Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2017"
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Theo Vos1, Amanuel Alemu Abajobir, Kalkidan Hassen Abate2, Cristiana Abbafati3 +775 more•Institutions (305)
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016.
10,401 citations
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Valery L. Feigin1, Amanuel Alemu Abajobir2, Kalkidan Hassen Abate3, Foad Abd-Allah4 +267 more•Institutions (138)
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors (GBD) study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions as discussed by the authors.
Abstract: Summary Background Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level. Methods We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development. Findings Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs. Interpretation Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services. Funding Bill & Melinda Gates Foundation.
2,995 citations
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Wellcome Trust Sanger Institute1, University of Cambridge2, University of Melbourne3, Netherlands Cancer Institute4, University of Amsterdam5, University of Warwick6, Cancer Council Victoria7, University of Utah8, Columbia University9, Central Manchester University Hospitals NHS Foundation Trust10, Chapel Allerton Hospital11, Guy's and St Thomas' NHS Foundation Trust12, National Institute for Health Research13, University of Glasgow14, St George's, University of London15, Curie Institute16, Paris Descartes University17, Erasmus University Rotterdam18, Radboud University Nijmegen19, VU University Medical Center20, Cancer Prevention Institute of California21, University of Toronto22, Lunenfeld-Tanenbaum Research Institute23, Fox Chase Cancer Center24, Huntsman Cancer Institute25, Leipzig University26, German Cancer Research Center27, University of Cologne28, Hospital Clínico San Carlos29, Pomeranian Medical University30, Laval University31, University of New South Wales32, St. Vincent's Health System33, Peter MacCallum Cancer Centre34, QIMR Berghofer Medical Research Institute35, Medical University of Vienna36, Copenhagen University Hospital37, Karolinska Institutet38, Lund University39
TL;DR: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location, a large cohort study recruited in 1997-2011 provides estimates of cancer risk based on BRCA1 and BRCa2 mutation carrier status.
Abstract: Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.
1,733 citations
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University of California, Los Angeles1, University of Utah2, University of South Florida3, University of Helsinki4, Primary Children's Hospital5, University of Groningen6, Norfolk and Norwich University Hospital7, Lund University8, Netherlands Cancer Institute9, University of Michigan10, Wake Forest University11, Ohio State University12, Peter MacCallum Cancer Centre13, University of Zurich14, University of Padua15, Pennsylvania State University16, Saint Louis University17, Tom Baker Cancer Centre18, University of Washington19, University of Lausanne20, Guy's and St Thomas' NHS Foundation Trust21, University of Kiel22, Thomas Jefferson University23, Sunnybrook Research Institute24, Vanderbilt University25, University of Queensland26, Fox Chase Cancer Center27, Greenville Health System28, Stony Brook University29, University Health Network30, Memorial Sloan Kettering Cancer Center31, Roswell Park Cancer Institute32, Northwestern University33, University of Wisconsin-Madison34, Rush University Medical Center35, Tel Aviv Sourasky Medical Center36, Dartmouth College37, Johns Hopkins University38, University of Louisville39, University of Barcelona40, University of Sydney41
TL;DR: Immediate completion lymph‐node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma‐specific survival among patients with melanoma and sentinel‐node metastases.
Abstract: BackgroundSentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. MethodsIn an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. ResultsImmediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in t...
946 citations
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Wellcome Trust Sanger Institute1, Newcastle University2, Brigham and Women's Hospital3, Broad Institute4, University of Exeter5, Wellcome Trust Centre for Human Genetics6, Canterbury Christ Church University7, University of Edinburgh8, Torbay Hospital9, Royal Hospital for Sick Children10, Ninewells Hospital11, Guy's and St Thomas' NHS Foundation Trust12, University of Oxford13, John Radcliffe Hospital14, Norfolk and Norwich University Hospital15, King's College London16, University of the Witwatersrand17, University of Manchester18, Manchester Academic Health Science Centre19, University of Nottingham20
TL;DR: This work identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease and identified 3 associated variants that are correlated with expression changes in response to immune stimulus at two of these genes.
Abstract: Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.
