Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2018"
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Gregory A. Roth1, Gregory A. Roth2, Degu Abate3, Kalkidan Hassen Abate4 +1025 more•Institutions (333)
TL;DR: Non-communicable diseases comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5–74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional causes accounted for 18·6% (17·9–19·6), and injuries 8·0% (7·7–8·2).
5,211 citations
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The Royal Marsden NHS Foundation Trust1, University of Birmingham2, University College London3, University of Salford4, University of Manchester5, Guy's and St Thomas' NHS Foundation Trust6, St James's University Hospital7, Kantonsspital St. Gallen8, Beatson West of Scotland Cancer Centre9, Clatterbridge Cancer Centre NHS Foundation Trust10, Cardiff University11, University of Wolverhampton12, University of Glasgow13, University Hospitals Birmingham NHS Foundation Trust14, Queen Alexandra Hospital15, University of London16, Gloucestershire Hospitals NHS Foundation Trust17, Royal Surrey County Hospital18, Queen's University Belfast19, East Lancashire Hospitals NHS Trust20, Freeman Hospital21, Singleton Hospital22, Royal Devon and Exeter Hospital23, Telford24
TL;DR: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer, and the benefit would be greatest in patients with a low metastatic burden.
794 citations
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Evangelos Evangelou1, Evangelos Evangelou2, Helen R. Warren3, Helen R. Warren4 +338 more•Institutions (93)
TL;DR: In this article, the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry was conducted.
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future
728 citations
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Institute of Cancer Research1, King's College London2, Cardiff University3, Beatson West of Scotland Cancer Centre4, Imperial College London5, Nottingham University Hospitals NHS Trust6, The Breast Cancer Research Foundation7, Myriad Genetics8, Maidstone and Tunbridge Wells NHS Trust9, Weston Park Hospital10, University of North Carolina at Chapel Hill11, Francis Crick Institute12, University College London Hospitals NHS Foundation Trust13, Guy's and St Thomas' NHS Foundation Trust14, The Royal Marsden NHS Foundation Trust15, Manchester Academic Health Science Centre16, University of California, San Francisco17
TL;DR: The phase 3 TNT Trial in subjects with triple-negative breast cancer supports the superiority of carboplatin over docetaxel in BRCA1/2-mutated tumors and a greater response to taxanes in the nonbasal subtype, and concludes that patients with advanced TNBC benefit from characterization of BRC a/2 mutations, but not BRC1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy.
Abstract: Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.
620 citations
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TL;DR: Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date, and 9p loss is identified as a highly selected event driving metastasis and ccRCC-related mortality.
559 citations
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TL;DR: Treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose‐limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo, in this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut.
Abstract: BACKGROUND Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).
452 citations
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The Royal Marsden NHS Foundation Trust1, Francis Crick Institute2, Guy's and St Thomas' NHS Foundation Trust3, University of the Basque Country4, Wellcome Trust Sanger Institute5, University College London6, Max Delbrück Center for Molecular Medicine7, Eötvös Loránd University8, Technical University of Denmark9, Boston Children's Hospital10, Katholieke Universiteit Leuven11
TL;DR: The insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance and identify genetic diversity and chromosomal complexity as determinants of patient outcome.
440 citations
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Carolyn S. Calfee1, Kevin L. Delucchi1, Pratik Sinha1, Michael A. Matthay1 +163 more•Institutions (7)
TL;DR: Although HARP-2 found no difference in 28-day survival between placebo and simvastatin, significantly different survival was identified across patients stratified by treatment and subphenotype (p<0·0001), and within the hyperinflammatory subphenotypes, patients treated with simVastatin had significantly higher 28- day survival than did those given placebo.
404 citations
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TL;DR: Comprehensive genomic characterization identified distinct genetic subgroups and provided a classification of myeloproliferative neoplasms on the basis of causal biologic mechanisms and may support the treatment of patients with myelofibrosis.
Abstract: Background Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment. Methods We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes. We developed a genomic classification for myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients. Classification and prognostic models were validated in an external cohort. Results A total of 2035 patients were included in the analysis. A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms, and demographic variables independently predicted whether patients received a diagnosis of essential thrombocythemia as compared with polycythemia vera or a diagnosis of chronic-phase disease as compared with myelofibrosis. We defined eight genomic subgroups that showed distinct clinical phenotypes, including blood counts, risk of leukemic transformation, and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in patients with chronic-phase myeloproliferative neoplasms and myelofibrosis. The predicted and observed outcomes correlated well in internal cross-validation of a training cohort and in an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy. Conclusions Comprehensive genomic characterization identified distinct genetic subgroups and provided a classification of myeloproliferative neoplasms on the basis of causal biologic mechanisms. Integration of genomic data with clinical variables enabled the personalized predictions of patients’ outcomes and may support the treatment of patients with myeloproliferative neoplasms. (Funded by the Wellcome Trust and others.)
