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A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age.Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy.Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD.Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility.Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

BACKGROUND: Ocrelizumab maintains B-cell depletion via six-monthly dosing. Whilst this controls relapsing multiple sclerosis, it also inhibits seroconversion following SARS-CoV-2 vaccination unlike that seen following alemtuzumab and cladribine treatment. Emerging reports suggest that 1-3% B-cell repopulation facilitates seroconversion after CD20-depletion. OBJECTIVE: To determine the frequency of B-cell repopulation levels during and after ocrelizumab treatment. METHODS: Relapse data, lymphocyte and CD19 B-cell numbers were obtained following requests to clinical trial data-repositories. Information was extracted from the phase II ocrelizumab extension (NCT00676715) trial and the phase III cladribine tablet (NCT00213135) and alemtuzumab (NCT00530348/NCT00548405) trials obtained clinical trial data requests RESULTS: Only 3-5% of people with MS exhibit 1% B-cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease-breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B-cells during treatment with either cladribine or alemtuzumab. CONCLUSIONS: Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. However, few people repopulate peripheral B-cells with standard ocrelizumab dosing. Controlled studies are warranted to examine a view that delaying the dosing interval by 3-6 months may allow more people to potentially seroconvert after vaccination.

Background The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. Methods In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. Results The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration). Conclusions Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).

ObjectivesThe aim of this study was to test whether household environmental hygiene and behavioural conditions moderated associations between diarrhoea and enteric pathogen detection in infants 5 months of age in Kenya and pathogen sources, including latrine access, domestic animal co-habitation and public food sources.DesignCross-sectional study utilising enrolment survey data of households participating in the Safe Start cluster-randomised controlled trial .SettingKisumu, Kenya.ParticipantsA total of 898 caregivers with 5-month (22 week ± 1 week) aged infants were enrolled in the study and completed the enrolment survey.Primary and secondary outcome measuresOutcomes were (1) caregiver-reported 7-day diarrhoea prevalence and (2) count of types of enteric viruses, bacteria and parasites in infant stool. Exposures and effect modifiers included water access and treatment, cohabitation with domestic animals, sanitation access, handwashing practices, supplemental feeding, access to refrigeration and flooring.ResultsReported handwashing after handling animals (adjusted odds ratio (aOR)=0.20; 95% CI=0.06 to 0.50) and before eating (aOR=0.44; 95% CI=0.26 to 0.73) were strongly associated with lower risk of caregiver-reported diarrhoea, while cohabitation with animals (aOR=1.54; 95% CI=1.01 to 2.34) living in a household with vinyl-covered dirt floors (aOR=0.60; 95% CI=0.45 to 0.87) were strongly associated with pathogen codetection in infants. Caregiver handwashing after child (p=0.02) or self-defecation (p=0.03) moderated the relationship between shared sanitation access and infant exposure to pathogens, specifically private latrine access was protective against pathogen exposure of infants in households, where caregivers washed hands after defecation. In the absence of handwashing, access to private sanitation posed no benefits over shared latrines for protecting infants from exposure.ConclusionOur evidence highlights eliminating animal cohabitation and improving flooring, postdefecation and food-related handwashing, and safety and use of cow milk sources as interventions to prevent enteric pathogen exposure of young infants in Kenya.Trial registration numberNCT03468114

Background Promoting good hand hygiene in older children is an important measure to reduce the burden of common diseases such as diarrhoea and acute respiratory infections. The evidence around what works to change this behaviour, however, is unclear. Objectives To aid future intervention design and effective use of resources, this review aims to identify the individual components used in hand hygiene interventions and assesses their contribution to intended behavioural change. Methods We systematically searched seven databases for experimental studies evaluating hand hygiene interventions targeting children (age 5–12) and quantitively reporting hand hygiene behaviour. Interventions in each study were categorised as ‘promising’, or ‘non-promising’ according to whether they led to a positive change in the targeted behaviour. Behaviour change techniques (BCTs) were identified across interventions using a standard taxonomy and a novel promise ratio calculated for each (the ratio of promising to non-promising interventions featuring the BCT). ‘Promising’ BCTs were those with a promise ratio of ≥2. BCTs were ranked from most to least promising. Results Our final analysis included 19 studies reporting 22 interventions across which 32 unique BCTs were identified. The most frequently used were ‘demonstration of the behaviour’, ‘instruction on how to perform the behaviour’ and ‘adding objects to the environment’. Eight BCTs had a promise ratio of ≥2 and the five most promising were ‘demonstration of the behaviour’, ‘information about social and environmental consequences’, ‘salience of consequences’, ‘adding objects to the environment’, and ‘instruction on how to perform the behaviour’. Conclusions Our findings suggest that hand hygiene interventions targeting older children should employ a combination of promising BCTs that ensure children understand the behaviour and the consequences of their hand hygiene habits, appropriate hardware is available, and social support is provided. Researchers are encouraged to consistently and transparently describe evaluated interventions to allow promising components to be identified and replicated.

