Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2019"
Newcastle University1, Newcastle upon Tyne Hospitals NHS Foundation Trust2, University of Exeter3, University of Cambridge4, Imperial College London5, Chelsea and Westminster Hospital NHS Foundation Trust6, Royal Liverpool and Broadgreen University Hospital NHS Trust7, Pennine Acute Hospitals NHS Trust8, University of Manchester9, King's College London10, Guy's and St Thomas' NHS Foundation Trust11, Barts Health NHS Trust12, Queen Mary University of London13, University of Leeds14, Leeds Teaching Hospitals NHS Trust15, Royal College of Surgeons in Ireland16, University of Edinburgh17, Western General Hospital18, University Hospitals Bristol NHS Foundation Trust19, Glasgow Royal Infirmary20, University of Glasgow21, Queen Elizabeth Hospital Birmingham22, University of Birmingham23, University College London24, University College London Hospitals NHS Foundation Trust25, Brighton and Sussex University Hospitals NHS Trust26, Brighton and Sussex Medical School27, University of Wolverhampton28, University Hospital of Wales29
TL;DR: Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care.
Abstract: Ulcerative colitis and Crohn’s disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn’s and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn’s disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn’s disease, including patients, their families and friends.
1,140 citations
University of Sydney1, Guy's and St Thomas' NHS Foundation Trust2, University of British Columbia3, Harvard University4, Monash University5, Royal Prince Alfred Hospital6, St. Vincent's Health System7, Garvan Institute of Medical Research8, Auckland City Hospital9, Sydney Adventist Hospital10, Mater Misericordiae University Hospital11, University College Dublin12, University of Alberta13, University of Adelaide14, Queen's University15, Ottawa Hospital Research Institute16, University of Ottawa17, University of Melbourne18, Royal Adelaide Hospital19, Royal Cornwall Hospital20
TL;DR: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression.
Abstract: Background Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. Methods In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. Results A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P Conclusions Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).
865 citations
Population Health Research Institute1, Brigham and Women's Hospital2, Katholieke Universiteit Leuven3, University of Grenoble4, King's College London5, Hospital Universitario La Paz6, Memorial Hospital of South Bend7, University of Texas at Austin8, Guy's and St Thomas' NHS Foundation Trust9, Dresden University of Technology10, Autonomous University of Madrid11, University of Calgary12
TL;DR: In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti–factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria.
Abstract: Background Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. Methods We evaluated 352 patients who had acute major b...
612 citations
TL;DR: Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide and can be targeted towards vulnerable populations if they are informed by variations in mortality rates.
Abstract: Objectives To use the estimates from the Global Burden of Disease Study 2016 to describe patterns of suicide mortality globally, regionally, and for 195 countries and territories by age, sex, and Socio-demographic index, and to describe temporal trends between 1990 and 2016. Design Systematic analysis. Main outcome measures Crude and age standardised rates from suicide mortality and years of life lost were compared across regions and countries, and by age, sex, and Socio-demographic index (a composite measure of fertility, income, and education). Results The total number of deaths from suicide increased by 6.7% (95% uncertainty interval 0.4% to 15.6%) globally over the 27 year study period to 817 000 (762 000 to 884 000) deaths in 2016. However, the age standardised mortality rate for suicide decreased by 32.7% (27.2% to 36.6%) worldwide between 1990 and 2016, similar to the decline in the global age standardised mortality rate of 30.6%. Suicide was the leading cause of age standardised years of life lost in the Global Burden of Disease region of high income Asia Pacific and was among the top 10 leading causes in eastern Europe, central Europe, western Europe, central Asia, Australasia, southern Latin America, and high income North America. Rates for men were higher than for women across regions, countries, and age groups, except for the 15 to 19 age group. There was variation in the female to male ratio, with higher ratios at lower levels of Socio-demographic index. Women experienced greater decreases in mortality rates (49.0%, 95% uncertainty interval 42.6% to 54.6%) than men (23.8%, 15.6% to 32.7%). Conclusions Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide. Suicide mortality was variable across locations, between sexes, and between age groups. Suicide prevention strategies can be targeted towards vulnerable populations if they are informed by variations in mortality rates.