395 citations
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TL;DR: The data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.
392 citations
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TL;DR: In combination with dietary and physical activity counselling, semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared with placebo at all doses.
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TL;DR: The fecal metabolome largely reflects gut microbial composition and is strongly associated with visceral-fat mass, thereby illustrating potential mechanisms underlying the well-established microbial influence on abdominal obesity.
Abstract: The human gut microbiome plays a key role in human health
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, but 16S characterization lacks quantitative functional annotation
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. The fecal metabolome provides a functional readout of microbial activity and can be used as an intermediate phenotype mediating host–microbiome interactions
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. In this comprehensive description of the fecal metabolome, examining 1,116 metabolites from 786 individuals from a population-based twin study (TwinsUK), the fecal metabolome was found to be only modestly influenced by host genetics (heritability (H2) = 17.9%). One replicated locus at the NAT2 gene was associated with fecal metabolic traits. The fecal metabolome largely reflects gut microbial composition, explaining on average 67.7% (±18.8%) of its variance. It is strongly associated with visceral-fat mass, thereby illustrating potential mechanisms underlying the well-established microbial influence on abdominal obesity. Fecal metabolic profiling thus is a novel tool to explore links among microbiome composition, host phenotypes, and heritable complex traits. Comprehensive fecal metabolic profiling in 786 individuals from TwinsUK provides insights into the influence of host genetics and gut microbial composition on metabolites that may mediate microbiome-associated phenotypes.
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Mayo Clinic1, University of Florence2, University of Insubria3, Cornell University4, Icahn School of Medicine at Mount Sinai5, University of Texas MD Anderson Cancer Center6, University of Texas Health Science Center at San Antonio7, University of Paris8, Heidelberg University9, University of Barcelona10, Guy's and St Thomas' NHS Foundation Trust11, Queen's University Belfast12, RWTH Aachen University13, Catholic University of the Sacred Heart14, University of Hamburg15, Leibniz University of Hanover16, Uppsala University17
TL;DR: This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs), and both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea.
Abstract: This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.
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TL;DR: A global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends and a estimates of health-related SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous.
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TL;DR: Genomics England’s ambitious plans to embed genomic medicine into routine patient care are well underway and Clare Turnbull and colleagues discuss its progress.
Abstract: In partnership with NHS England, Genomics England’s ambitious plans to embed genomic medicine into routine patient care are well underway. Clare Turnbull and colleagues discuss its progress
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Christopher J L Murray1, Charlton S K H Callender1, Xie Rachel Kulikoff1, Vinay Srinivasan1 +1092 more•Institutions (424)
TL;DR: This work estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods and used the cohort-component method of population projection, with inputs of fertility, mortality, population, and migration data.
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TL;DR: The epidemiology and the public health response for the first diagnosed cases of monkeypox outside the African continent since 2003 are described.
Abstract: In early September 2018, two cases of monkeypox were reported in the United Kingdom (UK), diagnosed on 7 September in Cornwall (South West England) and 11 September in Blackpool (North West England). The cases were epidemiologically unconnected and had recently travelled to the UK from Nigeria, where monkeypox is currently circulating. We describe the epidemiology and the public health response for the first diagnosed cases outside the African continent since 2003.
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Lund University1, Autonomous University of Barcelona2, Ludwig Maximilian University of Munich3, Russian National Research Medical University4, Masaryk University5, University of Edinburgh6, Radboud University Nijmegen7, University of Nottingham8, Sahlgrenska University Hospital9, Guy's and St Thomas' NHS Foundation Trust10, RMIT University11, University of Perugia12
TL;DR: The ESAP provides a basic road map and sets targets for the implementation of evidence-based preventive actions and stroke services to 2030 and overall, 30 targets and 72 research priorities were identified for the seven domains.
