Showing papers by "St Thomas' Hospital published in 2017"
St George’s University Hospitals NHS Foundation Trust1, New York University2, McMaster University3, Brown University4, Catholic University of the Sacred Heart5, Autonomous University of Barcelona6, University of Manitoba7, Emory University8, Hebrew University of Jerusalem9, University of Toronto10, University of Pittsburgh11, St Thomas' Hospital12, University College London13, Vanderbilt University14, Keio University15, Memorial Hospital of South Bend16, Rowan University17, University of Mississippi18, Rush University Medical Center19, University of Ulsan20, Universidade Federal do Rio Grande do Sul21, Federal University of São Paulo22, Regions Hospital23, Washington University in St. Louis24, University of Ottawa25, University of Sydney26, University of New South Wales27, Fujita Health University28, University of Copenhagen29, Sapienza University of Rome30, Christiana Care Health System31, Stanford University32, King Abdullah University of Science and Technology33, University of Kansas34, Harvard University35, California Pacific Medical Center36, University of Amsterdam37, Université libre de Bruxelles38, Houston Methodist Hospital39
TL;DR: A consensus committee of 55 international experts representing 25 international organizations was assembled at key international meetings (forSurviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012 as discussed by the authors ).
Abstract: Objective:To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012.”Design:A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for
2,414 citations
Ghent University Hospital1, Johns Hopkins University2, Baylor College of Medicine3, Karolinska Institutet4, Johns Hopkins University School of Medicine5, National Health Service6, Royal National Orthopaedic Hospital7, University of Brescia8, Erasmus University Medical Center9, French Institute of Health and Medical Research10, Northwick Park Hospital11, Boston Children's Hospital12, University of Southern Denmark13, University College London14, Shinshu University15, Hospital for Sick Children16, St Thomas' Hospital17, Izaak Walton Killam Health Centre18, Radboud University Nijmegen19, Innsbruck Medical University20
TL;DR: The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes, and revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders.
Abstract: The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.
1,075 citations
TL;DR: To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double‐blind, placebo‐controlled study of adults with moderate‐to‐severe systemic lupus erythematosus (SLE).
Abstract: Objective
To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate-to-severe systemic lupus erythematosus (SLE).
Methods
Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4-gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]–based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent-to-treat (ITT) population and type I IFN–high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2-sided), within each of the 2 study populations for the primary end point analysis.
Results
The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo-treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ-specific end points. Herpes zoster was more frequent in the anifrolumab-treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively).
Conclusion
Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE.
614 citations
Virginia Mason Medical Center1, University of Birmingham2, University of São Paulo3, University of Michigan4, Toronto General Hospital5, St Thomas' Hospital6, Aix-Marseille University7, University of Amsterdam8, University of Texas MD Anderson Cancer Center9, Keio University10, Queen Mary University of London11, Harvard University12, Katholieke Universiteit Leuven13, Tata Memorial Hospital14, University Hospitals Birmingham NHS Foundation Trust15, Trinity College, Dublin16, University of Cologne17, University of Queensland18, Erasmus University Rotterdam19
TL;DR: Standardized methods provide contemporary international benchmarks for reporting outcomes after esophagectomy, using a standardized dataset with specific definitions to prospectively collect international data to provide a benchmark for complications and outcomes associated with esphagectomy.
Abstract: Objective:Utilizing a standardized dataset with specific definitions to prospectively collect international data to provide a benchmark for complications and outcomes associated with esophagectomy.Summary of Background Data:Outcome reporting in oncologic surgery has suffered from the lack of a stand
453 citations
TL;DR: The present article reviews the challenges posed by infective endocarditis and outlines current and future strategies to limit its impact.
387 citations
University of Catania1, University of Pisa2, St Thomas' Hospital3, University of Liège4, Copenhagen University Hospital5, Queen Elizabeth Hospital Birmingham6, McGill University Health Centre7, Ludwig Maximilian University of Munich8, Queen Mary University of London9, Erasmus University Rotterdam10, University of Bern11, Leiden University12
TL;DR: Standardized definitions of structural deterioration and valve failure in assessing long-term durability of transcatheter and surgical aortic bioprosthetic valves are proposed.
