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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 The Wash’Em process was developed to improve the design of handwashing behaviour change programmes in outbreaks and fragile humanitarian settings, ensuring that programmes are able to be designed rapidly while still being contextualised and evidence-based. The approach was widely used during the COVID-19 pandemic to inform prevention programmes. This study aims to compare data emerging from the use of the Wash’Em process during the pandemic, to understand whether commonalities in programming constraints or the determinants of handwashing behaviour existed across countries. Methods We conducted a secondary data analysis of summary data entered into the Wash’Em Programme Designer Software. This summary data was drawn from the use of the Wash’Em Rapid Assessment Tools in 38 settings during the pandemic. Data was verified prior to inclusion; descriptively summarised and then statistical summaries of homogeneity were derived. Results Wash’Em was implemented as intended during the pandemic, typically taking a small number of humanitarian staff less than a week to complete. Most humanitarian actors reported using the programmatic recommendations suggested by the process but did so within relatively short-term and poorly financed prevention programmes. Homogeneity in the responses to the Rapid Assessment Tools was low indicating that the determinants of handwashing behaviour during the pandemic were predominantly shaped by pre-existing factors within the context rather than the nature of the health threat. Conclusion Hygiene programmes during outbreaks should avoid ‘copying and pasting’ interventions from one setting to another and instead make time to holistically understand the behavioural determinants in a specific context and develop programme activities that are designed to address these. Particular attention should be given to factors in the physical and social environment which may enable or constrain handwashing behaviour, pre-existing disease vulnerabilities, and the secondary and non-health impacts of outbreaks. Wash’Em provides one feasible way of contextualising handwashing interventions in outbreak or fragile humanitarians settings.

Background Shared sanitation facilities are used by over 500 million people around the world. Most research evidence indicates that shared sanitation conveys higher risk than household sanitation for many adverse health outcomes, including stunting and diarrhoea. However, studies often fail to account for variation between different types of shared facility. As informal housing development outpaces sanitation infrastructure, it is imperative to understand which components of shared facilities may mitigate the health risks of shared sanitation use. Methods This cross-sectional study determines whether sanitation improvement or compound hygiene were associated with stunting or diarrhoeal prevalence in a population of children under five living in Maputo, Mozambique who rely on shared sanitation facilities. The study uses logistic and linear multivariable regression analysis to search for associations and control for potential confounding factors. Results 346 children (43.9%) in the study population were stunted (height-for-age z-score Conclusions Use of an improved latrine is associated with decreased odds of stunting, even among users of shared sanitation. This effect remained after controlling for age, sex, wealth, breastfeeding status, and maternal education level. There was no evidence of an association between latrine improvement and diarrhoea. Further investigation is necessary to isolate the attributes of shared sanitation facilities that may lead to the greatest reduction in health risk.

Background and ObjectivesDementia is a growing socioeconomic challenge that requires early intervention. Identifying biomarkers that reliably predict clinical progression early in the disease process would better aid selection of individuals for future trial participation. Here, we compared the ability of baseline, single time-point biomarkers (CSF amyloid 1–42, CSF ptau-181, white matter hyperintensities (WMH), cerebral microbleeds, whole-brain volume, and hippocampal volume) to predict decline in cognitively normal individuals who later converted to mild cognitive impairment (MCI) (CNtoMCI) and those with MCI who later converted to an Alzheimer disease (AD) diagnosis (MCItoAD).MethodsStandardized baseline biomarker data from AD Neuroimaging Initiative 2 (ADNI2)/GO and longitudinal diagnostic data (including ADNI3) were used. Cox regression models assessed biomarkers in relation to time to change in clinical diagnosis using all follow-up time points available. Models were fit for biomarkers univariately and together in a multivariable model. Hazard ratios (HRs) were compared to evaluate biomarkers. Analyses were performed separately in CNtoMCI and MCItoAD groups.ResultsFor CNtoMCI (n = 189), there was strong evidence that higher WMH volume (individual model: HR 1.79,p= 0.002; fully adjusted model: HR 1.98,p= 0.003) and lower hippocampal volume (individual: HR 0.54,p= 0.001; fully adjusted: HR 0.40,p< 0.001) were associated with conversion to MCI individually and independently. For MCItoAD (n = 345), lower hippocampal (individual model: HR 0.45,p< 0.001; fully adjusted model: HR 0.55,p< 0.001) and whole-brain volume (individual: HR 0.31,p< 0.001; fully adjusted: HR 0.48,p= 0.02), increased CSF ptau (individual: HR 1.88,p< 0.001; fully adjusted: HR 1.61,p< 0.001), and lower CSF amyloid (individual: HR 0.37,p< 0.001; fully adjusted: HR 0.62,p= 0.008) were most strongly associated with conversion to AD individually and independently.DiscussionLower hippocampal volume was a consistent predictor of clinical conversion to MCI and AD. CSF and brain volume biomarkers were predictive of conversion to AD from MCI, whereas WMH were predictive of conversion to MCI from cognitively normal. The predictive ability of WMH in the CNtoMCI group may be interpreted as some being on a different pathologic pathway, such as vascular cognitive impairment.