Abstract: Two previous pan-European consensus meetings, the 1995 and 2006 Helsingborg meetings, were convened to review the scientific evidence and the state of current services to identify priorities for research and development and to set targets for the development of stroke care for the decade to follow. Adhering to the same format, the European Stroke Organisation (ESO) prepared a European Stroke Action Plan (ESAP) for the years 2018 to 2030, in cooperation with the Stroke Alliance for Europe (SAFE). The ESAP included seven domains: primary prevention, organisation of stroke services, management of acute stroke, secondary prevention, rehabilitation, evaluation of stroke outcome and quality assessment and life after stroke. Research priorities for translational stroke research were also identified. Documents were prepared by a working group and were open to public comments. The final document was prepared after a workshop in Munich on 21-23 March 2018. Four overarching targets for 2030 were identified: (1) to reduce the absolute number of strokes in Europe by 10%, (2) to treat 90% or more of all patients with stroke in Europe in a dedicated stroke unit as the first level of care, (3) to have national plans for stroke encompassing the entire chain of care, (4) to fully implement national strategies for multisector public health interventions. Overall, 30 targets and 72 research priorities were identified for the seven domains. The ESAP provides a basic road map and sets targets for the implementation of evidence-based preventive actions and stroke services to 2030.
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TL;DR: In this article, the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment was investigated.
Abstract: Background Interleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD). Objective We investigated the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment. Methods A randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12. Results In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate. Limitations Protocol-mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations. Conclusion When combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD.
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University of Basel1, University of Southampton2, Uppsala University3, Queen Elizabeth Hospital Birmingham4, Sapienza University of Rome5, Charité6, University of Lisbon7, University of Nice Sophia Antipolis8, University of Bern9, Guy's and St Thomas' NHS Foundation Trust10, University of Hohenheim11
TL;DR: Despite the methodological difficulties in creating non-disease specific guidelines, the evidence behind several important aspects of nutritional support for polymorbid medical inpatients was reviewed and summarized into practical clinical recommendations.
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TL;DR: Local anesthetic systemic toxicity is a life-threatening adverse event that may occur after the administration of local anesthetic drugs through a variety of routes and can be mitigated by targeting the modifiable risk factors and restricting drug dosage.
Abstract: Local anesthetic systemic toxicity (LAST) is a life-threatening adverse event that may occur after the administration of local anesthetic drugs through a variety of routes. Increasing use of local anesthetic techniques in various healthcare settings makes contemporary understanding of LAST highly relevant. Recent data have demonstrated that the underlying mechanisms of LAST are multifactorial, with diverse cellular effects in the central nervous system and cardiovascular system. Although neurological presentation is most common, LAST often presents atypically, and one-fifth of the reported cases present with isolated cardiovascular disturbance. There are several risk factors that are associated with the drug used and the administration technique. LAST can be mitigated by targeting the modifiable risk factors, including the use of ultrasound for regional anesthetic techniques and restricting drug dosage. There have been significant developments in our understanding of LAST treatment. Key advances include early administration of lipid emulsion therapy, prompt seizure management, and careful selection of cardiovascular supportive pharmacotherapy. Cognizance of the mechanisms, risk factors, prevention, and therapy of LAST is vital to any practitioner using local anesthetic drugs in their clinical practice.
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Icahn School of Medicine at Mount Sinai1, University of Michigan2, Cleveland Clinic3, Northwestern University4, University of Toronto5, University of Szeged6, Beatson West of Scotland Cancer Centre7, Stanford University8, University of California, San Diego9, Guy's and St Thomas' NHS Foundation Trust10, Mayo Clinic11, University of Texas MD Anderson Cancer Center12
TL;DR: In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms.
Abstract: Importance Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib. Objective To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia. Design, Setting, and Participants For this phase 3 randomized international multicenter study—the PERSIST-2 study—of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 10 9 /L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly. Interventions Patients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT. Main Outcomes and Measures Coprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data. Results Overall, 311 patients (mean [SD] age, 63.70 [9.08] years; 171 men [55%] and 140 women [45%]) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients [18%] vs 2 patients [3%]; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients [25%] vs 10 patients [14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; ≥50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients [31%], 34 patients [32%], 18 patients [18%]), and anemia (28 patients [27%], 23 patients [22%], 14 patients [14%]). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%). Conclusions and Relevance In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms. Trial Registration clinicaltrials.gov Identifier:NCT02055781
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TL;DR: Assessment of factors that can influence tissue and immune responses to food antigens, the current understanding of immune tolerance development, the role of the gastrointestinal microbiota, and current knowledge regarding immunologic mechanisms involved in desensitization and sustained unresponsiveness are assessed.
