres in France, we enrolled patients aged 18–75 years with prostate-specific antigen concentrations of 20 ng/mL or less, and with stage T2c or lower prostate cancer. Eligible patients had been referred for prostate multiparametric MRI before a first set of prostate biopsies, with a planned interval of less than 3 months between MRI and biopsies. An operator masked to multiparametric MRI results did a systematic biopsy by obtaining 12 systematic cores and up to two cores targeting hypoechoic lesions. In the same patient, another operator targeted up to two lesions seen on MRI with a Likert score of 3 or higher (three cores per lesion) using targeted biopsy based on multiparametric MRI findings. Patients with negative multiparametric MRI (Likert score ≤2) had systematic biopsy only. The primary outcome was the detection of clinically significant prostate cancer of International Society of Urological Pathology grade group 2 or higher (csPCa-A), analysed in all patients who received both systematic and targeted biopsies and whose results from both were available for pathological central review, including patients who had protocol deviations. This study is registered with ClinicalTrials.gov, number NCT02485379, and is closed to new participants. Findings Between July 15, 2015, and Aug 11, 2016, we enrolled 275 patients. 24 (9%) were excluded from the analysis. 53 (21%) of 251 analysed patients had negative (Likert ≤2) multiparametric MRI. csPCa-A was detected in 94 (37%) of 251 patients. 13 (14%) of these 94 patients were diagnosed by systematic biopsy only, 19 (20%) by targeted biopsy only, and 62 (66%) by both techniques. Detection of csPCa-A by systematic biopsy (29·9%, 95% CI 24·3–36·0) and targeted biopsy (32·3%, 26·5–38·4) did not differ significantly (p=0·38). csPCa-A would have been missed in 5·2% (95% CI 2·8–8·7) of patients had systematic biopsy not been done, and in 7·6% (4·6–11·6) of patients had targeted biopsy not been done. Four grade 3 post-biopsy adverse events were reported (3 cases of prostatitis, and 1 case of urinary retention with haematuria). Interpretation There was no difference between systematic biopsy and targeted biopsy in the detection of ISUP grade group 2 or higher prostate cancer; however, this detection was improved by combining both techniques and both techniques showed substantial added value. Thus, obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer but does not seem to avoid the need for systematic biopsy. Funding French National Cancer Institute.
625 citations
National and Kapodistrian University of Athens1, University of Brescia2, Utrecht University3, University of Paris4, University of Barcelona5, Paris Descartes University6, University of Navarra7, Charité8, University of Kent9, Dubai Hospital10, University of Pisa11, University of Padua12, University Hospital of Bern13, Sheba Medical Center14, Karolinska University Hospital15, University of Lorraine16, National Institutes of Health17
TL;DR: Evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults based on evidence from a systematic literature review and expert opinion were formulated and voted.
Abstract: The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2-3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3-4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research.
568 citations
TL;DR: The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index.
Abstract: Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
517 citations
TL;DR: This Review critically evaluates the studies on the origin, fate and functions of vascular smooth muscle cells (VSMCs) in atherosclerosis, highlighting the importance of developmental origin, clonal expansion and plasticity of VSMCs cells in Atherosclerosis and summarizing the roles of VS MCs and VSMC-derived cells in plaque development and progression.
Abstract: Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the 'response to injury' and 'vulnerable plaque' hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.
Icahn School of Medicine at Mount Sinai1, Technische Universität München2, University of Florida3, University of Catania4, Aix-Marseille University5, Beth Israel Deaconess Medical Center6, McMaster University7, Food and Drug Administration8, Harvard University9, University of London10, Uppsala University11, Seoul National University Hospital12, Kyoto University13, Pharmaceuticals and Medical Devices Agency14, Columbia University Medical Center15, National University of Ireland, Galway16, Scripps Health17, Durham University18, Core Laboratories19, Erasmus University Medical Center20, University of Bern21, Paris Descartes University22, Duke University23
TL;DR: This research presents a novel probabilistic approach that allows us to assess the importance of knowing the carrier and removal status of canine coronavirus, as a source of infection for other animals.
Abstract: Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limi ...
TL;DR: A patient-centred, individualized, multi-modal and interdisciplinary integrated approach should be taken to maximize the quality of the patient’s ‘endometriosis life’ and how health-care professionals could rethink endometRIosis diagnosis and management is highlighted.