472 citations
Nicholas A. Kennedy1, Nicholas A. Kennedy2, Nicholas A. Kennedy3, Graham A. Heap1 +157 more•Institutions (15)
TL;DR: Clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal are identified.
369 citations
Children's Hospital Oakland Research Institute1, University of Tennessee Health Science Center2, University of Cincinnati3, Kenya Medical Research Institute4, Cairo University5, Alexandria University6, Brigham and Women's Hospital7, Sultan Qaboos University8, Emory University9, Columbia University10, Queen Mary University of London11, University of Illinois at Chicago12, University of Alabama at Birmingham13, American University of Beirut14, Guy's and St Thomas' NHS Foundation Trust15
TL;DR: Voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis in this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, consistent with inhibition of HbS polymerization and indicate a disease-modifying potential.
Abstract: Background Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favora...
340 citations
TL;DR: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal, and until robust predictors of relapse are defined, treatment should continue indefinitely.
334 citations
Vanderbilt University Medical Center1, Vanderbilt University2, University of Pennsylvania3, Queen Mary University of London4, National Institute for Health Research5, Veterans Health Administration6, Emory University7, VA Boston Healthcare System8, University of Ioannina9, Imperial College London10, University of Leicester11, University of Bordeaux12, University of Michigan13, University of Cambridge14, McMaster University15, University of Dundee16, COMSATS Institute of Information Technology17, University of Newcastle18, Lund University19, Leiden University Medical Center20, University Medical Center Groningen21, University of Edinburgh22, Guy's and St Thomas' NHS Foundation Trust23, King's College London24, University of Texas Health Science Center at Houston25, University of Liverpool26, Broad Institute27, Boston University28, University of London29, University of Bristol30, Washington University in St. Louis31, university of lille32, Wellcome Trust Centre for Human Genetics33, University of Eastern Finland34, Wellcome Trust Sanger Institute35, National Institutes of Health36, Population Health Research Institute37, Brigham and Women's Hospital38, University of Sassari39, Wellcome Trust40, University of Oxford41, Harokopio University42, University of Washington43, Harvard University44, VA Palo Alto Healthcare System45, Stanford University46
TL;DR: Analysis of blood pressure data from the Million Veteran Program trans-ethnic cohort identifies common and rare variants, and genetically predicted gene expression across multiple tissues associated with systolic, diastolic and pulse pressure in over 775,000 individuals.
Abstract: In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
310 citations
University of Oxford1, University of Bristol2, University of Exeter3, University of Aberdeen4, Maimonides Medical Center5, Radboud University Nijmegen6, St George's, University of London7, Macquarie University8, Guy's and St Thomas' NHS Foundation Trust9, University of Minnesota10, Cornell University11
TL;DR: This article updates and extends the IDEAL Recommendations, identifies areas for future research, and discusses the ethical problems faced by investigators at each IDEAL stage, to widen the practical use of IDEAL.
Abstract: Objective:To update, clarify, and extend IDEAL concepts and recommendations.Background:New surgical procedures, devices, and other complex interventions need robust evaluation for safety, efficacy, and effectiveness. Unlike new medicines, there is no internationally agreed evaluation pathway for gen
234 citations
TL;DR: A statistical framework that models distinct disease stages and competing risks of mortality from breast cancer and to predict the risk of relapse is presented and use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates.
Abstract: The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1–6. It is therefore essential to identify patients who have a high risk of late relapse7–9. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns10,11; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47–62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials. A statistical framework for breast-cancer recurrence uses long-term follow-up data and a knowledge of molecular subcategories to model distinct disease stages and to predict the risk of relapse.