Abstract: Although oral tolerance is the normal physiologic response to ingested antigens, a breakdown in this process appears to have occurred in the past 2 decades, leading to an increasing prevalence of sensitization to food allergens. Over the past decade, basic research has intensified in an attempt to better understand the mechanisms leading to sensitization and disease versus desensitization and short- and long-term tolerance. In this review we assess various factors that can influence tissue and immune responses to food antigens, the current understanding of immune tolerance development, the role of the gastrointestinal microbiota, and current knowledge regarding immunologic mechanisms involved in desensitization and sustained unresponsiveness, although perhaps the latter is more appropriately termed remission.
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TL;DR: In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations.
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
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Mohsen Naghavi1, Laurie B. Marczak1, Michael Kutz1, Katya Anne Shackelford1 +191 more•Institutions (112)
TL;DR: Between 195 000 and 276 000 firearm injury deaths globally in 2016 were estimated, the majority of which were firearm homicides, and there was variation among countries and across demographic subgroups.
Abstract: Importance Understanding global variation in firearm mortality rates could guide prevention policies and interventions. Objective To estimate mortality due to firearm injury deaths from 1990 to 2016 in 195 countries and territories. Design, Setting, and Participants This study used deidentified aggregated data including 13 812 location-years of vital registration data to generate estimates of levels and rates of death by age-sex-year-location. The proportion of suicides in which a firearm was the lethal means was combined with an estimate of per capita gun ownership in a revised proxy measure used to evaluate the relationship between availability or access to firearms and firearm injury deaths. Exposures Firearm ownership and access. Main Outcomes and Measures Cause-specific deaths by age, sex, location, and year. Results Worldwide, it was estimated that 251 000 (95% uncertainty interval [UI], 195 000-276 000) people died from firearm injuries in 2016, with 6 countries (Brazil, United States, Mexico, Colombia, Venezuela, and Guatemala) accounting for 50.5% (95% UI, 42.2%-54.8%) of those deaths. In 1990, there were an estimated 209 000 (95% UI, 172 000 to 235 000) deaths from firearm injuries. Globally, the majority of firearm injury deaths in 2016 were homicides (64.0% [95% UI, 54.2%-68.0%]; absolute value, 161 000 deaths [95% UI, 107 000-182 000]); additionally, 27% were firearm suicide deaths (67 500 [95% UI, 55 400-84 100]) and 9% were unintentional firearm deaths (23 000 [95% UI, 18 200-24 800]). From 1990 to 2016, there was no significant decrease in the estimated global age-standardized firearm homicide rate (−0.2% [95% UI, −0.8% to 0.2%]). Firearm suicide rates decreased globally at an annualized rate of 1.6% (95% UI, 1.1-2.0), but in 124 of 195 countries and territories included in this study, these levels were either constant or significant increases were estimated. There was an annualized decrease of 0.9% (95% UI, 0.5%-1.3%) in the global rate of age-standardized firearm deaths from 1990 to 2016. Aggregate firearm injury deaths in 2016 were highest among persons aged 20 to 24 years (for men, an estimated 34 700 deaths [95% UI, 24 900-39 700] and for women, an estimated 3580 deaths [95% UI, 2810-4210]). Estimates of the number of firearms by country were associated with higher rates of firearm suicide ( P R2 = 0.21) and homicide ( P R2 = 0.35). Conclusions and Relevance This study estimated between 195 000 and 276 000 firearm injury deaths globally in 2016, the majority of which were firearm homicides. Despite an overall decrease in rates of firearm injury death since 1990, there was variation among countries and across demographic subgroups.
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TL;DR: The document aims to offer an appraisal of all relevant literature up to July 2017, focusing on any key developments, and address important, practical clinical questions relating to the primary guideline objective.
Abstract: The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of lichen sclerosus (LS) in adults (18+ years), children (0-12 years) and young people (13-17 years). The document aims to. offer an appraisal of all relevant literature up to July 2017, focusing on any key developments. address important, practical clinical questions relating to the primary guideline objective. provide guideline recommendations and if appropriate research recommendations. The guideline is presented as a detailed review with highlighted recommendations for practical use in primary care and in secondary care clinics, in addition to an updated Patient Information Leaflet (PIL; available on the BAD website, http://www.bad.org.uk/for-the-public/patient-information-leaflets). This article is protected by copyright. All rights reserved.