Abstract: Endometriosis is a chronic inflammatory disease defined as the presence of endometrial tissue outside the uterus, which causes pelvic pain and infertility. This disease should be viewed as a public health problem with a major effect on the quality of life of women as well as being a substantial economic burden. In light of the considerable progress with diagnostic imaging (for example, transvaginal ultrasound and MRI), exploratory laparoscopy should no longer be used to diagnose endometriotic lesions. Instead, diagnosis of endometriosis should be based on a structured process involving the combination of patient interviews, clinical examination and imaging. Notably, a diagnosis of endometriosis often leads to immediate surgery. Therefore, rethinking the diagnosis and management of endometriosis is warranted. Instead of assessing endometriosis on the day of the diagnosis, gynaecologists should consider the patient's 'endometriosis life'. Medical treatment is the first-line therapeutic option for patients with pelvic pain and no desire for immediate pregnancy. In women with infertility, careful consideration should be made regarding whether to provide assisted reproductive technologies prior to performing endometriosis surgery. Modern endometriosis management should be individualized with a patient-centred, multi-modal and interdisciplinary integrated approach.
TL;DR: The mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood as discussed by the authors. But, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity.
Abstract: Despite its position as the first-line drug for treatment of type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. In addition, the discovery that metformin inhibits the mitochondrial respiratory chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations in cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase 1 and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3-phosphate dehydrogenase have been proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide 1 and the intestinal bile acid pool and alterations in gut microbiota composition.
University of Paris1, University of São Paulo2, Polytechnic University of Milan3, University of Texas Southwestern Medical Center4, Université de Montréal5, Paris Descartes University6, Pompeu Fabra University7, University of British Columbia8, University of New South Wales9, Loyola University Chicago10, Veterans Health Administration11, Katholieke Universiteit Leuven12, Guangzhou Medical University13, Kingston General Hospital14, University of Edinburgh15, University of Verona16, Laval University17, University of Zurich18, Northumbria University19, St. Paul's Hospital20, National and Kapodistrian University of Athens21, University of Grenoble22
TL;DR: This ERS task force summarises the most recent scientific and methodological developments regarding respiratory mechanics and respiratory muscle assessment by addressing the validity, precision, reproducibility, prognostic value and responsiveness to interventions of various methods.
Abstract: Assessing respiratory mechanics and muscle function is critical for both clinical practice and research purposes. Several methodological developments over the past two decades have enhanced our understanding of respiratory muscle function and responses to interventions across the spectrum of health and disease. They are especially useful in diagnosing, phenotyping and assessing treatment efficacy in patients with respiratory symptoms and neuromuscular diseases. Considerable research has been undertaken over the past 17 years, since the publication of the previous American Thoracic Society (ATS)/European Respiratory Society (ERS) statement on respiratory muscle testing in 2002. Key advances have been made in the field of mechanics of breathing, respiratory muscle neurophysiology (electromyography, electroencephalography and transcranial magnetic stimulation) and on respiratory muscle imaging (ultrasound, optoelectronic plethysmography and structured light plethysmography). Accordingly, this ERS task force reviewed the field of respiratory muscle testing in health and disease, with particular reference to data obtained since the previous ATS/ERS statement. It summarises the most recent scientific and methodological developments regarding respiratory mechanics and respiratory muscle assessment by addressing the validity, precision, reproducibility, prognostic value and responsiveness to interventions of various methods. A particular emphasis is placed on assessment during exercise, which is a useful condition to stress the respiratory system.
TL;DR: The reactivity of the mouse intestinal immune system during the first weeks after birth and into adulthood is explored, finding that inhibition of the weaning reaction led to pathological imprinting and increased susceptibility to colitis, allergic inflammation, and cancer later in life.
Jeroen R. Huyghe1, Stephanie A. Bien1, Tabitha A. Harrison1, Hyun Min Kang2 +221 more•Institutions (68)
TL;DR: Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.
Abstract: To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
TL;DR: Remedying the diagnostic delay requires increased patient education and timely referral to a women's healthcare provider and a shift in physician approach to the disorder, which is expected to simplify endometriosis diagnosis and make the process accessible to more clinicians and patients, culminating in earlier effective management.