Introduction: Improving handwashing with soap (HWWS) among children in humanitarian emergencies has the potential to reduce the transmission of several important infectious diseases. However, there is limited evidence on which approaches are effective in increasing HWWS among children in humanitarian settings. One recent innovation – the “Surprise Soap” intervention – was shown to be successful in a small-scale efficacy trial in a humanitarian setting in Iraq. This intervention includes soap with embedded toys delivered through a short household session comprising a glitter game, instruction of how and when to wash hands, and HWWS practice. Whilst promising, this approach has not been evaluated at programmatic scale in a complex humanitarian setting. Methods: We conducted a cluster-randomised controlled equivalence trial of the Surprise Soap intervention in IDP camps in Kahda district, Somalia. Proportionate stratified random sampling was employed to recruit 200 households, with at least one child aged 5-12, across the camps. Eligible households were randomly allocated to receive the Surprise Soap intervention (n=100) or an active comparator handwashing intervention in which plain soap was delivered in a short household session comprising standard health-based messaging and instruction of how and when to wash hands (n=100). The primary outcome was the proportion of pre-specified occasions when HWWS was practiced by children aged 5-12 years, measured at baseline, 4-weeks, 12 weeks, and 16 weeks post invention delivery. Results: HWWS increased in both groups (by 48 percentage points in the intervention group and 51 percentage points in the control group, at the 4-wee follow up), however, there was no evidence of a difference in HWWS between the groups at the 4-week (adjusted RR (aRR)=1.0, 95% CI 0.9–1.1), 12-week (aRR=1.1, 95% CI 0.9–1.3), or 16-week (aRR=1.0, 95% CI 0.9–1.2) follow-up. Conclusions: In a complex humanitarian setting, where soap availability and past exposure to handwashing promotion was low, it appears that well-designed targeted handwashing interventions can increase child HWWS and potentially reduce disease risk, but the Surprise Soap intervention offers no marginal benefit that would justify the additional costs.

BACKGROUND: Understanding the pulmonary impact of changes in early life nutritional status over time in a paediatric CF population may help inform how to use nutritional assessment to guide clinical care. National registry data provides an opportunity to study patterns of weight gain over time at the level of the individual, and thus to gain detailed understanding of the relationship between early weight trajectories and later lung function in children with Cystic Fibrosis (CF). METHODS: Using data from the United Kingdom (UK) and Canadian CF Registries, a mixed effects linear regression model was used to describe children's weight and BMI z-score trajectories from age 1 to 5 years. The intercept (weight-for-age at age 1) and slope (weight-for-age trajectory) from this model were then used as covariates in a linear regression of first lung function measurement at age 6 years. RESULTS: In both the UK and Canadian data, greater weight-for-age z-score at age 1 year and greater change in weight-for-age over time were associated with higher FEV1% predicted. A greater weight-for-age z-score at age 1 year was associated with a higher FEV1% predicted (UK: 3.78% (95% CI: 1.76; 4.70); Canada: 3.20% (95%CI: 1.76, 4.70)). These associations were reproduced for BMI z-scores and FVC% predicted. CONCLUSIONS: Early weight-for-age, specifically at age 1 year, and weight-for-age trajectories across early childhood are associated with later lung function. This relationship persists after adjustment for potential confounders. Current guidelines may need to be updated to place less emphasis on a specific cut-off (such as the 10th percentile) and encourage tracking of weight-for-age over time.

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.

