Showing papers by "St Thomas' Hospital published in 2018"

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.

Abstract: This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Sectionof the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA(2)LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

2018 update of the EULAR recommendations for the management of Behçet’s syndrome

Abstract: Several new treatment modalities with different mechanisms of action have been studied in patients with Behcet's syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.

EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy

Abstract: Food allergy can result in considerable morbidity, impairment of quality of life, and healthcare expenditure. There is therefore interest in novel strategies for its treatment, particularly food allergen immunotherapy (FA-AIT) through the oral (OIT), sublingual (SLIT), or epicutaneous (EPIT) routes. This Guideline, prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force on Allergen Immunotherapy for IgE-mediated Food Allergy, aims to provide evidence-based recommendations for active treatment of IgE-mediated food allergy with FA-AIT. Immunotherapy relies on the delivery of gradually increasing doses of specific allergen to increase the threshold of reaction while on therapy (also known as desensitization) and ultimately to achieve post-discontinuation effectiveness (also known as tolerance or sustained unresponsiveness). Oral FA-AIT has most frequently been assessed: here, the allergen is either immediately swallowed (OIT) or held under the tongue for a period of time (SLIT). Overall, trials have found substantial benefit for patients undergoing either OIT or SLIT with respect to efficacy during treatment, particularly for cow's milk, hen's egg, and peanut allergies. A benefit post-discontinuation is also suggested, but not confirmed. Adverse events during FA-AIT have been frequently reported, but few subjects discontinue FA-AIT as a result of these. Taking into account the current evidence, FA-AIT should only be performed in research centers or in clinical centers with an extensive experience in FA-AIT. Patients and their families should be provided with information about the use of FA-AIT for IgE-mediated food allergy to allow them to make an informed decision about the therapy.

Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study

Abstract: Summary Background Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. Methods We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers ( BRCA -positive) versus all non-carriers ( BRCA -negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. Findings Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1 , 137 with BRCA2 ). After a median follow-up of 8·2 years (IQR 6·0–9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA -positive and BRCA -negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5–98·4] vs 96·6% [95·8–97·3]; at 5 years: 83·8% [79·3–87·5] vs 85·0% [83·5–86·4]; at 10 years: 73·4% [67·4–78·5] vs 70·1% [67·7–72·3]; hazard ratio [HR] 0·96 [95% CI 0·76–1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89–97] vs 91% [88–94]; HR 0·59 [95% CI 0·35–0·99]; p=0·047) but not 5 years (81% [73–87] vs 74% [70–78]; HR 1·13 [0·70–1·84]; p=0·62) or 10 years (72% [62–80] vs 69% [63–74]; HR 2·12 [0·82–5·49]; p=0·12). Interpretation Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. Funding Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.

A universal standard for the validation of blood pressure measuring devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement

Abstract: Copyright © 2018 Wolters Kluwer Health, Inc., and American Heart Association, Inc. This article has been copublished in Hypertension. In the last 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring and the International Organization for Standardization (ISO) have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers and manufacturers would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by AAMI, ESH and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.

Incidence, predictors, and clinical outcomes of coronary obstruction following transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: insights from the VIVID registry

Abstract: Aims: There are limited data on coronary obstruction following transcatheter valve-in-valve (ViV) implantation inside failed aortic bioprostheses The objectives of this study were to determine the incidence, predictors, and clinical outcomes of coronary obstruction in transcatheter ViV procedures Methods and results: A total of 1612 aortic procedures from the Valve-in-Valve International Data (VIVID) Registry were evaluated Data were subject to centralized blinded corelab computed tomography (CT) analysis in a subset of patients The virtual transcatheter valve to coronary ostium distance (VTC) was determined A total of 37 patients (23%) had clinically evident coronary obstruction Baseline clinical characteristics in the coronary obstruction patients were similar to controls Coronary obstruction was more common in stented bioprostheses with externally mounted leaflets or stentless bioprostheses than in stented with internally mounted leaflets bioprostheses (61% vs 37% vs 08%, respectively; P < 0001) CT measurements were obtained in 20 (54%) and 90 (54%) of patients with and without coronary obstruction, respectively VTC distance was shorter in coronary obstruction patients in relation to controls (324 ± 222 vs 630 ± 234, respectively; P < 0001) Using multivariable analysis, the use of a stentless or stented bioprosthesis with externally mounted leaflets [odds ratio (OR): 767; 95% confidence interval (CI): 314-187; P < 0001] associated with coronary obstruction for the global population In a second model with CT data, a shorter VTC distance predicted this complication (OR: 022 per 1 mm increase; 95% CI: 009-051; P < 0001), with an optimal cut-off level of 4 mm (area under the curve: 0943; P < 0001) Coronary obstruction was associated with a high 30-day mortality (529% vs 39% in the controls, respectively; P < 0001) Conclusion: Coronary obstruction following aortic ViV procedures is a life-threatening complication that occurred more frequently in patients with prior stentless or stented bioprostheses with externally mounted leaflets and in those with a short VTC