TL;DR: A critical appraisal of the epidemiology, pathobiology, neuropathology, and neuroimaging of vascular cognitive impairment and dementia and of current diagnostic and therapeutic approaches is provided to shed light on new basic and clinical research avenues that may lead to mitigating one of the most devastating human conditions.
TL;DR: The updated ESCEO stepwise algorithm, developed by consensus from clinical experts in OA and informed by available evidence for the benefits and harms of various treatments, provides practical, current guidance that will enable clinicians to deliver patient-centric care in Oa practice.
TL;DR: The critical components of the TME in solid tumours and how they shape the immune cell contexture are reviewed, and numerous studies evaluating its clinical significance are summarized from a prognostic and theranostic perspective.
Abstract: The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)-in particular, the degree of tumour infiltration by cytotoxic T cells-can predict a patient's clinical outcome. More recently, studies in renal cell cancer have highlighted the importance of assessing the phenotype of the infiltrating T cells to predict early relapse. Furthermore, intricate interactions with non-immune cellular players such as endothelial cells and fibroblasts modulate the clinical impact of immune cells in the TME. Here, we review the critical components of the TME in solid tumours and how they shape the immune cell contexture, and we summarise numerous studies evaluating its clinical significance from a prognostic and theranostic perspective.
Erasmus University Rotterdam1, University of Southampton2, University Hospital Southampton NHS Foundation Trust3, University of Porto4, Paris Descartes University5, Sorbonne6, Maastricht University7, University of Southern California8, University of Crete9, National and Kapodistrian University of Athens10, University Medical Center Groningen11, Université de Sherbrooke12, Norwegian Institute of Public Health13, University of Bologna14, Nofer Institute of Occupational Medicine15, University of California, Davis16, Harvard University17, University of Illinois at Chicago18, University of Valencia19, National Institutes of Health20, University of Turku21, University of Bristol22, Helmholtz Centre for Environmental Research - UFZ23, Jagiellonian University Medical College24, Åbo Akademi University25, Harokopio University26, Public Health Research Institute27, University of Southern Denmark28, University of Copenhagen29, La Trobe University30, University of Helsinki31, University of Turin32, Radboud University Nijmegen33, University of Trieste34, University of Bergen35, Ludwig Maximilian University of Munich36, Slovak Medical University37, Utrecht University38, Pompeu Fabra University39
TL;DR: In this meta-analysis of pooled individual participant data from 25 cohort studies, the risk for adverse maternal and infant outcomes varied by gestational weight gain and across the range of prepregnancy weights, however, the optimal gestations weight gain ranges had limited predictive value for the outcomes assessed.
Abstract: Importance Both low and high gestational weight gain have been associated with adverse maternal and infant outcomes, but optimal gestational weight gain remains uncertain and not well defined for all prepregnancy weight ranges. Objectives To examine the association of ranges of gestational weight gain with risk of adverse maternal and infant outcomes and estimate optimal gestational weight gain ranges across prepregnancy body mass index categories. Design, Setting, and Participants Individual participant-level meta-analysis using data from 196 670 participants within 25 cohort studies from Europe and North America (main study sample). Optimal gestational weight gain ranges were estimated for each prepregnancy body mass index (BMI) category by selecting the range of gestational weight gain that was associated with lower risk for any adverse outcome. Individual participant-level data from 3505 participants within 4 separate hospital-based cohorts were used as a validation sample. Data were collected between 1989 and 2015. The final date of follow-up was December 2015. Exposures Gestational weight gain. Main Outcomes and Measures The main outcome termedany adverse outcomewas defined as the presence of 1 or more of the following outcomes: preeclampsia, gestational hypertension, gestational diabetes, cesarean delivery, preterm birth, and small or large size for gestational age at birth. Results Of the 196 670 women (median age, 30.0 years [quartile 1 and 3, 27.0 and 33.0 years] and 40 937 were white) included in the main sample, 7809 (4.0%) were categorized at baseline as underweight (BMI Conclusions and Relevance In this meta-analysis of pooled individual participant data from 25 cohort studies, the risk for adverse maternal and infant outcomes varied by gestational weight gain and across the range of prepregnancy weights. The estimates of optimal gestational weight gain may inform prenatal counseling; however, the optimal gestational weight gain ranges had limited predictive value for the outcomes assessed.