813 citations
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Guy's and St Thomas' NHS Foundation Trust1, John Radcliffe Hospital2, University of Nottingham3, Brigham and Women's Hospital4, ISMETT5, Banaras Hindu University6, Newton Wellesley Hospital7, Madras Institute of Orthopaedics and Traumatology8, University of the West Indies9, University of Michigan10, Sahlgrenska University Hospital11, Queen Mary University of London12, Aga Khan University13, University of Manchester14, Virginia Commonwealth University15, University of Padua16, Changi General Hospital17, King's College London18, Southampton General Hospital19, Texas Tech University Health Sciences Center20, McMaster University21, University Hospital Waterford22, Turku University Hospital23, University of Mainz24, Bezmialem Foundation University25, Colchester Hospital University NHS Foundation Trust26, Kent State University27, Guy's Hospital28, Cairo University29, Children's of Alabama30
TL;DR: The development of the STROCSS guideline (Strengthening the Reporting of Cohort Studies in Surgery), consisting of a 17-item checklist, is described and it is hoped its use will increase the transparency and reporting quality of such studies.
736 citations
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Wellcome Trust Sanger Institute1, Guy's and St Thomas' NHS Foundation Trust2, Lund University3, AstraZeneca4, Erasmus University Medical Center5, University of Queensland6, Memorial Sloan Kettering Cancer Center7, University of Iceland8, Hanyang University9, Wellcome Trust10, Radboud University Nijmegen11, University of Amsterdam12, University of Oslo13, Royal Brisbane and Women's Hospital14, Curie Institute15, Université libre de Bruxelles16, King's College London17, University of Antwerp18, Harvard University19, Cambridge University Hospitals NHS Foundation Trust20
TL;DR: In this article, a weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples with 98.7% sensitivity (area under the curve (AUC) = 0.98).
Abstract: Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.
710 citations
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23 Feb 2017
TL;DR: Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.
Abstract: Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (cafe-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.
639 citations
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University of Kiel1, University of São Paulo2, Boston Children's Hospital3, Furtwangen University4, University of Mainz5, Carleton University6, Sahlgrenska University Hospital7, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico8, Guy's and St Thomas' NHS Foundation Trust9, University of Queensland10, Erasmus University Rotterdam11, RWTH Aachen University12
TL;DR: A new classification of core processes involved in chest EIT examinations and data analysis is provided, and a structured framework to categorise and understand the relationships among analysis approaches and their clinical roles is provided.
Abstract: Electrical impedance tomography (EIT) has undergone 30 years of development. Functional chest examinations with this technology are considered clinically relevant, especially for monitoring regional lung ventilation in mechanically ventilated patients and for regional pulmonary function testing in patients with chronic lung diseases. As EIT becomes an established medical technology, it requires consensus examination, nomenclature, data analysis and interpretation schemes. Such consensus is needed to compare, understand and reproduce study findings from and among different research groups, to enable large clinical trials and, ultimately, routine clinical use. Recommendations of how EIT findings can be applied to generate diagnoses and impact clinical decision-making and therapy planning are required. This consensus paper was prepared by an international working group, collaborating on the clinical promotion of EIT called TRanslational EIT developmeNt stuDy group. It addresses the stated needs by providing (1) a new classification of core processes involved in chest EIT examinations and data analysis, (2) focus on clinical applications with structured reviews and outlooks (separately for adult and neonatal/paediatric patients), (3) a structured framework to categorise and understand the relationships among analysis approaches and their clinical roles, (4) consensus, unified terminology with clinical user-friendly definitions and explanations, (5) a review of all major work in thoracic EIT and (6) recommendations for future development (193 pages of online supplements systematically linked with the chief sections of the main document). We expect this information to be useful for clinicians and researchers working with EIT, as well as for industry producers of this technology.
555 citations
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Cleveland Clinic1, University of Ottawa2, Duke University3, Regions Hospital4, University of Tennessee5, Baylor University Medical Center6, Emory University7, University of California, Davis8, University of California, Los Angeles9, Riverside Methodist Hospital10, Northwestern University11, Guy's and St Thomas' NHS Foundation Trust12, University of Pittsburgh13, Yeshiva University14, University of Newcastle15, university of lille16, University of Melbourne17, Lille University of Science and Technology18, University of Helsinki19, Harvard University20, University of Maryland, Baltimore21
TL;DR: Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors.