Abstract: Hancock J, Mehilli J, Byrne RA, Baumbach A, Kappetein AP, Windecker S, Bax J, Haude M. Standardized definitions of structural deterioration and valve failure in assessing long-term durability of transcatheter and surgical aortic bioprosthetic valves: a consensus statement from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) endorsed by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac Surg 2017;52:408–17.
383 citations
TL;DR: It is confirmed that Rosamund Snow will not be attending this year's T in the Park.
Abstract: 这是一系列来自患者的零星文章中的最后一篇，他们的经历为医生提供了生动教程。关于"你的患者在想什么"系列的更多信息，请联系患者编辑Rosamund Snow (rsnow@bmj.com)。
335 citations
TL;DR: The epidemiology of renal recovery, of the association between AKI and the development of CKD, and the importance of post-discharge follow-up of AKI patients and suggestions for its incorporation into clinical practice are reviewed.
Abstract: Acute kidney injury (AKI) is a frequent complication of critical illness and carries a significant risk of short- and long-term mortality, chronic kidney disease (CKD) and cardiovascular events. The degree of renal recovery from AKI may substantially affect these long-term endpoints. Therefore maximising recovery of renal function should be the goal of any AKI prevention and treatment strategy. Defining renal recovery is far from straightforward due in part to the limitations of the tests available to assess renal function. Here, we discuss common pitfalls in the evaluation of renal recovery and provide suggestions for improved assessment in the future. We review the epidemiology of renal recovery and of the association between AKI and the development of CKD. Finally, we stress the importance of post-discharge follow-up of AKI patients and make suggestions for its incorporation into clinical practice. Summary key points are that risk factors for non-recovery of AKI are age, CKD, comorbidity, higher severity of AKI and acute disease scores. Second, AKI and CKD are mutually related and seem to have a common denominator. Third, despite its limitations full recovery of AKI may best be defined as the absence of AKI criteria, and partial recovery as a fall in AKI stage. Fourth, after an episode of AKI, serial follow-up measurements of serum creatinine and proteinuria are warranted to diagnose renal impairment and prevent further progression. Measures to promote recovery are similar to those preventing renal harm. Specific interventions promoting repair are still experimental.
281 citations
TL;DR: The current evidence for keratoconus' complex genetics is reviewed and the presently identified genes/loci and potential candidate gene/ loci are evaluated.
281 citations
TL;DR: Midwall LGE identifies a group of patients with dilated cardiomyopathy and an LVEF ≥40% at increased risk of SCD and low risk of nonsudden death who may benefit from implantable cardioverter defibrillator implantation.
Abstract: Background:Current guidelines only recommend the use of an implantable cardioverter defibrillator in patients with dilated cardiomyopathy for the primary prevention of sudden cardiac death (SCD) in...
247 citations
TL;DR: The results of recent randomised controlled trials have allowed the formulation of new recommendations and/or increase the strength of previous recommendations, but in many domains the available evidence remains insufficient, resulting from the limited quality of the clinical trials and the poor reporting of kidney outcomes.
Abstract: Background
Acute kidney injury (AKI) in the intensive care unit is associated with significant mortality and morbidity
TL;DR: This work demonstrates that the use of large publicly available datasets is essential for improving the robustness of wearable-monitoring algorithms for use in clinical practice.