Hannover Medical School1, Boston Children's Hospital2, Royal National Orthopaedic Hospital3, Great Ormond Street Hospital4, Paris Descartes University5, Charité6, Necker-Enfants Malades Hospital7, Great Ormond Street Hospital for Children NHS Foundation Trust8, University of Oviedo9, Katholieke Universiteit Leuven10, University of Lyon11, University of Florence12, Karolinska University Hospital13, French Institute of Health and Medical Research14, Aarhus University Hospital15
TL;DR: It is recommended that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency.
Abstract: X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care. In this Evidence-Based Guideline on X-linked hypophosphataemia, the authors identify the criteria for diagnosis of this disease, provide guidance for medical and surgical treatment and explain the challenges of follow-up.
Bruce C.V. Campbell1, Charles B. L. M. Majoie2, Gregory W. Albers3, Bijoy K Menon4 +1293 more•Institutions (26)
TL;DR: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome.
Abstract: BACKGROUND: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. METHODS: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. FINDINGS: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30-0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69-0·86] per 10 mL, pinteraction=0·29; diffusion MRI OR 0·87 [0·81-0·94] per 10 mL, pinteraction=0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. INTERPRETATION: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. FUNDING: Medtronic.
Erasmus University Medical Center1, University of Porto2, University of Western Australia3, Stockholm County Council4, Paris Descartes University5, Maastricht University6, French Institute of Health and Medical Research7, National and Kapodistrian University of Athens8, University Medical Center Groningen9, University of Valencia10, University of Southampton11, Liverpool School of Tropical Medicine12, Université de Sherbrooke13, Norwegian Institute of Public Health14, University of Bologna15, University of Crete16, University Hospital Southampton NHS Foundation Trust17, Ludwig Maximilian University of Munich18, Nofer Institute of Occupational Medicine19, University of California20, Harvard University21, University of Illinois at Chicago22, National Institutes of Health23, Wageningen University and Research Centre24, University of Turku25, Helmholtz Centre for Environmental Research - UFZ26, Jagiellonian University Medical College27, Åbo Akademi University28, Harokopio University29, University College Dublin30, University of Calgary31, Boston Children's Hospital32, University of Copenhagen33, University College Cork34, VU University Medical Center35, University of Helsinki36, University of Turin37, Radboud University Nijmegen38, University of Trieste39, University of Bergen40, Slovak Medical University41, Utrecht University42, Pompeu Fabra University43, Bradford Royal Infirmary44, University of Bristol45
TL;DR: In this paper, the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact were assessed.
TL;DR: Therapeutic strategies aimed at preserving and/or restoring the integrity of the endothelial glycocalyx, reversing the procoagulant and pro-inflammatory phenotype of injured endothelial cells and slowing renal fibrosis hold promise for the treatment of renal disease.
Abstract: The kidney harbours different types of endothelia, each with specific structural and functional characteristics. The glomerular endothelium, which is highly fenestrated and covered by a rich glycocalyx, participates in the sieving properties of the glomerular filtration barrier and in the maintenance of podocyte structure. The microvascular endothelium in peritubular capillaries, which is also fenestrated, transports reabsorbed components and participates in epithelial cell function. The endothelium of large and small vessels supports the renal vasculature. These renal endothelia are protected by regulators of thrombosis, inflammation and complement, but endothelial injury (for example, induced by toxins, antibodies, immune cells or inflammatory cytokines) or defects in factors that provide endothelial protection (for example, regulators of complement or angiogenesis) can lead to acute or chronic renal injury. Moreover, renal endothelial cells can transition towards a mesenchymal phenotype, favouring renal fibrosis and the development of chronic kidney disease. Thus, the renal endothelium is both a target and a driver of kidney and systemic cardiovascular complications. Emerging therapeutic strategies that target the renal endothelium may lead to improved outcomes for both rare and common renal diseases.