Diarrhoeal disease remains a leading cause of mortality and morbidity worldwide. Cholera alone is estimated to cause 95,000 deaths per year, most of which occur in endemic settings with inadequate water access. Whilst a global strategy to eliminate cholera by 2030 calls for investment in improved drinking water services, there is limited rigorous evidence for the impact of improved water supply on endemic cholera transmission in low-income urban settings. Our protocol is designed to deliver a pragmatic health impact evaluation of a large-scale water supply intervention in Uvira (Democratic Republic of the Congo), a cholera transmission hotspot.A stepped-wedge cluster randomised trial (SW-CRT) was designed to evaluate the impact of a large-scale drinking water supply intervention on cholera incidence among the 280,000 inhabitants of Uvira. The city was divided into 16 clusters, where new community and household taps will be installed following a randomised sequence over a transition period of up to 8 weeks in each cluster. The primary trial outcomes are the monthly incidence of "confirmed" cholera cases (patients testing positive by rapid detection kit) and of "suspected" cholera cases (patients admitted to the cholera treatment centre). Concurrent process and economic evaluations will provide further information on the context, costs, and efficiency of the intervention.In this protocol, we describe a pragmatic approach to conducting rigorous research to assess the impacts of a complex water supply intervention on severe diarrhoeal disease and cholera in an unstable, low-resource setting representative of cholera-affected areas. In particular, we discuss a series of pre-identified risks and linked mitigation strategies as well as the value of combining different data collection methods and preparation of multiple analysis scenarios to account for possible deviations from the protocol. The study described here has the potential to provide robust evidence to support more effective cholera control in challenging, high-burden settings.This trial is registered on clinicaltrials.gov ( NCT02928341 , 10th October 2016) and has received ethics approval from the London School of Hygiene and Tropical Medicine (8913, 10603) and from the Ethics Committee from the School of Public Health, University of Kinshasa, Democratic Republic of the Congo (ESP/CE/088/2015).RESUME (VERSION FRANçAISE): Please note this translation has been generated by the authors and has not been checked against the original, peer-reviewed English version by the Journal. Any discrepancies between the two versions should be raised with the authors. Cette traduction a été préparée par les auteurs et sa conformité avec la version anglaise revue par les pairs n’a pas été vérifiée par le journal. Toute différence entre les deux versions doit être signalée aux auteurs. INTRODUCTION: Les maladies diarrhéiques restent une cause majeure de mortalité et morbidité dans le monde. Le choléra seul cause environ 95’000 morts par an, dont la plupart dans des contextes endémiques où l’accès à l’eau est inadéquat. Tandis qu’une stratégie globale pour l’élimination du choléra d’ici à 2030 appelle des investissements dans l’amélioration des services d’approvisionnement en eau, il y a peu de données probantes et rigoureuses sur l’impact d’un approvisionnement en eau amélioré sur la transmission endémique du choléra dans les contextes urbains à faibles ressources. Notre protocole d’étude est conçu pour livrer une évaluation d’impact épidémiologique pragmatique d’une intervention d’approvisionnement en eau à large échelle à Uvira, République Démocratique du Congo, un point focal de transmission du choléra. MéTHODES/CONCEPTION: Un essai randomisé par grappes par échelons (stepped-wedge cluster randomised trial, SW-CRT) a été conçu pour évaluer l’impact d’une intervention d’approvisionnement en eau potable à large échelle sur l’incidence du choléra parmi les 280'000 habitants d’Uvira. La ville a été divisée en 16 grappes, dans lesquelles de nouvelles bornes fontaines et branchements individuels seront installés suivant une séquence randomisée sur une période allant jusqu’à 8 semaines par grappe. Le principal résultat de l’essai sera l’incidence mensuelle des cas de choléra « confirmés » (patients positifs par tests de détection rapide) et des cas « suspects » (patients admis au centre de traitement du choléra). Des évaluations de processus et économique menées en parallèle fourniront des informations complémentaires sur le contexte, les coûts et l’efficience de l’intervention. DISCUSSION: Dans ce protocole, nous présentons une approche pragmatique pour effectuer une recherche rigoureuse visant à évaluer les impacts d’une intervention complexe d’approvisionnement en eau sur la diarrhée sévère et le choléra dans un contexte instable et à faibles ressources, représentatif des zones affectées par le choléra. En particulier, nous considérons une série de risques pré-identifiés et les stratégies de mitigation associées ainsi que la valeur de combiner différentes méthodes de collecte de données et de préparer de multiples scénarios d’analyse pour tenir compte d’éventuelles déviations du protocole. L’étude présentée ici a le potentiel de fournir des évidences scientifiques robustes pour soutenir des stratégies de contrôle du choléra plus efficientes dans les contextes difficiles qui sont fortement affectés. ENREGISTREMENT DE L’ESSAI: Cet essai est enregistré sur clinicaltrials.gov ( NCT02928341 , 10 octobre 2016) et a reçu les approbations éthiques de la London School of Hygiene and Tropical Medicine (8913, 10603) ainsi que de l’Ecole de Santé Publique de l’Université de Kinshasa, République Démocratique du Congo (ESP/CE/088/2015).