211 citations
Aleksejs Sazonovs1, Nicholas A Kennedy2, Nicholas A Kennedy3, Loukas Moutsianas1 +156 more•Institutions (10)
TL;DR: In an observational study, a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents is found and a randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA*05 improves patient outcomes by helping physicians select anti- TNF and combination therapies.
University of Amsterdam1, University College London2, Karolinska University Hospital3, Ghent University4, University of Barcelona5, Lund University6, Humanitas University7, Université de Montréal8, First Faculty of Medicine, Charles University in Prague9, Eastern Virginia Medical School10, Guy's and St Thomas' NHS Foundation Trust11, Ghent University Hospital12, University of California, Los Angeles13, University of Pittsburgh14, Katholieke Universiteit Leuven15, University of North Carolina at Chapel Hill16
TL;DR: Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients and may soon also become available for CRSwNP patients.
Abstract: Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients. The majority of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and over half of patients with asthma show a type 2 inflammatory signature in sinonasal mucosa and/or lungs. Importantly, both chronic respiratory diseases are frequent comorbidities, ensuring alleviation of both upper and lower airway pathology by systemic biological therapy. Type 2-targeting biologics such as anti-IgE, anti-IL4Rα, anti-IL5, and anti-IL5Rα have entered the market for selected pheno/endotypes of asthma patients and may soon also become available for CRSwNP patients. Given the high prevalence of chronic respiratory diseases and the high cost associated with biologics, patient selection is crucial in order to implement such therapies into chronic respiratory disease care pathways. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized a multidisciplinary Expert Board Meeting to discuss the positioning of biologics into the care pathways for CRSwNP patients with and without comorbid asthma.
University of Medicine and Pharmacy of Craiova1, University of Bergen2, King's College London3, Copenhagen University Hospital4, Ruhr University Bochum5, University of Pavia6, Ludwig Maximilian University of Munich7, Paris Descartes University8, University of Verona9, University of Bologna10, Innsbruck Medical University11, Medical University of Vienna12, University of Latvia13, Guy's and St Thomas' NHS Foundation Trust14, University of Milan15, Iuliu Hațieganu University of Medicine and Pharmacy16, French Institute of Health and Medical Research17
TL;DR: This manuscript describes the use of ultrasound elastography, with the exception of liver applications, and represents an update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use ofElastography.
Abstract: This manuscript describes the use of ultrasound elastography, with the exception of liver applications, and represents an update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography.
Guy's and St Thomas' NHS Foundation Trust1, King's College London2, University of Göttingen3, Charité4, Claude Bernard University Lyon 15, Radboud University Nijmegen6, Pasteur Institute7, University Hospital Heidelberg8, University of Duisburg-Essen9, University of Amsterdam10, University of Valladolid11, Carlos III Health Institute12, University of Barcelona13, National and Kapodistrian University of Athens14, University of Modena and Reggio Emilia15, University of Bonn16, University of Medicine and Pharmacy of Craiova17, University of Bern18
TL;DR: The role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy are discussed.
Abstract: Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care.
University of Cambridge1, University of Edinburgh2, Imperial College London3, UCL Institute of Child Health4, Great Ormond Street Hospital for Children NHS Foundation Trust5, John Radcliffe Hospital6, University College London7, St Mary's Hospital8, University of Manchester9, Newcastle University10, Newcastle upon Tyne Hospitals NHS Foundation Trust11, St Bartholomew's Hospital12, Guy's and St Thomas' NHS Foundation Trust13, Papworth Hospital14, Cambridge University Hospitals NHS Foundation Trust15, UCL Institute of Neurology16, King's College London17, University of Oxford18, UCL Institute of Ophthalmology19, Moorfields Eye Hospital20, Imperial College Healthcare21, Queen Mary University of London22
TL;DR: The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background, as indicated by population genetic evidence that selection shapes the evolving mtDNA phylogeny.
Abstract: Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.