Although there is an ever-increasing number of disease-modifying treatments for relapsing multiple sclerosis (MS), few appear to influence coronavirus disease 2019 (COVID-19) severity. There is concern about the use of anti-CD20-depleting monoclonal antibodies, due to the apparent increased risk of severe disease following severe acute respiratory syndrome corona virus two (SARS-CoV-2) infection and inhibition of protective anti-COVID-19 vaccine responses. These antibodies are given as maintenance infusions/injections and cause persistent depletion of CD20+ B cells, notably memory B-cell populations that may be instrumental in the control of relapsing MS. However, they also continuously deplete immature and mature/naïve B cells that form the precursors for infection-protective antibody responses, thus blunting vaccine responses. Seroconversion and maintained SARS-CoV-2 neutralizing antibody levels provide protection from COVID-19. However, it is evident that poor seroconversion occurs in the majority of individuals following initial and booster COVID-19 vaccinations, based on standard 6 monthly dosing intervals. Seroconversion may be optimized in the anti-CD20-treated population by vaccinating prior to treatment onset or using extended/delayed interval dosing (3–6 month extension to dosing interval) in those established on therapy, with B-cell monitoring until (1–3%) B-cell repopulation occurs prior to vaccination. Some people will take more than a year to replete and therefore protection may depend on either the vaccine-induced T-cell responses that typically occur or may require prophylactic, or rapid post-infection therapeutic, antibody or small-molecule antiviral treatment to optimize protection against COVID-19. Further studies are warranted to demonstrate the safety and efficacy of such approaches and whether or not immunity wanes prematurely as has been observed in the other populations.

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.).

The prevalence of enteric pathogen detection in children in low-income countries climbs rapidly between birth and 6 months of age. Few studies have tested whether improved household environmental and behavioral hygiene conditions protects infants from exposure to enteric pathogens spread via unhygienic human and animal sanitation conditions, especially during this early window of infancy. This cross-sectional study utilized enrollment survey data among households with 6 month old infants in Kisumu, Kenya participating in the Safe Start cluster-randomized controlled trial to estimate associations between household water access and treatment, animal vectors, sanitation access, hand washing practices, supplemental feeding, and flooring, with the outcomes of caregiver-reported 7-day diarrhea prevalence and sum count of different enteric viruses, bacteria, and parasites pathogens in infant stool. Then, we tested whether household environmental hygiene and behavioral practices moderated associations between infant exposure outcomes and latrine access and domestic animal co-habitation. We found that reported handwashing after handling animals and before eating were strongly associated with lower risk of caregiver-reported diarrhea, while owning and co-habitating with animals (versus no animals), living in a household with vinyl covered dirt floors (versus finished floors), and feeding infants cow milk (versus no milk) were strongly associated with pathogen detection in infants. Caregiver handwashing after child or self-defecation moderated the relationship between shared sanitation (vs private) sanitation access and infant exposure to pathogens such that handwashing had the greatest benefit for preventing pathogen exposure of infants in households with private latrines. In the absence of handwashing, access to private sanitation posed no benefits over shared latrines for protecting infants from exposure. Our evidence highlights eliminating animal co-habitation, improving flooring, improving post-defecation and food-related handwashing, and improving safety of cow milk sources and/or safe household storage of milk as interventions to prevent enteric pathogen exposure of infants less than 6 months age.Key QuestionsWhat is already known?The population prevalence of enteric infections and diarrhea climbs rapidly in the first year of life. Risk factors for pediatric infections include unhygienic human and animal sanitary conditions that introduce feces into the environment, as well as intermediate environmental and behavioral exposure pathways. Research examining the mitigating role of improved environmental and behavioral conditions in preventing infant exposure to human and animal sanitary conditions is limited.What are the new findings?Contact with domestic animals and feeding infants cow milk are leading risk factors for exposure to enteric pathogens by 6 months age in Kisumu, while handwashing after animal handling and before eating are protective factors against self-reported diarrhea. The benefits of access to a private improved latrine (versus shared) for protecting infants from pathogen exposure were conditional upon caregivers washing hands after defecation or child-defecation.What do the new findings imply?Interventions that keep animals out of infant living spaces and that improve food-related and post-defecation handwashing may be the most effective strategies for controlling the population prevalence of enteric infections in infants between birth and 6 months age in Kisumu and similar settings.

BackgroundCD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown.MethodsRelapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via the clinicalstudydatarequest.com portal.ResultsOnly 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.ConclusionsFew people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.

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

Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple sclerosis (MS) patients. Methods: Litak® was offered to MS-patients irrespective of disease course. Litak® 10 mg was administered for 3–4 days during week 1. Based on lymphocyte count at week 4, patients received another 0–3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts. Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17–72) years and EDSS 0–8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data ( n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data ( n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months. Conclusions: Litak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.