Abstract: BackgroundVasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. MethodsWe randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. ResultsA total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiote...
499 citations
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Papworth Hospital1, Abertawe Bro Morgannwg University Health Board2, St James's University Hospital3, Newcastle University4, Manchester Royal Infirmary5, Western General Hospital6, National Institutes of Health7, Guy's and St Thomas' NHS Foundation Trust8, British Thoracic Society9, University of Manchester10, Great Ormond Street Hospital for Children NHS Foundation Trust11, Southmead Hospital12, Queen Alexandra Hospital13, University of Cambridge14
TL;DR: Recommendations and recommendations on what samples should be used to detect pulmonary non-tuberculous mycobacterial infection and how to define lung disease attributable to NTM infection are presented.
Abstract: Section 4: What is the evidence for transmission of NTM between individuals?
Recommendation
Section 5: How should the lung disease attributable to NTM infection be defined?
Recommendation
Good practice point
Section 6: What samples should be used to detect pulmonary non-tuberculous mycobacterial infection?
Recommendations
Good practice points
Section …
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TL;DR: In this paper, the authors use the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.
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TL;DR: The Global Burden of Disease Study 2013 as discussed by the authors includes estimates of global morbidity and mortality due to skin diseases, including 15 skin conditions, including dermatitis, contact, and seborrheic dermatitis.
Abstract: Importance Disability secondary to skin conditions is substantial worldwide. The Global Burden of Disease Study 2013 includes estimates of global morbidity and mortality due to skin diseases. Objective To measure the burden of skin diseases worldwide. Data Sources For nonfatal estimates, data were found by literature search using PubMed and Google Scholar in English and Spanish for years 1980 through 2013 and by accessing administrative data on hospital inpatient and outpatient episodes. Data for fatal estimates were based on vital registration and verbal autopsy data. Study Selection Skin disease data were extracted from more than 4000 sources including systematic reviews, surveys, population-based disease registries, hospital inpatient data, outpatient data, cohort studies, and autopsy data. Data metrics included incidence, prevalence, remission, duration, severity, deaths, and mortality risk. Data Extraction and Synthesis Data were extracted by age, time period, case definitions, and other study characteristics. Data points were modeled with Bayesian meta-regression to generate estimates of morbidity and mortality metrics for skin diseases. All estimates were made with 95% uncertainty intervals. Main Outcomes and Measures Disability-adjusted life years (DALYs), years lived with disability, and years of life lost from 15 skin conditions in 188 countries. Results Skin conditions contributed 1.79% to the global burden of disease measured in DALYs from 306 diseases and injuries in 2013. Individual skin diseases varied in size from 0.38% of total burden for dermatitis (atopic, contact, and seborrheic dermatitis), 0.29% for acne vulgaris, 0.19% for psoriasis, 0.19% for urticaria, 0.16% for viral skin diseases, 0.15% for fungal skin diseases, 0.07% for scabies, 0.06% for malignant skin melanoma, 0.05% for pyoderma, 0.04% for cellulitis, 0.03% for keratinocyte carcinoma, 0.03% for decubitus ulcer, and 0.01% for alopecia areata. All other skin and subcutaneous diseases composed 0.12% of total DALYs. Conclusions and Relevance Skin and subcutaneous diseases were the 18th leading cause of global DALYs in Global Burden of Disease 2013. Excluding mortality, skin diseases were the fourth leading cause of disability worldwide.
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King's College London1, Guy's and St Thomas' NHS Foundation Trust2, University College London3, Northumbria Healthcare NHS Foundation Trust4, Newcastle University5, University of Liverpool6, University of Wolverhampton7, Swansea University8, University of Oxford9, Papworth Hospital10, Imperial College London11, University of Leeds12
TL;DR: Among patients with persistent hypercapnia following an acute exacerbation of COPD, adding home noninvasive ventilation to home oxygen therapy prolonged the time to readmission or death within 12 months.