The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults

Abstract: NICE has accredited the process used by the BSR to produce its guidance on the management of systemic lupus erythematosus in adults. Accreditation is valid for 5 years from 10 June 2013. More information on accreditation can be viewed at www.nice.org.uk/accreditation. For full details on our accreditation visit: www.nice.org.uk/accreditation. Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Rheumatology Department, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Royal National Hospital for Rheumatic Diseases, Bath, Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre, The Kellgren Centre for Rheumatology, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, Louise Coote Lupus Unit, Guy’s Hospital, London, Laurie Pike Health Centre, Modality Partnership, Birmingham, Department of Rheumatology, Freeman Hospital, Newcastle upon Tyne, Department of Medicine, University of Cambridge, Lupus and Vasculitis Unit, Addenbrooke’s Hospital, Cambridge, Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, Division of Women’s Health, King’s College London, Section of Renal Medicine and Vascular Inflammation, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London, LUPUS UK, Romford, Essex and Centre for Rheumatology, University College London, London, UK

European Association of Preventive Cardiology (EAPC) and European Association of Cardiovascular Imaging (EACVI) joint position statement: recommendations for the indication and interpretation of cardiovascular imaging in the evaluation of the athlete’s heart

Abstract: Antonio Pelliccia (Chairperson), Stefano Caselli (Co-chairperson)*, Sanjay Sharma, Cristina Basso, Jeroen J. Bax, Domenico Corrado, Antonello D’Andrea, Flavio D’Ascenzi, Fernando M. Di Paolo, Thor Edvardsen, Sabiha Gati, Maurizio Galderisi, Hein Heidbuchel, Alain Nchimi, Koen Nieman, Michael Papadakis, Cataldo Pisicchio, Christian Schmied, Bogdan A. Popescu, Gilbert Habib, Diederick Grobbee, and Patrizio Lancellotti (Chairperson)

Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma.

Abstract: Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

Abstract: The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories However, these entities seem to belong to a much wider phenotypic spectrum To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca2+ homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage

Cardiac and Vascular Surgery-Associated Acute Kidney Injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.

Abstract: Acute kidney injury (AKI) occurs in 7% to 18% of hospitalized patients and complicates the course of 50% to 60% of those admitted to the intensive care unit, carrying both significant mortality and morbidity.[1][1] Even though many cases of AKI are reversible within days to weeks of occurrence, data

Gut microbial diversity is associated with lower arterial stiffness in women

Abstract: Aims The gut microbiome influences metabolic syndrome (MetS) and inflammation and is therapeutically modifiable. Arterial stiffness is poorly correlated with most traditional risk factors. Our aim was to examine whether gut microbial composition is associated with arterial stiffness. Methods and results We assessed the correlation between carotid-femoral pulse wave velocity (PWV), a measure of arterial stiffness, and gut microbiome composition in 617 middle-aged women from the TwinsUK cohort with concurrent serum metabolomics data. Pulse wave velocity was negatively correlated with gut microbiome alpha diversity (Shannon index, Beta(SE)= -0.25(0.07), P = 1 × 10-4) after adjustment for covariates. We identified seven operational taxonomic units associated with PWV after adjusting for covariates and multiple testing-two belonging to the Ruminococcaceae family. Associations between microbe abundances, microbe diversity, and PWV remained significant after adjustment for levels of gut-derived metabolites (indolepropionate, trimethylamine oxide, and phenylacetylglutamine). We linearly combined the PWV-associated gut microbiome-derived variables and found that microbiome factors explained 8.3% (95% confidence interval 4.3-12.4%) of the variance in PWV. A formal mediation analysis revealed that only a small proportion (5.51%) of the total effect of the gut microbiome on PWV was mediated by insulin resistance and visceral fat, c-reactive protein, and cardiovascular risk factors after adjusting for age, body mass index, and mean arterial pressure. Conclusions Gut microbiome diversity is inversely associated with arterial stiffness in women. The effect of gut microbiome composition on PWV is only minimally mediated by MetS. This first human observation linking the gut microbiome to arterial stiffness suggests that targeting the microbiome may be a way to treat arterial ageing.

