Influence of vitamin D supplementation on growth, body composition, pubertal development and spirometry in South African schoolchildren: a randomised controlled trial (ViDiKids).

OBJECTIVE: To determine whether weekly oral vitamin D supplementation influences growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. DESIGN: Phase 3 double-blind randomised placebo-controlled trial. SETTING: Socioeconomically disadvantaged peri-urban district of Cape Town, South Africa. PARTICIPANTS: 1682 children of black African ancestry attending government primary schools and aged 6-11 years at baseline. INTERVENTIONS: Oral vitamin D3 (10 000 IU/week) versus placebo for 3 years. MAIN OUTCOME MEASURES: Height-for-age and body mass index-for-age, measured in all participants; Tanner scores for pubertal development, spirometric lung volumes and body composition, measured in a subset of 450 children who additionally took part in a nested substudy. RESULTS: Mean serum 25-hydroxyvitamin D3 concentration at 3-year follow-up was higher among children randomised to receive vitamin D versus placebo (104.3 vs 64.7 nmol/L, respectively; mean difference (MD) 39.7 nmol/L, 95% CI 37.6 to 41.9 nmol/L). No statistically significant differences in height-for-age z-score (adjusted MD (aMD) -0.08, 95% CI -0.19 to 0.03) or body mass index-for-age z-score (aMD -0.04, 95% CI -0.16 to 0.07) were seen between vitamin D versus placebo groups at follow-up. Among substudy participants, allocation to vitamin D versus placebo did not influence pubertal development scores, % predicted forced expiratory volume in 1 s (FEV1), % predicted forced vital capacity (FVC), % predicted FEV1/FVC, fat mass or fat-free mass. CONCLUSIONS: Weekly oral administration of 10 000 IU vitamin D3 boosted vitamin D status but did not influence growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT02880982, South African National Clinical Trials Register DOH-27-0916-5527.

Influence of vitamin D supplementation on bone mineral content, bone turnover markers, and fracture risk in South African schoolchildren: multicenter double-blind randomized placebo-controlled trial (ViDiKids).

Randomized controlled trials (RCTs) to determine the influence of vitamin D on BMC and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n = 450) nested within a phase 3 RCT of weekly oral supplementation with 10 000 IU vitamin D3 vs placebo for 3 yr in HIV-uninfected Cape Town schoolchildren aged 6-11 yr. Outcomes were BMC at the whole body less head (WBLH) and LS and serum 25-hydroxyvitamin D3 (25(OH)D3), PTH, alkaline phosphatase, C-terminal telopeptide, and PINP. Incidence of fractures was a secondary outcome of the main trial (n = 1682). At baseline, mean serum 25(OH)D3 concentration was 70.0 nmol/L (SD 13.5), and 5.8% of participants had serum 25(OH)D3 concentrations <50 nmol/L. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI, 36.1 to 43.6) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95% CI, -0.94 to -0.17). However, no interarm differences were seen for WBLH BMC (aMD -8.0 g, 95% CI, -30.7 to 14.7) or LS BMC (aMD -0.3 g, 95% CI, -1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomized to vitamin D vs placebo (7/755 vs 10/758 attending at least 1 follow-up; adjusted odds ratio 0.70, 95% CI, 0.27 to 1.85). In conclusion, a 3-yr course of weekly oral vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome.

Vitamin D­the "sunshine vitamin"­is essential for helping the body to absorb calcium from the diet, which is laid down in bone to improve its strength. There is a lack of clinical trials testing whether vitamin D supplements can improve bone content of calcium and other minerals, or reduce risk of bone fractures (broken bones) in children of Black African ancestry. We therefore conducted such a study, recruiting 1682 schoolchildren aged 6­11 yr living in Cape Town, South Africa. We found that a weekly dose of 10 000 international units (250 micrograms) of vitamin D3, given by mouth for 3 yr, was effective in boosting vitamin D levels in trial participants who received it. However, this did not have any effect on bone content of calcium and other minerals. Relatively few children experienced a broken bone during the study, so we were unable to say with confidence whether or not vitamin D supplements might affect this outcome.