Dokuz Eylül University1, McMaster University2, University of Modena and Reggio Emilia3, St James's University Hospital4, University of Paris5, Guy's and St Thomas' NHS Foundation Trust6, King's College London7, Autonomous University of Barcelona8, Medical University of Warsaw9, University of Grenoble10, University of Freiburg11, University Medical Center Groningen12, University of Bern13, Witten/Herdecke University14
TL;DR: The task force conditionally supports the application of LTH-NIV to improve health outcome by targeting a reduction in carbon dioxide in COPD patients with persistent hypercapnic respiratory failure.
Abstract: Background While the role of acute non-invasive ventilation (NIV) has been shown to improve outcome in acute life-threatening hypercapnic respiratory failure in chronic obstructive pulmonary disease (COPD), the evidence of clinical efficacy of long-term home NIV (LTH-NIV) for management of COPD is less. This document provides evidence-based recommendations for the clinical application of LTH-NIV in chronic hypercapnic COPD patients. Materials and methods The European Respiratory Society Task Force (TF) committee was composed of clinicians, methodologists and experts in the field of LTH-NIV. The committee developed recommendations based on the GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology. The GRADE Evidence to Decision framework was used to formulate recommendations. A number of topics were addressed under a narrative format which provides a useful context for clinicians and patients. Results The TF committee delivered conditional recommendations for four actionable PICO (target population-intervention-comparator-outcome) questions, 1) suggesting for the use of LTH-NIV in stable hypercapnic COPD; 2) suggesting for the use of LTH-NIV in COPD patients following a COPD exacerbation requiring acute NIV 3) suggesting for the use of NIV settings targeting a reduction in carbon dioxide and 4) suggesting for using fixed pressure support as first choice ventilator mode. Conclusions Managing hypercapnia may be an important intervention for improving the health outcome of COPD patients with chronic respiratory failure. The TF conditionally supports the application of LTH-NIV to improve health outcome by targeting a reduction in carbon dioxide in COPD patients with persistent hypercapnic respiratory failure. These recommendations should be applied in clinical practice by practitioners that routinely care for chronic hypercapnic COPD patients.
University of Cambridge1, National Institute for Health Research2, The Breast Cancer Research Foundation3, University of Warwick4, Peterborough City Hospital5, Norfolk and Norwich University Hospital6, Northwood University7, University of Sussex8, University of Birmingham9, University of Southampton10, Royal Derby Hospital11, Guy's and St Thomas' NHS Foundation Trust12, Freeman Hospital13, Newcastle upon Tyne Hospitals NHS Foundation Trust14, Novartis15, Western General Hospital16, University of Exeter17, University of Leeds18, University of Manchester19
TL;DR: 6-month trastuzumab treatment is shown to be non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events, which support consideration of reduced duration trastzumab for women at similar risk of recurrence as to those included in the trial.
TL;DR: After 3 yr of prostate-specific antigen (PSA) testing, it is demonstrated that after 3’yr of screening, more serious prostate cancers are detected in men with BRCA2 mutations than in those without these mutations.
TL;DR: Both continuous positive airway pressure (CPAP) and noninvasive ventilation (NIV) improve clinical symptoms, quality of life, gas exchange, and sleep disordered breathing in OHS patients and are considered the first-line treatment modality for OHS phenotype with concomitant severe obstructive sleep apnoea.
Abstract: Obesity hypoventilation syndrome (OHS) is defined as hypercapnia during wakefulness in an obese patient, without any other known cause, accompanied with some form of sleep-disordered breathing as reported by Mokhlesi et al. (Proc Am Thorac Soc 5:218–25, 2008). Although the effects of OHS are inadequately studied, available data show that morbidity and mortality are high. Among those with obstructive sleep apnea (OSA), risk factors for having OHS include a higher body mass index (BMI), an increased severity of sleep-disordered breathing, and a restrictive defect on pulmonary function testing. While the pathophysiology of the disorder remains unclear, it likely involves the presence of several defects, most notably a blunted central respiratory drive. The most effective treatment option consists of ventilatory support during sleep, in the form of positive airway pressure therapy, with or without supplemental oxygen.