Abstract: Goal: Current methods for estimating respiratory rate (RR) from the photoplethysmogram (PPG) typically fail to distinguish between periods of high- and low-quality input data, and fail to perform well on independent “validation” datasets. The lack of robustness of existing methods directly results in a lack of penetration of such systems into clinical practice. The present work proposes an alternative method to improve the robustness of the estimation of RR from the PPG. Methods: The proposed algorithm is based on the use of multiple autoregressive models of different orders for determining the dominant respiratory frequency in the three respiratory-induced variations (frequency, amplitude, and intensity) derived from the PPG. The algorithm was tested on two different datasets comprising 95 eight-minute PPG recordings (in total) acquired from both children and adults in different clinical settings, and its performance using two window sizes (32 and 64 seconds) was compared with that of existing methods in the literature. Results: The proposed method achieved comparable accuracy to existing methods in the literature, with mean absolute errors (median, 25 $\text {th}$ –75 $\text {th}$ percentiles for a window size of 32 seconds) of 1.5 (0.3–3.3) and 4.0 (1.8–5.5) breaths per minute (for each dataset respectively), whilst providing RR estimates for a greater proportion of windows (over 90% of the input data are kept). Conclusion: Increased robustness of RR estimation by the proposed method was demonstrated. Significance: This work demonstrates that the use of large publicly available datasets is essential for improving the robustness of wearable-monitoring algorithms for use in clinical practice.
TL;DR: The use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation and alleviated the alloimmune‐mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs.
Queen Mary University of London1, University of Birmingham2, Academic Medical Center3, VU University Medical Center4, King's College London5, University of Graz6, St Thomas' Hospital7, University of Southern Denmark8, University College Dublin9, University of Adelaide10, Technical University of Madrid11, State University of Campinas12, University of North Carolina at Chapel Hill13, University of Antwerp14, Katholieke Universiteit Leuven15, Monash University16, Norwegian School of Sport Sciences17, University of Manitoba18, University of Melbourne19, Alexandria University20, University of Mazandaran21, Oslo University Hospital22, University of Tampere23, University of Western Australia24, University of Modena and Reggio Emilia25, California Polytechnic State University26, Federal University of São Paulo27, Technische Universität München28, University of Copenhagen29, Norwegian University of Science and Technology30, Lund University31, Odense University Hospital32, University of Health Sciences Antigua33, Copenhagen University Hospital34, Keele University35
TL;DR: Diet and lifestyle interventions in pregnancy are clinically effective in reducing GWG irrespective of risk factors, with no effects on composite maternal and fetal outcomes.
Abstract: Background: Diet- and physical activity-based interventions in pregnancy have the potential to alter maternal and child outcomes. Objectives: To assess whether or not the effects of diet and lifestyle interventions vary in subgroups of women, based on maternal body mass index (BMI), age, parity, Caucasian ethnicity and underlying medical condition(s), by undertaking an individual patient data (IPD) meta-analysis. We also evaluated the association of gestational weight gain (GWG) with adverse pregnancy outcomes and assessed the cost-effectiveness of the interventions. Data sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects and Health Technology Assessment database were searched from October 2013 to March 2015 (to update a previous search). Review methods: Researchers from the International Weight Management in Pregnancy Collaborative Network shared the primary data. For each intervention type and outcome, we performed a two-step IPD random-effects meta-analysis, for all women (except underweight) combined and for each subgroup of interest, to obtain summary estimates of effects and 95% confidence intervals (CIs), and synthesised the differences in effects between subgroups. In the first stage, we fitted a linear regression adjusted for baseline (for continuous outcomes) or a logistic regression model (for binary outcomes) in each study separately; estimates were combined across studies using random-effects meta-analysis models. We quantified the relationship between weight gain and complications, and undertook a decision-analytic model-based economic evaluation to assess the cost-effectiveness of the interventions. Results: Diet and lifestyle interventions reduced GWG by an average of 0.70 kg (95% CI-0.92 to-0.48 kg; 33 studies, 9320 women). The effects on composite maternal outcome [summary odds ratio (OR) 0.90, 95% CI 0.79 to 1.03; 24 studies, 8852 women] and composite fetal/neonatal outcome (summary OR 0.94, 95% CI 0.83 to 1.08; 18 studies, 7981 women) were not significant. The effect did not vary with baseline BMI, age, ethnicity, parity or underlying medical conditions for GWG, and composite maternal and fetal outcomes. Lifestyle interventions reduce Caesarean sections (OR 0.91, 95% CI 0.83 to 0.99), but not other individual maternal outcomes such as gestational diabetes mellitus (OR 0.89, 95% CI 0.72 to 1.10), pre-eclampsia or pregnancy-induced hypertension (OR 0.95, 95% CI 0.78 to 1.16) and preterm birth (OR 0.94, 95% CI 0.78 to 1.13). There was no significant effect on fetal outcomes. The interventions were not cost-effective. GWG, including adherence to the Institute of Medicine-recommended targets, was not associated with a reduction in complications. Predictors of GWG were maternal age (summary estimate-0.10 kg, 95% CI-0.14 to-0.06 kg) and multiparity (summary estimate-0.73 kg, 95% CI-1.24 to-0.23 kg). Limitations: The findings were limited by the lack of standardisation in the components of intervention, residual heterogeneity in effects across studies for most analyses and the unavailability of IPD in some studies. Conclusion: Diet and lifestyle interventions in pregnancy are clinically effective in reducing GWG irrespective of risk factors, with no effects on composite maternal and fetal outcomes. Future work: The differential effects of lifestyle interventions on individual pregnancy outcomes need evaluation. Study registration: This study is registered as PROSPERO CRD42013003804.