Clinical features of type 1 diabetes in older adults and the impact of intermittently scanned continuous glucose monitoring: An Association of British Clinical Diabetologists (ABCD) study.

AIMS: To evaluate the clinical features and impact of flash glucose monitoring in older adults with type 1 diabetes (T1D) across age groups defined as young-old, middle-old, and old-old. MATERIALS AND METHODS: Clinicians were invited to submit anonymized intermittently scanned continuous glucose monitoring (isCGM) user data to a secure web-based tool within the National Health Service secure network. We collected baseline data before isCGM initiation, such as demographics, glycated haemoglobin (HbA1c) values from the previous 12 months, Gold scores and Diabetes Distress Scale (DDS2) scores. For analysis, people with diabetes were classified as young-old (65-75 years), middle-old (>75-85 years) and old-old (>85 years). We compared baseline clinical characteristics across the age categories using a t test. All the analyses were performed in R 4.1.2. RESULTS: The study involved 1171 people with diabetes in the young-old group, 374 in the middle-old group, and 47 in the old-old group. There were no significant differences in baseline HbA1c and DDS2 scores among the young-old, middle-old, and old-old age groups. However, Gold score increased with age (3.20 [±1.91] in the young-old vs. 3.46 [±1.94] in the middle-old vs. 4.05 [±2.28] in the old-old group; p < 0.0001). This study showed reduced uptake of insulin pumps (p = 0.005) and structured education (Dose Adjustment For Normal Eating [DAFNE] course; p = 0.007) in the middle-old and old-old populations compared to the young-old population with T1D. With median isCGM use of 7 months, there was a significant improvement in HbA1c in the young-old (p < 0.001) and old-old groups, but not in the middle-old group. Diabetes-related distress score (measured by the DDS2) improved in all three age groups (p < 0.001) and Gold score improved (p < 0.001) in the young-old and old-old populations but not in the middle-old population. There was also a significant improvement in resource utilization across the three age categories following the use of is CGM. CONCLUSION: This study demonstrated significant differences in hypoglycaemia awareness and insulin pump use across the older age groups of adults with T1D. The implementation of isCGM demonstrated significant improvements in HbA1c, diabetes-related distress, hypoglycaemia unawareness, and resource utilization in older adults with T1D.

Intermittently scanned continuous glucose monitoring and hypoglycaemia awareness in drivers with diabetes: Insights from the Association of British Clinical Diabetologists Nationwide audit.

AIM: Frequent hypoglycaemia results in disruption to usual hypoglycaemic autonomic responses leading to impaired awareness of hypoglycaemia, which is associated with an increased risk of severe hypoglycaemia requiring third-party assistance (SH). The UK Driving and Vehicle Licensing Agency (DVLA) does not permit car driving if they have either a complete loss of hypoglycaemia awareness or more than one SH event a year. METHODS: The FreeStyle Libre (FSL) Association of British Clinical Diabetologists (ABCD) Nationwide Audit consists of data collected by clinicians during routine clinical work, submitted into a secure web-based tool held within the National Health Service (NHS) N3 network. Analysis of paired baseline and follow-up data for people with type 1 diabetes who also held a driving licence was undertaken. RESULTS: The study consisted of 6304 people who had data recorded about driving status from 102 UK specialist diabetes centres, of which 4218 held a driving licence: 4178 a group 1, standard licence, 33 a group 2, large lorries and buses, seven a taxi licence; 1819 did not drive. Paired baseline and follow-up data were available for a sub-cohort of 1606/4218. At a mean follow-up of 6.9 months [95% CI (6.8, 7.1)], the Gold score had improved (2.3 ± 1.5 vs. 2.0 ± 1.3 p < .001), and the number of people who experienced an SH episode was also significantly lower (12.1% vs. 2.7%, p < .001). CONCLUSION: This study suggests that intermittently scanned continuous glucose monitoring may improve impaired awareness of hypoglycaemia and reduce the number of people with type 1 diabetes with a driving licence experiencing a severe hypoglycaemic episode.