University of Zurich1, Guy's and St Thomas' NHS Foundation Trust2, National and Kapodistrian University of Athens3, Katholieke Universiteit Leuven4, Universidade Federal do Rio Grande do Sul5, Royal Hospital for Sick Children6, University of Edinburgh7, University of Grenoble8, University of Bern9, University of Hasselt10, Maastricht University Medical Centre11, Chiang Mai University12, University of Paris13, Medical University of Graz14, Queen's University15, Los Angeles Biomedical Research Institute16, Northumbria University17
TL;DR: The protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions are summarized, standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill are presented, and patients' perspectives on CPET obtained through an online survey are provided.
Abstract: The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients9 perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2–3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data.
TL;DR: Advice is presented for the organisational and clinical management of anaesthesia for day‐case surgery in adults and children based on previously published recommendations, clinical studies and expert opinion.
Abstract: Guidelines are presented for the organisational and clinical management of anaesthesia for day-case surgery in adults and children. The advice presented is based on previously published recommendations, clinical studies and expert opinion.
University of Salford1, University of Manchester2, University of Birmingham3, The Royal Marsden NHS Foundation Trust4, University College London5, Guy's and St Thomas' NHS Foundation Trust6, Institute of Cancer Research7, University of Bern8, Beatson West of Scotland Cancer Centre9, University of Glasgow10, Northampton Community College11, Cardiff University12
TL;DR: Coadministration of abiraterone acetate and prednisolone with androgen deprivation therapy (ADT) is associated with prolonged overall survival and disease control, compared with ADT alone, in all men with metastatic disease starting hormone therapy for the first time.
TL;DR: To evaluate the global prevalence of erectile dysfunction (ED); as well as its association with physiological and pathological ageing by examining the relationship between ED and cardiovascular disease, benign prostatic hyperplasia, and dementia.
Abstract: Objective To evaluate the global prevalence of erectile dysfunction (ED); as well as its association with physiological and pathological ageing by examining the relationship between ED and cardiovascular disease (CVD), benign prostatic hyperplasia (BPH), and dementia. We also aimed to characterise discrepancies caused by the use of different ED screening tools. Methods The Excerpta Medica dataBASE (EMBASE) and Medical Literature Analysis and Retrieval System Online (MEDLINE) were searched to find population-based studies investigating the prevalence of ED and the association between ED and CVD, BPH, and dementia in the general population. Results The global prevalence of ED was 3-76.5%. ED was associated with increasing age. Use of the International Index of Erectile Function (IIEF) and Massachusetts Male Aging Study (MMAS)-derived questionnaire identified a high prevalence of ED in young men. ED was positively associated with CVD. Men with ED have an increased risk of all-cause mortality odds ratio (OR) 1.26 (95% confidence interval [CI] 1.01-1.57), as well as CVD mortality OR 1.43 (95% CI 1.00-2.05). Men with ED are 1.33-6.24-times more likely to have BPH then men without ED, and 1.68-times more likely to develop dementia than men without ED. Conclusion ED screening tools in population-based studies are a major source of discrepancy. Non-validated questionnaires may be less sensitive than the IIEF and MMAS-derived questionnaire. ED constitutes a large burden on society given its high prevalence and impact on quality of life, and is also a risk factor for CVD, dementia, and all-cause mortality.
Memorial Sloan Kettering Cancer Center1, St George's, University of London2, European Society for Medical Oncology3, Guy's and St Thomas' NHS Foundation Trust4, University of Oxford5, University of Leicester6, University of Toulouse7, University of Texas MD Anderson Cancer Center8, The Royal Marsden NHS Foundation Trust9, Institute of Cancer Research10
TL;DR: Analysis of paired sequencing data from 17 152 cancer samples has generated recommendations regarding germline-focussed analyses of tumour-only sequencing data, indications for germline follow-up testing and guidance on patient information-giving and consent.