TL;DR: Outflow tract obstruction is a feared and potentially lethal complication of transcatheter mitral valve replacement (TMVR),Mitral valve-in-valve (ViV), and valve- in-ring (ViR) procedures as well as implantation of transCatheter heart valves in calcific mitral valves disease.
Abstract: Outflow tract obstruction is a feared and potentially lethal complication of transcatheter mitral valve replacement (TMVR), mitral valve-in-valve (ViV), and valve-in-ring (ViR) procedures as well as implantation of transcatheter heart valves in calcific mitral valve disease. These procedures
TL;DR: The role of endogenous RAGE ligands/effectors in normo- and pathophysiological processes is described, the current status of exogenous small-molecule inhibitors of RAGE is summarized, and key strategies for future therapeutic intervention are identified.
Abstract: The receptor for advanced glycation endproducts (RAGE) is an ubiquitous, transmembrane, immunoglobulin-like receptor that exists in multiple isoforms and binds to a diverse range of endogenous extracellular ligands and intracellular effectors. Ligand binding at the extracellular domain of RAGE initiates a complex intracellular signaling cascade, resulting in the production of reactive oxygen species (ROS), immunoinflammatory effects, cellular proliferation, or apoptosis with concomitant upregulation of RAGE itself. To date, research has mainly focused on the correlation between RAGE activity and pathological conditions, such as cancer, diabetes, cardiovascular diseases, and neurodegeneration. Because RAGE plays a role in many pathological disorders, it has become an attractive target for the development of inhibitors at the extracellular and intracellular domains. This review describes the role of endogenous RAGE ligands/effectors in normo- and pathophysiological processes, summarizes the current status o...
University of Bristol1, King's College London2, Cairo University3, Children's of Alabama4, University Hospital of Wales5, Great Ormond Street Hospital6, St James's University Hospital7, Boston Children's Hospital8, Manchester Academic Health Science Centre9, Newcastle upon Tyne Hospitals NHS Foundation Trust10, University of Southampton11, St Thomas' Hospital12
TL;DR: Deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.
Cedars-Sinai Medical Center1, University of Hamburg2, Ruhr University Bochum3, Vita-Salute San Raffaele University4, Technische Universität München5, University of Zurich6, Brighton and Sussex University Hospitals NHS Trust7, University of Texas Health Science Center at Houston8, University of Catania9, Leiden University Medical Center10, Valve Corporation11, Hospital General Universitario Gregorio Marañón12, Sunnybrook Health Sciences Centre13, St Thomas' Hospital14, university of lille15, Hospital Clínico San Carlos16, Martin Luther University of Halle-Wittenberg17, Erasmus University Rotterdam18, Scott & White Hospital19
TL;DR: TAVR using the new-generation devices was associated with improved procedural outcomes in treating patients with pure native AR, and significant post-procedural AR was independently associated with increased mortality.