Ethical and Information Governance Considerations for Promoting Digital Social Interventions in Primary Care.

Promoting online peer support beyond the informal sector to statutory health services requires ethical considerations and evidence-based knowledge about its impact on patients, health care professionals, and the wider health care system. Evidence on the effectiveness of digital interventions in primary care is sparse, and definitive guidance is lacking on the ethical concerns arising from the use of social media as a means for health-related interventions and research. Existing literature examining ethical issues with digital interventions in health care mainly focuses on apps, electronic health records, wearables, and telephone or video consultations, without necessarily covering digital social interventions, and does not always account for primary care settings specifically. Here we address the ethical and information governance aspects of undertaking research on the promotion of online peer support to patients by primary care clinicians, related to medical and public health ethics.

Non-randomised feasibility study testing a primary care intervention to promote engagement in an online health community for adults with troublesome asthma: protocol.

INTRODUCTION: In the UK, approximately 4.3 million adults have asthma, with one-third experiencing poor asthma control, affecting their quality of life, and increasing their healthcare use. Interventions promoting emotional/behavioural self-management can improve asthma control and reduce comorbidities and mortality. Integration of online peer support into primary care services to foster self-management is a novel strategy. We aim to co-design and evaluate an intervention for primary care clinicians to promote engagement with an asthma online health community (OHC). Our protocol describes a 'survey leading to a trial' design as part of a mixed-methods, non-randomised feasibility study to test the feasibility and acceptability of the intervention. METHODS AND ANALYSIS: Adults on the asthma registers of six London general practices (~3000 patients) will be invited to an online survey, via text messages. The survey will collect data on attitudes towards seeking online peer support, asthma control, anxiety, depression, quality of life, information on the network of people providing support with asthma and demographics. Regression analyses of the survey data will identify correlates/predictors of attitudes/receptiveness towards online peer support. Patients with troublesome asthma, who (in the survey) expressed interest in online peer support, will be invited to receive the intervention, aiming to reach a recruitment target of 50 patients. Intervention will involve a one-off, face-to-face consultation with a practice clinician to introduce online peer support, sign patients up to an established asthma OHC, and encourage OHC engagement. Outcome measures will be collected at baseline and 3 months post intervention and analysed with primary care and OHC engagement data. Recruitment, intervention uptake, retention, collection of outcomes, and OHC engagement will be assessed. Interviews with clinicians and patients will explore experiences of the intervention. ETHICS AND DISSEMINATION: Ethical approval was obtained from a National Health Service Research Ethics Committee (reference: 22/NE/0182). Written consent will be obtained before intervention receipt and interview participation. Findings will be shared via dissemination to general practices, conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05829265.

Vitamin D supplementation to prevent tuberculosis infection in South African schoolchildren: multicenter phase 3 double-blind randomized placebo-controlled trial (ViDiKids).

OBJECTIVES: To determine whether weekly oral supplementation with 10,000 IU vitamin D3 for 3 years reduces the risk of sensitization to M. tuberculosis in South African schoolchildren aged 6-11 years with negative QuantiFERON-tuberculosis (TB) Gold Plus (QFT-Plus) assay results at baseline. METHODS: We conducted a phase 3 randomized placebo-controlled trial in 1682 children attending 23 primary schools in Cape Town. The primary outcome was a positive end-trial QFT-Plus result, analyzed using a mixed effects logistic regression model with the school of attendance included as a random effect. RESULTS: 829 vs. 853 QFT-Plus-negative children were randomized to receive vitamin D3 vs. placebo, respectively. Mean end-study 25(OH)D concentrations in participants randomized to vitamin D vs. placebo were 104.3 vs 64.7 nmol/l, respectively (95% confidence interval for difference, 37.6 to 41.9 nmol/l). A total of 76/667 (11.4%) participants allocated to vitamin D vs. 89/687 (13.0%) participants allocated to placebo tested QFT-Plus positive at 3-year follow-up (adjusted odds ratio 0.86, 95% confidence interval 0.62-1.19, P = 0.35). CONCLUSION: Weekly oral supplementation with 10,000 IU vitamin D3 for 3 years elevated serum 25(OH)D concentrations among QFT-Plus-negative Cape Town schoolchildren but did not reduce their risk of QFT-Plus conversion.