We conducted a controlled before-and-after trial to evaluate the impact of an onsite urban sanitation intervention on the prevalence of enteric infection, soil transmitted helminth re-infection, and diarrhea among children in Maputo, Mozambique. A non-governmental organization replaced existing poor-quality latrines with pour-flush toilets with septic tanks serving household clusters. We enrolled children aged 1-48 months at baseline and measured outcomes before and 12 and 24 months after the intervention, with concurrent measurement among children in a comparable control arm. Despite nearly exclusive use, we found no evidence that intervention affected the prevalence of any measured outcome after 12 or 24 months of exposure. Among children born into study sites after intervention, we observed a reduced prevalence of Trichuris and Shigella infection relative to the same age group at baseline (

Background : In multiple sclerosis (MS) neurofilament light chain (NfL) is a marker of neuronal damage secondary to inflammation and neurodegeneration. NfL levels drop after commencement of disease-modifying treatment, especially the highly active ones. However, the factors that influence this drop are unknown. Objective : To examine the patient and treatment-related factors that influence CSF NfL before and after starting treatment. Methods : Eligible patients across two centres with two CSF NfL measurements, clinical and MRI data were included as part of an observational cohort study. Results : Data were available in 61 patients, of which 40 were untreated at the first CSF sampling (T1) and treated at the second (T2; mean T1-T2: 19 months). CSF NfL reduction correlated with age (beta=1.24 95%CI(1.07,1.43); R2=0.17; p=0.005), Expanded Disability Status Scale (EDSS) (beta=1.12 95%CI(1.00,1.25); R2=0.21; p=0.05) and the type of MS (beta=0.63 95%CI(0.43, 0.92); R2=0.12; p=0.018; reference=relapsing MS). The treatment effect on a baseline NfL of 702 pg/mL was 451 pg/ml 95%CI(374,509) in a 30-year-old versus 228 pg/ml 95%CI(63,350) in a 60-year-old. There was no association in CSF NfL reduction with BMI, disease duration or sex. In cladribine- and alemtuzumab-treated patients, the CSF NfL T2/T1 ratio did not correlate with lymphocyte depletion rate at 23 weeks. Conclusions : In this observational study, we found that factors reflecting early disease stage, including a younger age, lower disability and relapsing MS were associated with treatment response in CSF NfL. Other factors were not found to be related, including lymphopaenia in highly-active treatments.

Background: Case-mix classification is a focus of international attention in considering how best to manage and fund services, by providing a basis for fairer comparison of resource utilization. Yet there is little evidence of the best ways to establish case mix for child and adolescent mental health services (CAMHS).Aim: To develop a case mix classification for CAMHS that is clinically meaningful and predictive of number of appointments attended and to investigate the influence of presenting problems, context and complexity factors and provider variation.Method: We analysed 4573 completed episodes of outpatient care from 11 English CAMHS. Cluster analysis, regression trees and a conceptual classification based on clinical best practice guidelines were compared regarding their ability to predict number of appointments, using mixed effects negative binomial regression.Results: The conceptual classification is clinically meaningful and did as well as data-driven classifications in accounting for number of appointments. There was little evidence for effects of complexity or context factors, with the possible exception of school attendance problems. Substantial variation in resource provision between providers was not explained well by case mix.Conclusion: The conceptually-derived classification merits further testing and development in the context of collaborative decision making.