TL;DR: Quantitative methods to perform PET in standardized ways have also been developed which may further improve response assessment including a quantitative extension to the DC (qPET), which may have advantages in providing a continuous scale to refine the threshold for adequate/inadequate response in specific clinical situations or treatment optimization in trials.
Abstract: PET using 18F-FDG for treatment monitoring in patients with lymphoma is one of the most well-developed clinical applications. PET/CT is nowadays used during treatment to assess chemosensitivity, with response-adapted therapy given according to ‘interim’ PET in clinical practice to adults and children with Hodgkin lymphoma. PET is also used to assess remission from disease and to predict prognosis in the pretransplant setting. Mature data have been reported for the common subtypes of aggressive B-cell lymphomas, with more recent data also supporting the use of PET for response assessment in T-cell lymphomas. The Deauville five-point scale incorporating the Deauville criteria (DC) is recommended for response assessment in international guidelines. FDG uptake is graded in relation to the reference regions of normal mediastinum and liver. The DC have been validated in most lymphoma subtypes. The DC permit the threshold for adequate or inadequate response to be adapted according to the clinical context or research question. It is important for PET readers to understand how the DC have been applied in response-adapted trials for correct interpretation and discussion with the multidisciplinary team. Quantitative methods to perform PET in standardized ways have also been developed which may further improve response assessment including a quantitative extension to the DC (qPET). This may have advantages in providing a continuous scale to refine the threshold for adequate/inadequate response in specific clinical situations or treatment optimization in trials. qPET is also less observer-dependent and limits the problem of optical misinterpretation due to the influence of background activity.
Cedars-Sinai Medical Center1, Leiden University2, Ruhr University Bochum3, University of Hamburg4, St Thomas' Hospital5, Houston Methodist Hospital6, University of Alabama at Birmingham7, Technische Universität München8, University of Bern9, University of Texas Health Science Center at Houston10, NewYork–Presbyterian Hospital11, Université de Montréal12, Sunnybrook Health Sciences Centre13, Leeds Teaching Hospitals NHS Trust14, Brighton and Sussex University Hospitals NHS Trust15, University of Zurich16, Hospital General Universitario Gregorio Marañón17, Valve Corporation18, Brigham and Women's Hospital19
TL;DR: In this paper, the authors evaluated the outcomes of transcatheter mitral valve replacement in patients with failed mitral bioprosthetic valves (ViV) and annuloplasty rings (valve-in-ring [ViR]).
TL;DR: Proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.
Abstract: Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen–DR4(DRB1*0401)–restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group’s daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell–specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.
University of Tasmania1, Norwegian University of Science and Technology2, Auckland University of Technology3, Royal Hobart Hospital4, St Thomas' Hospital5, Taipei Veterans General Hospital6, Imperial College London7, University College London8, National Institute for Health Research9, Aarhus University Hospital10, Shanghai Jiao Tong University11, Abbott Northwestern Hospital12, Flinders University13, Nagoya City University14, Chiba University15, University of Erlangen-Nuremberg16, Polytechnic Institute of Coimbra17, University of Perugia18, Kumamoto University19, Guy's and St Thomas' NHS Foundation Trust20, State University of New York Upstate Medical University21, Monash University22, University of Auckland23, University of North Carolina at Chapel Hill24, Tokyo Medical University25, VU University Medical Center26, University of Duisburg-Essen27, University of Tokushima28
TL;DR: Cuff BP has variable accuracy for measuring either brachial or aortic intra-arterial BP, and this adversely influences correct BP classification, indicating that stronger accuracy standards for BP devices may improve cardiovascular risk management.
King's College London1, Guy's and St Thomas' NHS Foundation Trust2, St Thomas' Hospital3, University of Texas Southwestern Medical Center4, University of Seville5, Leiden University Medical Center6, Pontifical Catholic University of Chile7, American University of Beirut8, Hospital Sant Joan de Déu Barcelona9
TL;DR: 3D models are accurate replicas of the cardiovascular anatomy and improve the understanding of complex CHD and help redefining the surgical approach.