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Cardiff University1, University of Salford2, Institute of Cancer Research3, University College London4, Guy's and St Thomas' NHS Foundation Trust5, University of Bern6, Kantonsspital St. Gallen7, Clatterbridge Cancer Centre NHS Foundation Trust8, University of Glasgow9, Beatson West of Scotland Cancer Centre10, The Royal Marsden NHS Foundation Trust11, University of Wolverhampton12, Poole Hospital13, Worcestershire Acute Hospitals NHS Trust14, Royal Derby Hospital15, Manchester Academic Health Science Centre16, University of Manchester17, Queen Elizabeth Hospital Birmingham18, Queen Alexandra Hospital19, The Queen's Medical Center20, Royal Sussex County Hospital21, Mount Vernon Hospital22, Western General Hospital23, Belfast City Hospital24, Queen's University Belfast25, University of Oxford26, Royal Surrey County Hospital27, Royal Devon and Exeter Hospital28, Hull and East Yorkshire Hospitals NHS Trust29, Telford30, Nottingham University Hospitals NHS Trust31, Musgrove Park Hospital32, Swansea University33, University of Birmingham34
TL;DR: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events.
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TL;DR: Evidence and practice guidance are provided to assist in delivering high-quality clinical service in relation to the low FODMAP diet.
Abstract: Dietary restriction of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) is effective in the management of functional gastrointestinal symptoms that occur in irritable bowel syndrome (IBS). Numerous reviews have been published regarding the evidence for their restriction in the low FODMAP diet; however, few reviews discuss the implementation of the low FODMAP diet in practice. The aim of this review is to provide practical guidance on patient assessment and the implementation and monitoring of the low FODMAP diet. Broadly speaking, the low FODMAP diet consists of three stages: FODMAP restriction; FODMAP reintroduction; and FODMAP personalisation. These stages can be covered in at least two dietetic appointments. The first appointment focuses on confirmation of diagnosis, comprehensive symptom and dietary assessment, detailed description of FODMAPs and their association with symptom induction, followed by counselling regarding FODMAP restriction. Dietary counselling should be tailored to individual needs and appropriate resources provided. At the second appointment, symptoms and diet are re-assessed and, if restriction has successfully reduced IBS symptoms, education is provided on FODMAP reintroduction to identify foods triggering symptoms. Following this, the patient can follow FODMAP personalisation for which a less restrictive diet is consumed that excludes their personal FODMAP triggers and enables a more diverse dietary intake. This review provides evidence and practice guidance to assist in delivering high-quality clinical service in relation to the low FODMAP diet.
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University of Bristol1, Great Western Hospital2, Staffordshire University3, North Tees and Hartlepool NHS Foundation Trust4, South Tees Hospitals NHS Trust5, Guy's and St Thomas' NHS Foundation Trust6, University of Manchester7, Lancashire Teaching Hospitals NHS Foundation Trust8, Cambridge University Hospitals NHS Foundation Trust9, Northumbria Healthcare NHS Foundation Trust10, Sherwood Forest Hospitals NHS Foundation Trust11, NHS Ayrshire and Arran12, Worcestershire Acute Hospitals NHS Trust13, United Hospitals14, Aintree University Hospitals NHS Foundation Trust15, Hampshire Hospitals NHS Foundation Trust16, University of Oxford17, North Bristol NHS Trust18, Sir Charles Gairdner Hospital19, University College London20
TL;DR: Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an ind welling catheter alone, with no deleterious effects.
Abstract: Background Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. Methods Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo thr...
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University of Tennessee at Chattanooga1, University of Pittsburgh2, Royal Melbourne Hospital3, University of Melbourne4, Guy's and St Thomas' NHS Foundation Trust5, Emory University6, University of Minnesota7, Mayo Clinic8, Baylor University Medical Center9, Barts Health NHS Trust10, Queen Mary University of London11, University of Texas Health Science Center at Houston12, Royal Surrey County Hospital13
TL;DR: In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement Therapy liberation was greater in the angiotensin II group versus the placebo group.
Abstract: OBJECTIVE: Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy. DESIGN: Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial. SETTING: ICUs. PATIENTS: Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo (n = 45 and n = 60, respectively). INTERVENTIONS: IV angiotensin II or placebo. MEASUREMENTS AND MAIN RESULTS: Primary end point: survival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of ≥ 10 mm Hg or increase to ≥ 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%-67%) and 30% (95% CI, 19%-41%) in patients treated with angiotensin II and placebo (p = 0.012), respectively. By day 7, 38% (95% CI, 25%-54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%-27%) placebo (p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%-68%) and 22% (95% CI, 12%-34%) of patients treated with angiotensin II and placebo (p = 0.001), respectively. CONCLUSIONS: In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II.