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 (

MRI-derived features of presumed cerebral small vessel disease are frequently found in Alzheimer’s disease. Influences of such markers on disease-progression measures are poorly understood. We measured markers of presumed small vessel disease (white matter hyperintensity volumes; cerebral microbleeds) on baseline images of newly enrolled individuals in the Alzheimer’s Disease Neuroimaging Initiative cohort (GO and 2) and used linear mixed models to relate these to subsequent atrophy and neuropsychological score change. We also assessed heterogeneity in white matter hyperintensity positioning within biomarker abnormality sequences, driven by the data, using the Subtype and Stage Inference algorithm. This study recruited both sexes and included: controls: [n = 159, mean(SD) age = 74(6) years]; early and late mild cognitive impairment [ns = 265 and 139, respectively, mean(SD) ages =71(7) and 72(8) years, respectively]; Alzheimer’s disease [n = 103, mean(SD) age = 75(8)] and significant memory concern [n = 72, mean(SD) age = 72(6) years]. Baseline demographic and vascular risk-factor data, and longitudinal cognitive scores (Mini-Mental State Examination; logical memory; and Trails A and B) were collected. Whole-brain and hippocampal volume change metrics were calculated. White matter hyperintensity volumes were associated with greater whole-brain and hippocampal volume changes independently of cerebral microbleeds (a doubling of baseline white matter hyperintensity was associated with an increase in atrophy rate of 0.3 ml/year for brain and 0.013 ml/year for hippocampus). Cerebral microbleeds were found in 15% of individuals and the presence of a microbleed, as opposed to none, was associated with increases in atrophy rate of 1.4 ml/year for whole brain and 0.021 ml/year for hippocampus. White matter hyperintensities were predictive of greater decline in all neuropsychological scores, while cerebral microbleeds were predictive of decline in logical memory (immediate recall) and Mini-Mental State Examination scores. We identified distinct groups with specific sequences of biomarker abnormality using continuous baseline measures and brain volume change. Four clusters were found; Group 1 showed early Alzheimer’s pathology; Group 2 showed early neurodegeneration; Group 3 had early mixed Alzheimer’s and cerebrovascular pathology; Group 4 had early neuropsychological score abnormalities. White matter hyperintensity volumes becoming abnormal was a late event for Groups 1 and 4 and an early event for 2 and 3. In summary, white matter hyperintensities and microbleeds were independently associated with progressive neurodegeneration (brain atrophy rates) and cognitive decline (change in neuropsychological scores). Mechanisms involving white matter hyperintensities and progression and microbleeds and progression may be partially separate. Distinct sequences of biomarker progression were found. White matter hyperintensity development was an early event in two sequences., Fiford et al. report that presumed small vessel disease markers (white matter hyperintensities and cerebral microbleeds) independently predict increased brain atrophy and cognitive decline. Data-driven analysis of sequences of biomarker abnormality identified distinct groups, two of which had white matter hyperintensity development as an early event., Graphical Abstract Graphical Abstract

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.

Introduction Within CF-EpiNet; Harnessing Data to Improve Lives (a CF Trust funded Strategic Research Centre) we will investigate relationships of lung function in early childhood with growth patterns (here considered as change in weight) before the age of five years. We use flexible longitudinal modelling methods to describe early growth trajectories, and identify factors associated with suboptimal growth. Methods Growth measurements from diagnosis to five years were extracted from two national CF registries: UK (n=2999, years 2007–2015) and Canada (n=2690, years 1990–2013). SITAR (super-imposition by translation and rotation) was used to model weight (kg) over the 5 years. Output parameters were average growth curve, summaries of growth velocity and overall weight. Associations of growth and growth velocity with sex, genotype and new born screening (NBS) were investigated. Results Most children in the UK had been diagnosed early in life (median age of diagnosis 0.06 years; inter quartile range 0.03 to 0.1) by NBS. 52% were homozygous for deltaF508. Despite similar initial average weight in boys and girls, males were heavier than females over the first five years. Children homozygous for deltaF508 were lighter than other children. No tested factor was associated with velocity of weight gain. Only 10% of the Canadian children were diagnosed by NBS, and, overall, the age at diagnosis was later (median 0.17 years; inter quartile range 0.08 to 0.53). Over the first five years, Canadian CF children were lighter than those in the UK (figure 1). Associations of weight with sex and genotype were similar to those seen in the UK. In addition, we observed that those diagnosed by NBS were heavier than those who were not. Conclusions In children with CF there are sex differences in weight during the first 5 years, despite similar initial weight. In Canada, NBS has a positive impact on early growth. SITAR allows exploration of growth patterns in CF patients, but time independent characteristics were not associated with velocity of growth. Statistical modelling incorporating time dependent factors (e.g., infections, treatments) are required to explain variability of growth trajectories.

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.