Abstract: OBJECTIVES To evaluate the impact of 3D printed models (3D models) on surgical planning in complex congenital heart disease (CHD). METHODS A prospective case-crossover study involving 10 international centres and 40 patients with complex CHD (median age 3 years, range 1 month-34 years) was conducted. Magnetic resonance imaging and computed tomography were used to acquire and segment the 3D cardiovascular anatomy. Models were fabricated by fused deposition modelling of polyurethane filament, and dimensions were compared with medical images. Decisions after the evaluation of routine clinical images were compared with those after inspection of the 3D model and intraoperative findings. Subjective satisfaction questionnaire was provided. RESULTS 3D models accurately replicate anatomy with a mean bias of -0.27 ± 0.73 mm. Ninety-six percent of the surgeons agree or strongly agree that 3D models provided better understanding of CHD morphology and improved surgical planning. 3D models changed the surgical decision in 19 of the 40 cases. Consideration of a 3D model refined the planned biventricular repair, achieving an improved surgical correction in 8 cases. In 4 cases initially considered for conservative management or univentricular palliation, inspection of the 3D model enabled successful biventricular repair. CONCLUSIONS 3D models are accurate replicas of the cardiovascular anatomy and improve the understanding of complex CHD. 3D models did not change the surgical decision in most of the cases (21 of 40 cases, 52.5% cases). However, in 19 of the 40 selected complex cases, 3D model helped redefining the surgical approach.
Icahn School of Medicine at Mount Sinai1, University of South Florida2, University of Iowa3, Columbia University Medical Center4, New York University5, Sahlgrenska University Hospital6, University of Gothenburg7, UCL Institute of Neurology8, Rutgers University9, University of Barcelona10, Polytechnic University of Catalonia11, King's College London12, St Thomas' Hospital13, Université de Montréal14
TL;DR: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2‐year follow-up, suggesting sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms.
Abstract: Rationale: Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer’s disease. However, how sleep apnea affects longit...
Queen Mary University of London1, St Bartholomew's Hospital2, University of Southampton3, Cambridge University Hospitals NHS Foundation Trust4, University Hospital of South Manchester NHS Foundation Trust5, King's College London6, Castle Hill Hospital7, University of Sussex8, St Thomas' Hospital9, Southend University Hospital NHS Foundation Trust10, University College London11, Cleveland Clinic12, Polaris Industries13, Leicester Royal Infirmary14
TL;DR: In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient malignant pleural mesothelioma and warrants further clinical investigation inArginine-dependent cancers.
Abstract: Importance Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. Objective To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. Design, Setting, and Participants A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. Interventions Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m 2 , weekly intramuscular) plus best supportive care (BSC) or BSC alone. Main Outcomes and Measures The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti–ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18 F-fluorodeoxyglucose positron-emission tomography. Results Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group ( P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group ( P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, −1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group ( P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. Conclusions and Relevance In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. Trial Registration clinicaltrials.gov Identifier:NCT01279967
Radboud University Nijmegen1, Heidelberg University2, University of Cagliari3, University of Melbourne4, University of Dundee5, Katholieke Universiteit Leuven6, University of Nottingham7, University of Southampton8, University College Cork9, University College London10, University of Hong Kong11, St Thomas' Hospital12
TL;DR: A systematic review and meta-analysis of the effects of methylphenidate, amphetamines, and atomoxetine on diastolic and systolic blood pressure (DBP, SBP) and heart rate (HR) in children and adolescents with ADHD found no significant differences between the three medications.