Fluid Optimisation in Emergency Laparotomy (FLO-ELA) Trial: study protocol for a multi-centre randomised trial of cardiac output-guided fluid therapy compared to usual care in patients undergoing major emergency gastrointestinal surgery.

INTRODUCTION: Postoperative morbidity and mortality in patients undergoing major emergency gastrointestinal surgery are a major burden on healthcare systems. Optimal management of perioperative intravenous fluids may reduce mortality rates and improve outcomes from surgery. Previous small trials of cardiac-output guided haemodynamic therapy algorithms in patients undergoing gastrointestinal surgery have suggested this intervention results in reduced complications and a modest reduction in mortality. However, this existing evidence is based mainly on elective (planned) surgery, with little evaluation in the emergency setting. There are fundamental clinical and pathophysiological differences between the planned and emergency surgical setting which may influence the effects of this intervention. A large definitive trial in emergency surgery is needed to confirm or refute the potential benefits observed in elective surgery and to inform widespread clinical practice. METHODS: The FLO-ELA trial is a multi-centre, parallel-group, open, randomised controlled trial. 3138 patients aged 50 and over undergoing major emergency gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intra-venous fluid, or usual care without cardiac output monitoring. The trial intervention will be carried out during surgery and for up to 6 h postoperatively. The trial is funded through an efficient design call by the National Institute for Health and Care Research Health Technology Assessment (NIHR HTA) programme and uses existing routinely collected datasets for the majority of data collection. The primary outcome is the number of days alive and out of hospital within 90 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation. Participant recruitment started in September 2017 with a 1-year internal pilot phase and is ongoing at the time of publication. DISCUSSION: This will be the largest contemporary randomised trial examining the effectiveness of perioperative cardiac output-guided haemodynamic therapy in patients undergoing major emergency gastrointestinal surgery. The multi-centre design and broad inclusion criteria support the external validity of the trial. Although the clinical teams delivering the trial interventions will not be blinded, significant trial outcome measures are objective and not subject to detection bias. TRIAL REGISTRATION: ISRCTN 14729158. Registered on 02 May 2017.

Continuous glucose monitoring for diabetes: potential pitfalls for the general physician.

A 31-year-old man presented systemically unwell with diabetic ketoacidosis (DKA). He was using an intermittently scanned continuous glucose monitoring (CGM) device that had been recording low or normal glucose readings for the 48 hours prior to admission. The sensor site had become infected, and we believe this soft tissue infection caused his CGM device to record falsely low glucose readings leading the patient to erroneously lower his insulin doses and take extra carbohydrates, precipitating DKA. CGM devices measure glucose levels in the interstitial fluid. When interstitial glucose readings do not match symptoms or expectations, a capillary blood glucose reading should be taken to correlate and impact treatment decisions. There will be an increase in patients presenting to hospital with CGM devices as the National Institute for Health and Care Excellence guidelines have recently been updated. We use this interesting clinical case to provide context for key learning points about CGM devices for the general physician.

A prospective study of risk factors associated with seroprevalence of SARS-CoV-2 antibodies in healthcare workers at a large UK teaching hospital.