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Abstract: Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

Oxidation of Atg3 and Atg7 mediates inhibition of autophagy.

Abstract: Macroautophagy (autophagy) is a crucial cellular stress response for degrading defective macromolecules and organelles, as well as providing bioenergetic intermediates during hypoxia and nutrient deprivation. Here we report a thiol-dependent process that may account for impaired autophagy during aging. This is through direct oxidation of key autophagy-related (Atg) proteins Atg3 and Atg7. When inactive Atg3 and Atg7 are protected from oxidation due to stable covalent interaction with their substrate LC3. This interaction becomes transient upon activation of Atg3 and Atg7 due to transfer of LC3 to phosphatidylethanolamine (lipidation), a process crucial for functional autophagy. However, loss in covalent-bound LC3 also sensitizes the catalytic thiols of Atg3 and Atg7 to inhibitory oxidation that prevents LC3 lipidation, observed in vitro and in mouse aorta. Here findings provide a thiol-dependent process for negatively regulating autophagy that may contribute to the process of aging, as well as therapeutic targets to regulate autophagosome maturation.

Transcatheter aortic valve implantation: current status and future perspectives.

Abstract: In the 16 years since the first pioneering procedure, transcatheter aortic valve implantation (TAVI) has come of age and become a routine strategy for aortic valve replacement, increasingly performed under conscious sedation via transfemoral access. Simplification of the procedure, accumulation of clinical experience, and improvements in valve design and delivery systems have led to a dramatic reduction in complication rates. These advances have allowed transition to lower risk populations, and outcome data from the PARTNER 2A and SURTAVI trials have established a clear evidence base for use in intermediate risk patients. Ongoing studies with an expanding portfolio of devices seem destined to expand indications for TAVI towards lower risk, younger and asymptomatic populations. In this article, we outline recent advances, new devices and current guidelines informing the use of TAVI, and describe remaining uncertainties that need to be addressed.

Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study

Abstract: Summary Background Tackling tuberculosis requires testing and treatment of latent tuberculosis in high-risk groups. The aim of this study was to estimate the predictive values of the tuberculin skin test (TST) and two interferon-γ release assays (IGRAs) for the development of active tuberculosis in high-risk groups—ie, people in recent contact with active tuberculosis cases and from high-burden countries. Method In this prospective cohort study, we recruited participants from 54 centres (eg, clinics, community settings) in London, Birmingham, and Leicester in the UK. Participants were eligible if they were aged 16 years or older and at high risk for latent tuberculosis infection (ie, recent contact with someone with active tuberculosis [contacts] or a migrant who had arrived in the UK in the past 5 years from—or who frequently travelled to—a country with a high burden of tuberculosis [migrants]). Exclusion criteria included prevalent cases of tuberculosis, and participants who were treated for latent tuberculosis after a positive test result in this study. Each participant received three tests (QuantiFERON-TB Gold-In Tube, T-SPOT. TB , and a Mantoux TST). A positive TST result was reported using three thresholds: 5 mm (TST-5), 10 mm (TST-10), and greater than 5 mm in BCG-naive or 15 mm in BCG-vaccinated (TST-15) participants. Participants were followed up from recruitment to development of tuberculosis or censoring. Incident tuberculosis cases were identified by national tuberculosis databases, telephone interview, and review of medical notes. Our primary objective was to estimate the prognostic value of IGRAs compared with TST, assessed by the ratio of incidence rate ratios and predictive values for tuberculosis development. The study was registered with ClinicalTrials.gov, NCT01162265, and is now complete. Findings Between May 4, 2010, and June 1, 2015, 10 045 people were recruited, of whom 9610 were eligible for inclusion. Of this cohort, 4861 (50·6%) were contacts and 4749 (49·4%) were migrants. Participants were followed up for a median of 2·9 years (range 21 days to 5·9 years). 97 (1·0%) of 9610 participants developed active tuberculosis (77 [1·2%] of 6380 with results for all three tests). In all tests, annual incidence of tuberculosis was very low in those who tested negatively (ranging from 1·2 per 1000 person-years, 95% CI 0·6–2·0 for TST-5 to 1·9 per 1000 person-years, 95% CI 1·3–2·7, for QuantiFERON-TB Gold In-Tube). Annual incidence in participants who tested positively were highest for T-SPOT. TB (13·2 per 1000 person-years, 95% CI 9·9–17·4), TST-15 (11·1 per 1000 person-years, 8·3–14·6), and QuantiFERON-TB Gold In-Tube (10·1 per 1000 person-years, 7·4–13·4). Positive results for these tests were significantly better predictors of progression than TST-10 and TST-5 (eg, ratio of test positivity rates in those progressing to tuberculosis compared with those not progressing T-SPOT. TB vs TST-5: 1·99, 95% CI 1·68–2·34; p Interpretation IGRA-based or BCG-stratified TST strategies appear most suited to screening for potential disease progression among high-risk groups. Further work will be needed to assess country-specific cost-effectiveness of each screening test, and in the absence of highly specific diagnostic tests, cheap non-toxic treatments need to be developed that could be given to larger groups of people at potential risk. Funding National Institute for Health Research Health Technology Assessment Programme 08-68-01.

Metabolic phenotype of skeletal muscle in early critical illness

Abstract: Objectives To characterise the sketetal muscle metabolic phenotype during early critical illness. Methods Vastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5). Measurements and main results From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (−27.4CN (95% CI −123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (−1859CN (IQR −5557–1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); p Conclusions Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting. Trial registration number NCT01106300.

Gut microbiome transition across a lifestyle gradient in Himalaya.

Abstract: The composition of the gut microbiome in industrialized populations differs from those living traditional lifestyles. However, it has been difficult to separate the contributions of human genetic and geographic factors from lifestyle. Whether shifts away from the foraging lifestyle that characterize much of humanity’s past influence the gut microbiome, and to what degree, remains unclear. Here, we characterize the stool bacterial composition of four Himalayan populations to investigate how the gut community changes in response to shifts in traditional human lifestyles. These groups led seminomadic hunting–gathering lifestyles until transitioning to varying levels of agricultural dependence upon farming. The Tharu began farming 250–300 years ago, the Raute and Raji transitioned 30–40 years ago, and the Chepang retain many aspects of a foraging lifestyle. We assess the contributions of dietary and environmental factors on their gut-associated microbes and find that differences in the lifestyles of Himalayan foragers and farmers are strongly correlated with microbial community variation. Furthermore, the gut microbiomes of all four traditional Himalayan populations are distinct from that of the Americans, indicating that industrialization may further exacerbate differences in the gut community. The Chepang foragers harbor an elevated abundance of taxa associated with foragers around the world. Conversely, the gut microbiomes of the populations that have transitioned to farming are more similar to those of Americans, with agricultural dependence and several associated lifestyle and environmental factors correlating with the extent of microbiome divergence from the foraging population. The gut microbiomes of Raute and Raji reveal an intermediate state between the Chepang and Tharu, indicating that divergence from a stereotypical foraging microbiome can occur within a single generation. Our results also show that environmental factors such as drinking water source and solid cooking fuel are significantly associated with the gut microbiome. Despite the pronounced differences in gut bacterial composition across populations, we found little differences in alpha diversity across lifestyles. These findings in genetically similar populations living in the same geographical region establish the key role of lifestyle in determining human gut microbiome composition and point to the next challenging steps of determining how large-scale gut microbiome reconfiguration impacts human biology.