Abstract: Many children and adolescents with attention deficit/hyperactivity disorder (ADHD) are treated with stimulant and non-stimulant medication. ADHD medication may be associated with cardiovascular effects. It is important to identify whether mean group effects translate into clinically relevant increases for some individual patients, and/or increase the risk for serious cardiovascular adverse events such as stroke or sudden death. To evaluate potential cardiovascular effects of these treatments, we conducted a systematic review and meta-analysis of the effects of methylphenidate (MPH), amphetamines (AMP), and atomoxetine (ATX) on diastolic and systolic blood pressure (DBP, SBP) and heart rate (HR) in children and adolescents with ADHD. We conducted systematic searches in electronic databases (PsychINFO, EMBASE and Medline) to identify published trials which involved individuals who were (i) diagnosed with ADHD and were aged between 0–18 years; (ii) treated with MPH, AMP or ATX and (iii) had their DBP and SBP and/or HR measured at baseline (pre) and the endpoint (post) of the study treatment. Studies with an open-label design or a double-blind randomised control design of any duration were included. Statistical analysis involved calculating differences between pre- and post-treatment measurements for the various cardiovascular parameters divided by the pooled standard deviation. Further, we assessed the percentage of clinically relevant increased BP or HR, or documented arrhythmias. Eighteen clinical trials met the inclusion criteria (10 for MPH, 5 for AMP, and 7 for ATX) with data from 5837 participants (80.7% boys) and average duration of 28.7 weeks (range 4–96 weeks). All three medications were associated with a small, but statistically significant pre–post increase of SBP (MPH: standard mean difference [SMD] 0.25, 95% confidence interval [CI] 0.08–0.42, p < 0.01; AMP: SMD 0.09, 95% CI 0.03–0.15, p < 0.01; ATX: SMD 0.16, 95% CI 0.04–0.27, p = 0.01). MPH did not have a pre–post effect on DBP and HR. AMP treatment was associated with a small but statistically significant pre–post increase of DBP (SMD 0.16, CI 0.03–0.29, p = 0.02), as was ATX treatment (SMD 0.22, CI 0.10–0.34, p < 0.01). AMP and ATX were associated with a small to medium statistically significant pre–post increase of HR (AMP: SMD 0.37, CI 0.13–0.60, p < 0.01; ATX: SMD 0.43, CI 0.26–0.60, p < 0.01). The head-to-head comparison of the three medications did not reveal significant differences. Sensitivity analyses revealed that AMP studies of <18 weeks reported higher effect sizes on DBP compared with longer duration studies (F(1) = 19.55, p = 0.05). Further, MPH studies published before 2007 reported higher effect sizes on SBP than studies after 2007 (F(1) = 5.346, p = 0.05). There was no effect of the following moderators: type of medication, doses, sample size, age, gender, type of ADHD, comorbidity or dropout rate. Participants on medication reported 737 (12.6%) other cardiovascular effects. Notably, 2% of patients discontinued their medication treatment due to any cardiovascular effect. However, in the majority of patients, the cardiovascular effects resolved spontaneously, medication doses were changed or the effects were not considered clinically relevant. There were no statistically significant differences between the medication treatments in terms of the severity of cardiovascular effects. Statistically significant pre–post increases of SBP, DBP and HR were associated with AMP and ATX treatment in children and adolescents with ADHD, while MPH treatment had a statistically significant effect only on SBP in these patients. These increases may be clinically significant for a significant minority of individuals that experience larger increases. Since increased BP and HR in general are considered risk factors for cardiovascular morbidity and mortality during adult life, paediatric patients using ADHD medication should be monitored closely and regularly for HR and BP.
University College London1, St Bartholomew's Hospital2, Mayo Clinic3, Universidad Francisco de Vitoria4, Kōchi University5, St Thomas' Hospital6, London Chest Hospital7, Nicosia General Hospital8, Columbia University Medical Center9, University of Michigan10, Erasmus University Rotterdam11, Clalit Health Services12, St George's, University of London13, Odense University Hospital14
TL;DR: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.
Abstract: BACKGROUND: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. METHODS: This was an observational, retrospective, longitudinal cohort study. RESULTS: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9-3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93-1.12), C-index of 0.70 (95% CI, 0.68-0.72), and D-statistic of 1.17 (95% CI, 1.05-1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8-2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96-13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. CONCLUSIONS: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.
TL;DR: Management strategies are proposed for presentation of suspected melanoma of the skin and the central nervous system in patients with CMN, including use of oral mitogen‐activated protein kinase kinase inhibitors in NRAS‐mutated tumours.