Gene transfer for hemophilia A offers the potential for a one-time disease altering treatment, eliminating the risk of bleeds while freeing patients from the burden of lifelong chronic therapy. SPK-8011 consists of a bioengineered AAV capsid expressing B domain-deleted factor VIII (FVIII) under the control of a liver-specific promoter. In pre-clinical studies, we showed a dose-dependent increase in circulating FVIII levels in non-human primates infused with SPK-8011. We conducted a Phase I/II study of SPK-8011 in 12 men (ages 18-52 years) with severe (n=11) or moderately severe (n=1) hemophilia A. Prior to gene therapy, 8/12 subjects were on prophylaxis, and 4/12 received on-demand treatment. Subjects were enrolled in 1 of 3 dose cohorts, 5E11 vg/kg (n=2), 1E12(n=3), or 2E12(N=7). Safety analysis showed no inhibitor formation. A single serious adverse event (SAE) was reported, associated with an immune response to AAV capsid characterized by simultaneous decline in FVIII, transaminase elevation peaking at Grade 2, and development of positive IFN-g ELISPOTs to capsid was observed beginning at week 6.5 after vector infusion. The asymptomatic transaminase elevation did not respond promptly to initiation of oral steroids and the subject received two infusions of IV methylprednisolone in hospital, thereby fulfilling SAE criteria. The SAE has resolved. All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis. Across the 12 subjects at 3 doses, there was a 97% reduction in annualized bleeding rate (ABR), and a 97% reduction in annualized infusion rate (AIR). In the 5E11 dose cohort, mean FVIII levels beginning 12 weeks post vector infusion are 13%, with no bleeding events, no elevated transaminase levels, no use of steroids, and stable FVIII expression out to 66 weeks (ongoing). In the 1E12 dose cohort, mean FVIII levels are 15% beginning at 12 weeks post-infusion and stable out to 46 weeks (ongoing). The first subject in the 1E12 dose infused a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second received multiple infusions for a traumatic bleed beginning at day 195. Declining FVIII levels triggered initiation of a course of tapering steroids in both subjects, at 12 and 7 weeks post vector infusion respectively, which led to stabilization of FVIII levels. The third subject has had no bleeding and did not receive factor infusions or steroids. In the 2E12 (highest) dose cohort, 5/7 subjects currently have FVIII levels 16-49%; their mean FVIII level beginning 12 weeks post-infusion is 30%. No bleeds have been reported among these subjects beginning 4 weeks post vector infusion. Additionally, 5/7 subjects in the 2E12 dose cohort received a course of steroids, initiated at 6-11 weeks post vector infusion, for one or more of the following: declining FVIII levels, rise in ALT above subject baseline, or elevated IFN-g ELISPOTs to AAV capsid. Steroid initiation normalized ALT levels and extinguished the ELISPOT signal in all cases; 2 subjects showed limited stabilization of FVIII levels, which fell to Our data indicate that the kinetics of SPK-8011 expression are similar to those observed with investigational SPK-9001 for hemophilia B. All subjects demonstrated durable transgene expression for up to 66 weeks post vector administration (data cutoff 7/13/18). On cumulative follow up of 345 weeks, SPK-8011 demonstrated a favorable safety profile with no evidence of FVIII inhibitor formation, a single SAE, and 2/12 subjects who experienced ALT elevation above the upper limit of normal that resolved with steroid initiation. Data from the 5E11 (lowest) dose cohort are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events. Given that 2 subjects in the 2E12 dose cohort lost some FVIII expression, which then stabilized on steroids, and 5/7 subjects in this cohort required steroids, prophylactic steroids may be warranted. We conclude that infusion of SPK-8011 in 12 subjects with severe or moderately severe hemophilia A resulted in safe, durable, dose-dependent FVIII expression resulting in an excellent preliminary efficacy profile with an overall 97% reduction in ABR and AIR. Disclosures High: Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. George:University of Pennsylvania: Equity Ownership; Pfizer: Consultancy. Ragni:CSL Behring: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo: Research Funding; Shire: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Bioverativ: Consultancy, Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; SPARK: Consultancy, Research Funding. Croteau:Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Genetech: Consultancy, Research Funding; CSL-Behring: Consultancy; Catalyst Biosciences: Consultancy; Bioveritiv: Consultancy; Biomarin: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Joseney-Antoine:Spark Therapeutics: Employment. Macdougall:Spark Therapeutics: Employment. Tompkins:Spark Therapeutics: Employment. Hait:Spark Therapeutics: Employment. Couto:Spark Therapeutics: Employment. Bassiri:Spark Therapeutics: Employment. Valentino:Spark Therapeutics: Employment. Carr:Spark Therapeutics: Employment. Hui:Spark Therapeutics: Employment. Wachtel:Spark Therapeutics: Employment. Takefman:Spark Therapeutics: Employment. Mingozzi:Spark Therapeutics, Inc.: Employment. Anguela:Spark Therapeutics, Inc.: Employment. Reape:Spark Therapeutics: Employment.