Abstract: Importance Outcomes after exacerbations of chronic obstructive pulmonary disease (COPD) requiring acute noninvasive ventilation (NIV) are poor and there are few treatments to prevent hospital readmission and death Objective To investigate the effect of home NIV plus oxygen on time to readmission or death in patients with persistent hypercapnia after an acute COPD exacerbation Design, Setting, and Participants A randomized clinical trial of patients with persistent hypercapnia (Paco 2 >53 mm Hg) 2 weeks to 4 weeks after resolution of respiratory acidemia, who were recruited from 13 UK centers between 2010 and 2015 Exclusion criteria included obesity (body mass index [BMI] >35), obstructive sleep apnea syndrome, or other causes of respiratory failure Of 2021 patients screened, 124 were eligible Interventions There were 59 patients randomized to home oxygen alone (median oxygen flow rate, 10 L/min [interquartile range {IQR}, 05-20 L/min]) and 57 patients to home oxygen plus home NIV (median oxygen flow rate, 10 L/min [IQR, 05-15 L/min]) The median home ventilator settings were an inspiratory positive airway pressure of 24 (IQR, 22-26) cm H 2 O, an expiratory positive airway pressure of 4 (IQR, 4-5) cm H 2 O, and a backup rate of 14 (IQR, 14-16) breaths/minute Main Outcomes and Measures Time to readmission or death within 12 months adjusted for the number of previous COPD admissions, previous use of long-term oxygen, age, and BMI Results A total of 116 patients (mean [SD] age of 67 [10] years, 53% female, mean BMI of 216 [IQR, 182-261], mean [SD] forced expiratory volume in the first second of expiration of 06 L [02 L], and mean [SD] Paco 2 while breathing room air of 59 [7] mm Hg) were randomized Sixty-four patients (28 in home oxygen alone and 36 in home oxygen plus home NIV) completed the 12-month study period The median time to readmission or death was 43 months (IQR, 13-138 months) in the home oxygen plus home NIV group vs 14 months (IQR, 05-39 months) in the home oxygen alone group, adjusted hazard ratio of 049 (95% CI, 031-077; P = 002) The 12-month risk of readmission or death was 634% in the home oxygen plus home NIV group vs 804% in the home oxygen alone group, absolute risk reduction of 170% (95% CI, 01%-340%) At 12 months, 16 patients had died in the home oxygen plus home NIV group vs 19 in the home oxygen alone group Conclusions and Relevance Among patients with persistent hypercapnia following an acute exacerbation of COPD, adding home noninvasive ventilation to home oxygen therapy prolonged the time to readmission or death within 12 months Trial Registration clinicaltrialsgov Identifier:NCT00990132
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TL;DR: In this article, the authors used 1000 Genomes Project-imputed genotype data in up to ∼370,000 women to identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development.
Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
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VU University Medical Center1, University of Alberta2, Edith Cowan University3, Netherlands Cancer Institute4, University of South Florida5, Utrecht University6, German Cancer Research Center7, Yale University8, Queensland University of Technology9, University of Maryland, Baltimore10, European University of Madrid11, Maastricht University12, University of Groningen13, University of Amsterdam14, University of Edinburgh15, University of Birmingham16, University of Glasgow17, University of Antwerp18, University of Oslo19, University of Hamburg20, University of Adelaide21, University of Newcastle22, Guy's and St Thomas' NHS Foundation Trust23, University Hospital Heidelberg24, King's College London25, Pennsylvania State University26, Oregon Health & Science University27, Johns Hopkins University28
TL;DR: In conclusion, exercise, and particularly supervised exercise, effectively improves QoL and PF in patients with cancer with different demographic and clinical characteristics during and following treatment.
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St. Michael's Hospital1, Queen's University2, Sunnybrook Health Sciences Centre3, Guy's and St Thomas' NHS Foundation Trust4, California Pacific Medical Center5, Johns Hopkins University School of Medicine6, Katholieke Universiteit Leuven7, University of Genoa8, Université libre de Bruxelles9, Houston Methodist Hospital10
TL;DR: A scoping review of the peer‐reviewed and gray literature was undertaken to assemble existing models for ICU stratification and present a proposed definition and classification of ICUs.
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Frederick Arce Vargas1, Andrew Furness1, Andrew Furness2, Isabelle Solomon1 +247 more•Institutions (7)
TL;DR: Use of an anti‐CD25 antibody with enhanced binding to activating Fc&ggr;Rs led to effective depletion of tumor‐infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors.
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TL;DR: T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.