Abstract: Congenital melanocytic naevi (CMN) are a known risk factor for melanoma, with the greatest risk currently thought to be in childhood. There has been controversy over the years about the incidence, and therefore over clinical management of CMN, due partly to the difficulties of histological diagnosis and partly to publishing bias towards cases of malignancy. Large cohort studies have demonstrated that risk in childhood is related to the severity of the congenital phenotype, not only cutaneous but neuroradiological. New understanding of the genetics of CMN offers the possibility of improvement in diagnosis of melanoma, identification of those at highest risk, and new treatment options. We review the world literature and our centre's experience over the last 25 years, including the molecular characteristics of melanoma in these patients and new melanoma incidence and outcome data from our prospective cohort. Management strategies are proposed for presentation of suspected melanoma of the skin and the CNS in patients with CMN, including use of oral MEK inhibitors in NRAS-mutated tumours. This article is protected by copyright. All rights reserved.
TL;DR: Percutaneous tricuspid valve intervention (both repair and replacement) is still in its infancy but may become a reliable option in future, especially for high-risk patients with isolated primary TR or with secondary TR related to advanced left-sided heart valve disease.
Abstract: Tricuspid regurgitation (TR) is a very frequent manifestation of valvular heart disease. It may be due to the primary involvement of the valve or secondary to pulmonary hypertension or to the left-sided heart valve disease (most commonly rheumatic and involving the mitral valve). The pathophysiology of secondary TR is complex and is intrinsically connected to the anatomy and function of the right ventricle. A systematic multimodality approach to diagnosis and assessment (based not only on the severity of the TR but also on the assessment of annular size, RV function and degree of pulmonary hypertension) is, therefore, essential. Once considered non-important, treatment of secondary TR is currently viewed as an essential concomitant procedure at the time of mitral (and, less frequently, aortic valve) surgery. Although the indications for surgical management of severe TR are now generally accepted (Class I), controversy persists concerning the role of intervention for moderate TR. However, there is a trend for intervention in this setting, especially at the time of surgery for left-sided heart valve disease and/or in patients with significant tricuspid annular dilatation (Class IIa). Currently, surgery remains the best approach for the interventional treatment of TR. Percutaneous tricuspid valve intervention (both repair and replacement) is still in its infancy but may become a reliable option in future, especially for high-risk patients with isolated primary TR or with secondary TR related to advanced left-sided heart valve disease.
TL;DR: The aim of this review is update on what cell death mechanisms that are operating particularly in the setting of the developing CNS, and the provision of alternative routes through which the cell undergoes death has to be taken into account in the hunt for novel brain protective strategies.
Abstract: Perinatal insults such as hypoxia-ischemia induces secondary brain injury. In order to develop the next generation of neuroprotective therapies, we urgently need to understand the underlying molecular mechanisms leading to cell death. The cell death mechanisms have been shown to be quite different in the developing brain compared to that in the adult. The aim of this review is update on what cell death mechanisms that are operating particularly in the setting of the developing CNS. In response to mild stress stimuli a number of compensatory mechanisms will be activated, most often leading to cell survival. Moderate-to-severe insults trigger regulated cell death. Depending on several factors such as the metabolic situation, cell type, nature of the stress stimulus, and which intracellular organelle(s) are affected, the cell undergoes apoptosis (caspase activation) triggered by BAX dependent mitochondrial permeabilzation, necroptosis (mixed lineage kinase domain-like activation), necrosis (via opening of the mitochondrial permeability transition pore), autophagic cell death (autophagy/Na+, K+-ATPase), or parthanatos (poly(ADP-ribose) polymerase 1, apoptosis-inducing factor). Severe insults cause accidental cell death that cannot be modulated genetically or by pharmacologic means. However, accidental cell death leads to the release of factors (damage-associated molecular patterns) that initiate systemic effects, as well as inflammation and (regulated) secondary brain injury in neighboring tissue. Furthermore, if one mode of cell death is inhibited, another route may step in at least in a scenario when upstream damaging factors predominate over protective responses. The provision of alternative routes through which the cell undergoes death has to be taken into account in the hunt for novel brain protective strategies.