Three-dimensional motion corrected sensitivity encoding reconstruction for multi-shot multi-slice MRI: Application to neonatal brain imaging.

Abstract: Purpose To introduce a methodology for the reconstruction of multi-shot, multi-slice magnetic resonance imaging able to cope with both within-plane and through-plane rigid motion and to describe its application in structural brain imaging. Theory and Methods The method alternates between motion estimation and reconstruction using a common objective function for both. Estimates of three-dimensional motion states for each shot and slice are gradually refined by improving on the fit of current reconstructions to the partial k-space information from multiple coils. Overlapped slices and super-resolution allow recovery of through-plane motion and outlier rejection discards artifacted shots. The method is applied to T2 and T1 brain scans acquired in different views. Results The procedure has greatly diminished artifacts in a database of 1883 neonatal image volumes, as assessed by image quality metrics and visual inspection. Examples showing the ability to correct for motion and robustness against damaged shots are provided. Combination of motion corrected reconstructions for different views has shown further artifact suppression and resolution recovery. Conclusion The proposed method addresses the problem of rigid motion in multi-shot multi-slice anatomical brain scans. Tests on a large collection of potentially corrupted datasets have shown a remarkable image quality improvement. Magn Reson Med, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Quantifying infective endocarditis risk in patients with predisposing cardiac conditions

Abstract: Aims: There are scant comparative data quantifying the risk of infective endocarditis (IE) and associated mortality in individuals with predisposing cardiac conditions. Methods and results: English hospital admissions for conditions associated with increased IE risk were followed for 5 years to quantify subsequent IE admissions. The 5-year risk of IE or dying during an IE admission was calculated for each condition and compared with the entire English population as a control. Infective endocarditis incidence in the English population was 36.2/million/year. In comparison, patients with a previous history of IE had the highest risk of recurrence or dying during an IE admission [odds ratio (OR) 266 and 215, respectively]. These risks were also high in patients with prosthetic valves (OR 70 and 62) and previous valve repair (OR 77 and 60). Patients with congenital valve anomalies (currently considered 'moderate risk') had similar levels of risk (OR 66 and 57) and risks in other 'moderate-risk' conditions were not much lower. Congenital heart conditions (CHCs) repaired with prosthetic material (currently considered 'high risk' for 6 months following surgery) had lower risk than all 'moderate-risk' conditions-even in the first 6 months. Infective endocarditis risk was also significant in patients with cardiovascular implantable electronic devices. Conclusion: These data confirm the high IE risk of patients with a history of previous IE, valve replacement, or repair. However, IE risk in some 'moderate-risk' patients was similar to that of several 'high-risk' conditions and higher than repaired CHC. Guidelines for the risk stratification of conditions predisposing to IE may require re-evaluation.

Hippocampal Radial Glial Subtypes and Their Neurogenic Potential in Human Fetuses and Healthy and Alzheimer's Disease Adults.

Abstract: Neuropathological conditions might affect adult granulogenesis in the adult human dentate gyrus. However, radial glial cells (RGCs) have not been well characterized during human development and aging. We have previously described progenitor and neuronal layer establishment in the hippocampal pyramidal layer and dentate gyrus from embryonic life until mid-gestation. Here, we describe RGC subtypes in the hippocampus from 13 gestational weeks (GW) to mid-gestation and characterize their evolution and the dynamics of neurogenesis from mid-gestation to adulthood in normal and Alzheimer's disease (AD) subjects. In the pyramidal ventricular zone (VZ), RGC density declined with neurogenesis from mid-gestation until the perinatal period. In the dentate area, morphologic and antigenic differences among RGCs were observed from early ages of development to adulthood. Density and proliferative capacity of dentate RGCs as well as neurogenesis were strongly reduced during childhood until 5 years, few DCX+ cells are seen in adults. The dentate gyrus of both control and AD individuals showed Nestin+ and/or GFAPδ+ cells displaying different morphologies. In conclusion, pools of morphologically, antigenically, and topographically diverse neural progenitor cells are present in the human hippocampus from early developmental stages until adulthood, including in AD patients, while their neurogenic potential seems negligible in the adult.