Abstract: PurposeTrastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study.MethodsIn the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review.ResultsT-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared wi...
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Catherine M. Phelan, Karoline Kuchenbaecker1, Karoline Kuchenbaecker2, Jonathan Tyrer1 +440 more•Institutions (156)
TL;DR: Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
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TL;DR: Both the 2-week and 4-week ixekizumab dosing regimens improved the signs and symptoms of patients with active psoriatic arthritis and who had previously inadequate response to tumour necrosis factor inhibitors, with a safety profile consistent with previous studies investigating ixeksedumab.
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TL;DR: In a placebo-controlled study of patients with IBS, a low FODMAP diet associates with adequate symptom relief and significantly reduced symptom scores compared with placebo.
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TL;DR: Once‐monthly subcutaneous administration of fitusiran resulted in dose‐dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies.
Abstract: BackgroundCurrent hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. MethodsIn this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to ass...
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TL;DR: The role of biomechanics, prostaglandin E2-mediated vasodilation and the activation of innate immune cells in the initiation phase of enthesitis, as well as the role of entheseal IL-23-responsive cells that augment inflammation by producing pro-inflammatory mediators such as IL-17A, IL-22 and TNF are addressed.
Abstract: Entheses are the insertion sites of tendons and ligaments to the bone surface and are essential structures for locomotion. Inflammation of the entheses (enthesitis) is a key feature of psoriatic arthritis and spondyloarthritis. To date, our conceptual understanding of enthesitis remains limited. This Review provides an insight into the pathophysiology of enthesitis, addressing the role of biomechanics, prostaglandin E2-mediated vasodilation and the activation of innate immune cells in the initiation phase of enthesitis, as well as the role of entheseal IL-23-responsive cells that augment inflammation by producing pro-inflammatory mediators such as IL-17A, IL-22 and TNF. In addition, the molecular steps that translate inflammation into resident tissue responses, resulting in new bone formation, are discussed. The second part of the article summarizes the clinical features of enthesitis, and the role of clinical and imaging instruments in detecting enthesitis are discussed together with their challenges and limitations. Finally, the Review summarizes the current treatment possibilities for enthesitis based on the aforementioned pathophysiological concepts, focusing on the role of cytokine-blocking agents.
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Imperial College London1, National Institutes of Health2, Swiss Institute of Allergy and Asthma Research3, University of Veterinary Medicine Vienna4, Medical University of Vienna5, Utrecht University6, Technische Universität München7, King's College London8, Guy's and St Thomas' NHS Foundation Trust9, Copenhagen University Hospital10, University of Paris11, Heidelberg University12
TL;DR: Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers that are predictive of the clinical response to AIT.
Abstract: Background
Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers.
Method
The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?).
Results
All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed.
Conclusions
It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.
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Roger L. Milne1, Roger L. Milne2, Karoline Kuchenbaecker3, Karoline Kuchenbaecker4 +509 more•Institutions (169)
TL;DR: A genome-wide association study (GWAS) of predominantly estrogen receptor (ER)-positive disease and BRCA1 mutation carrier GWAS observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies, which explain approximately 16% of the familial risk of this breast cancer subtype.
Abstract: Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
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TL;DR: The quality of evidence at the outcome level was "moderate", downgraded from "high" because of lack of blinding in the included trials, and potential causes of heterogeneity via sensitivity analyses.