TL;DR: Two novel neural network architectures to detect pulmonary lesions in chest x‐rays imagesthat use visual attention mechanisms are proposed, designed to learn from a large number of weakly‐labelled images and a small number of annotated images.
TL;DR: In this article, consensus guidelines for the treatment of MS in pregnancy were developed to encourage and facilitate discussions in this important area, drawing on available evidence from drug-specific pregnancy registers and published literature and have been scored by a panel of experts from a variety of disciplines using modified Delphi criteria.
Abstract: Multiple sclerosis (MS) is more common in women than men and is most commonly diagnosed in early adulthood; thus, many patients will not have completed their families at the time of diagnosis. There is increasing awareness of the importance of early treatment in preventing long-term disability in MS. Delaying treatment until women with MS have completed their families can lead to the development of irreversible disability in at least some cases. It is therefore important to discuss family planning and pregnancy proactively. However, to date there is limited evidence to inform such discussions. We set out to develop consensus guidelines for the treatment of MS in pregnancy to encourage and facilitate discussions in this important area. The guidelines draw on available evidence from drug-specific pregnancy registers and published literature and have been scored by a panel of experts from a variety of disciplines using modified Delphi criteria. They cover prepregnancy counselling, management during pregnancy, delivery and anaesthetic options, postpartum advice and specific advice regarding currently licensed disease-modifying drugs. As the complexity and range of available disease-modifying drugs increase, further data gathering via a UK-wide MS pregnancy register is recommended.
TL;DR: Migraine is a life span neurological disorder that follows an evolutive age-dependent change in its prevalence and even clinical presentations, and genetic and epigenetic factors, inflammatory processes and central sensitization may play an important role.
Abstract: Understanding the mechanisms of migraine remains challenging as migraine is not a static disorder, and even in its episodic form migraine remains an “evolutive” chronic condition. Considerable progress has been made in elucidating the pathophysiological mechanisms of migraine, associated genetic factors that may influence susceptibility to the disease, and functional and anatomical changes during the progression of a migraine attack or the transformation of episodic to chronic migraine. Migraine is a life span neurological disorder that follows an evolutive age-dependent change in its prevalence and even clinical presentations. As a disorder, migraine involves recurrent intense head pain and associated unpleasant symptoms. Migraine attacks evolve over different phases with specific neural mechanisms and symptoms being involved during each phase. In some patients, migraine can be transformed into a chronic form with daily or almost daily headaches. The mechanisms behind this evolutive process remain unknown, but genetic and epigenetic factors, inflammatory processes and central sensitization may play an important role.
TL;DR: Recommendations to assist the clinician in the optimal management of patients at risk of low muscle mass include place muscle mass at the core of nutritional assessment and management strategies and optimize nutrition to focus on muscle mass gain versus weight gain alone.
TL;DR: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild and resulted in a sustained increase in the annualized growth velocity for up to 42 months.
Abstract: Background Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosor...
Royal Devon and Exeter Hospital1, University of Exeter2, University Medical Center Groningen3, Wellcome Trust Sanger Institute4, Harvard University5, University of Paris6, Royal Derby Hospital7, University Hospital Southampton NHS Foundation Trust8, Mater Dei Hospital9, University of Alberta10, University of Queensland11, NHS Greater Glasgow and Clyde12, Örebro University13, London North West Healthcare NHS Trust14, Guy's and St Thomas' NHS Foundation Trust15, Queen Mary University of London16, Newcastle upon Tyne Hospitals NHS Foundation Trust17, Cedars-Sinai Medical Center18, Cambridge University Hospitals NHS Foundation Trust19, Barts Health NHS Trust20, Hull and East Yorkshire Hospitals NHS Trust21, Canberra Hospital22
TL;DR: The findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.
Abstract: Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.