Erasmus University Medical Center1, Medical University of Warsaw2, University of Valencia3, University of Porto4, Stockholm County Council5, Sorbonne6, Paris Descartes University7, University of Crete8, Maastricht University9, University of Southern California10, French Institute of Health and Medical Research11, National and Kapodistrian University of Athens12, University Medical Center Groningen13, University of Southampton14, Liverpool School of Tropical Medicine15, Norwegian Institute of Public Health16, Karolinska Institutet17, University of Bologna18, University Hospital Southampton NHS Foundation Trust19, Ludwig Maximilian University of Munich20, Nofer Institute of Occupational Medicine21, University of California, Davis22, University of Illinois at Chicago23, University of Western Australia24, National Institutes of Health25, University College Cork26, University of Bristol27, University of Turku28, Helmholtz Centre for Environmental Research - UFZ29, Jagiellonian University Medical College30, Åbo Akademi University31, Harokopio University32, University College Dublin33, University of Calgary34, Public Health Research Institute35, University of Southern Denmark36, University of Copenhagen37, La Trobe University38, Harvard University39, University of Helsinki40, University of Turin41, University of Trieste42, University of Bergen43, Slovak Medical University44, Boston Children's Hospital45, Utrecht University46, Pompeu Fabra University47, Bradford Royal Infirmary48
TL;DR: In this article, the authors conducted an individual participant data meta-analysis of data from 162,129 mothers and children from 37 pregnancy and birth cohort studies from Europe, North-America and Australia, using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal socio-demographic and life style related characteristics.
Abstract: Background:
Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these risks differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact.
Methods and Findings:
We conducted an individual participant data meta-analysis of data from 162,129 mothers and children from 37 pregnancy and birth cohort studies from Europe, North-America and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges with the risks of overweight/obesity in early- (2.0-5.0 years), mid- (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal socio-demographic and life style related characteristics. We observed that a higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (Odds Ratios (OR) for overweight/obesity in early-, mid- and late childhood, respectively: 1.66 (95% Confidence Interval (CI): 1.56, 1.78), OR 1.91 (95% CI: 1.85, 1.98), and OR 2.28 (95% CI: 2.08, 2.50) for maternal overweight, OR 2.43 (95% CI: 2.24, 2.64), OR 3.12 (95% CI: 2.98, 3.27), and OR 4.47 (95% CI: 3.99, 5.23) for maternal obesity, and OR 1.39 (95% CI: 1.30, 1.49), OR 1.55 (95% CI: 1.49, 1.60), and 1.72 (95% CI: 1.56, 1.91) for excessive gestational weight gain. The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity and excessive gestational weight gain ranged from 10.2 to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (P-values for interactions of maternal BMI with gestational weight gain: p=0.038, p<0.001 and p=0.637, in early-, mid- and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North-America and Australia, results need to be interpreted with caution with respect to other populations.
Conclusions:
In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.
Icahn School of Medicine at Mount Sinai1, Technische Universität München2, University of Florida3, University of Catania4, Aix-Marseille University5, Beth Israel Deaconess Medical Center6, McMaster University7, Food and Drug Administration8, Harvard University9, University of London10, Uppsala University11, Seoul National University Hospital12, Kyoto University13, Pharmaceuticals and Medical Devices Agency14, Columbia University Medical Center15, National University of Ireland, Galway16, Scripps Health17, Durham University18, Erasmus University Medical Center19, Core Laboratories20, University of Bern21, Paris Descartes University22, Duke University23
TL;DR: The proposed ARC-HBR consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention.
Abstract: Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention-related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018. These meetings were organized by the Cardiovascular European Research Center on behalf of the ARC-HBR group and included representatives of the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, as well as observers from the pharmaceutical and medical device industries. A consensus definition of patients at high bleeding risk was developed that was based on review of the available evidence. The definition is intended to provide consistency in defining this population for clinical trials and to complement clinical decision-making and regulatory review. The proposed ARC-HBR consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention.
TL;DR: An update is provided on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagic flux in vivo and discussing the potential to modulate Autophagy as a therapeutic strategy in the context of liver diseases.
Hannover Medical School1, University of Graz2, Vanderbilt University3, Paris Descartes University4, Katholieke Universiteit Leuven5, Aga Khan University6, University of Hamburg7, Amrita Institute of Medical Sciences and Research Centre8, University of Münster9, University of Cambridge10, National Institute for Health Research11, Boston Children's Hospital12, Charité13, Goethe University Frankfurt14, Lund University15, Sahlgrenska University Hospital16
TL;DR: Ten section task forces voted on the updated recommendations, based on the 2016 executive summary, and provided a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.
Abstract: The European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term "pulmonary hypertension" and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.