Abstract: BACKGROUND: Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes, reduce the risk of NEC. However, slow feed advancement may delay establishment of full enteral feeding and may be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine effects of slow rates of enteral feed advancement on the incidence of NEC, mortality, and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We used the standard Cochrane Neonatal search strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 5), MEDLINE via PubMed (1966 to June 2017), Embase (1980 to June 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to June 2017). We searched clinical trials databases, conference proceedings, previous reviews, and reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed effects of slow (up to 24 mL/kg/d) versus faster rates of advancement of enteral feed volumes upon the incidence of NEC in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported risk ratio (RR) and risk difference (RD) for dichotomous data, and mean difference (MD) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model for meta-analyses and explored potential causes of heterogeneity via sensitivity analyses. We assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified 10 RCTs in which a total of 3753 infants participated (2804 infants participated in one large trial). Most participants were stable very preterm infants of birth weight appropriate for gestation. About one-third of all participants were extremely preterm or extremely low birth weight (ELBW), and about one-fifth were small for gestational age (SGA), growth-restricted, or compromised in utero, as indicated by absent or reversed end-diastolic flow velocity (AREDFV) in the fetal umbilical artery. Trials typically defined slow advancement as daily increments of 15 to 20 mL/kg, and faster advancement as daily increments of 30 to 40 mL/kg. Trials generally were of good methodological quality, although none was blinded.Meta-analyses did not show effects on risk of NEC (typical RR 1.07, 95% CI 0.83 to 1.39; RD 0.0, 95% CI -0.01 to 0.02) or all-cause mortality (typical RR 1.15, 95% CI 0.93 to 1.42; typical RD 0.01, 95% CI -0.01 to 0.03). Subgroup analyses of extremely preterm or ELBW infants, or of SGA or growth-restricted or growth-compromised infants, showed no evidence of an effect on risk of NEC or death. Slow feed advancement delayed establishment of full enteral nutrition by between about one and five days. Meta-analysis showed borderline increased risk of invasive infection (typical RR 1.15, 95% CI 1.00 to 1.32; typical RD 0.03, 95% CI 0.00 to 0.05). The GRADE quality of evidence for primary outcomes was "moderate", downgraded from "high" because of lack of blinding in the included trials. AUTHORS' CONCLUSIONS: Available trial data do not provide evidence that advancing enteral feed volumes at daily increments of 15 to 20 mL/kg (compared with 30 to 40 mL/kg) reduces the risk of NEC or death in very preterm or VLBW infants, extremely preterm or ELBW infants, SGA or growth-restricted infants, or infants with antenatal AREDFV. Advancing the volume of enteral feeds at a slow rate results in several days of delay in establishing full enteral feeds and may increase the risk of invasive infection.
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Cardiff University1, Charité2, University of Messina3, Monash University4, University of York5, University of Toronto6, University of East London7, University Hospital Southampton NHS Foundation Trust8, University of Southampton9, St Mary's Hospital10, Heidelberg University11, National Institutes of Health12, Eskişehir Osmangazi University13, Erasmus University Rotterdam14, Odense University Hospital15, Bethel University16, Ruhr University Bochum17, Katholieke Universiteit Leuven18, Utrecht University19, Johns Hopkins University20, National and Kapodistrian University of Athens21, University Medical Center Groningen22, University of Groningen23, Nippon Medical School24, University of Milan25, University of Cyprus26, University College London27, University of Graz28, European Union29, Guy's and St Thomas' NHS Foundation Trust30, University of Edinburgh31
TL;DR: A systematic review to assess the effectiveness, cost‐effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis found it to be effective, cost-effective, and safe.
Abstract: Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. To inform the development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost-effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis. Methods: We searched nine international biomedical databases for published, in-progress, and unpublished evidence. Studies were independently screened by two reviewers against predefined eligibility criteria and critically appraised using established instruments. Our primary outcomes of interest were symptom, medication, and combined symptom and medication scores. Secondary outcomes of interest included cost-effectiveness and safety. Data were descriptively summarized and then quantitatively synthesized using random-effects meta-analyses. Results: We identified 5960 studies of which 160 studies satisfied our eligibility criteria. There was a substantial body of evidence demonstrating significant reductions in standardized mean differences (SMD) of symptom (SMD −0.53, 95% CI −0.63, −0.42), medication (SMD −0.37, 95% CI −0.49, −0.26), and combined symptom and medication (SMD −0.49, 95% CI −0.69, −0.30) scores while on treatment that were robust to prespecified sensitivity analyses. There was in comparison a more modest body of evidence on effectiveness post-discontinuation of AIT, suggesting a benefit in relation to symptom scores. Conclusions: AIT is effective in improving symptom, medication, and combined symptom and medication scores in patients with allergic rhinoconjunctivitis while on treatment, and there is some evidence suggesting that these benefits are maintained in relation to symptom scores after discontinuation of therapy.
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TL;DR: It is proposed that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.
Abstract: Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.
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TL;DR: The protocol for the development of the STROCSS Guideline for surgical cohort studies is provided and dissemination to interested parties and journals will be encouraged to endorse the reporting guideline.