OBJECTIVES: To describe the risk factors for SARS-CoV-2 infection in UK healthcare workers (HCWs). METHODS: We conducted a prospective sero-epidemiological study of HCWs at a major UK teaching hospital using a SARS-CoV-2 immunoassay. Risk factors for seropositivity were analysed using multivariate logistic regression. RESULTS: 410/5,698 (7·2%) staff tested positive for SARS-CoV-2 antibodies. Seroprevalence was higher in those working in designated COVID-19 areas compared with other areas (9·47% versus 6·16%) Healthcare assistants (aOR 2·06 [95%CI 1·14-3·71]; p=0·016) and domestic and portering staff (aOR 3·45 [95% CI 1·07-11·42]; p=0·039) had significantly higher seroprevalence than other staff groups after adjusting for age, sex, ethnicity and COVID-19 working location. Staff working in acute medicine and medical sub-specialities were also at higher risk (aOR 2·07 [95% CI 1·31-3·25]; p<0·002). Staff from Black, Asian and minority ethnic (BAME) backgrounds had an aOR of 1·65 (95% CI 1·32 - 2·07; p<0·001) compared to white staff; this increased risk was independent of COVID-19 area working. The only symptoms significantly associated with seropositivity in a multivariable model were loss of sense of taste or smell, fever, and myalgia; 31% of staff testing positive reported no prior symptoms. CONCLUSIONS: Risk of SARS-CoV-2 infection amongst HCWs is highly heterogeneous and influenced by COVID-19 working location, role, age and ethnicity. Increased risk amongst BAME staff cannot be accounted for solely by occupational factors.

Prevalence and Determinants of Vitamin D Deficiency in 1825 Cape Town Primary Schoolchildren: A Cross-Sectional Study.

Vitamin D deficiency (25-hydroxyvitamin D[25(OH)D] <50 nmol/L) is common among adults in Cape Town, South Africa, but studies investigating vitamin D status of children in this setting are lacking. We conducted a cross-sectional study to determine the prevalence and determinants of vitamin D deficiency in 1825 Cape Town schoolchildren aged 6−11 years. Prevalence of vitamin D deficiency was 7.6% (95% Confidence Interval [CI] 6.5% to 8.9%). Determinants of vitamin D deficiency included month of sampling (adjusted odds ratio [aOR] for July−September vs. January−March 10.69, 95% CI 5.02 to 22.77; aOR for October−December vs. January−March 6.73, 95% CI 2.82 to 16.08), older age (aOR 1.25 per increasing year, 95% CI: 1.01−1.53) and higher body mass index (BMI; aOR 1.24 per unit increase in BMI-for-age Z-score, 95% CI: 1.03−1.49). In a subset of 370 participants in whom parathyroid hormone (PTH) concentrations were measured; these were inversely related to serum 25(OH)D concentrations (p < 0.001). However, no association between participants with hyperparathyroidism (PTH >6.9 pmol/L) and vitamin D deficiency was seen (p = 0.42). In conclusion, we report that season is the major determinant of vitamin D status among Cape Town primary schoolchildren, with prevalence of vitamin D deficiency ranging from 1.4% in January−March to 22.8% in July−September.

Clinical- and cost-effectiveness of a technology-supported and solution-focused intervention (DIALOG+) in treatment of patients with chronic depression-study protocol for a multi-site, cluster randomised controlled trial [TACK].

BACKGROUND: Many with an acute depressive disorder go on to develop chronic depression, despite ongoing care. There are few specifically designed interventions to treat chronic depression. DIALOG+, a technology-assisted intervention based on the principles of solution-focused therapy, may be beneficial. It has been shown to be effective as a treatment for patients with psychotic disorders, especially in regards to increasing quality of life. DIALOG+ was designed to be flexibly applied and not diagnosis-specific, aiming to structure communication and generate a personally-tailored care plan. This cluster randomised controlled trial (RCT) is part of a programme of research to adapt and test DIALOG+ for patients with chronic depression. METHODS: Patients will be eligible for the trial, if they have exhibited symptoms of depression or non-psychotic low mood for at least 2 years, have regular contact with a clinician and have a low subjective quality of life and moderate depressive symptoms. Clinicians, who routinely see eligible patients, will be recruited from a number of sites across NHS England. Clusters will have between 1 and 6 patients per clinician and will be randomised in a 1:1 ratio to either the intervention (DIALOG+) or active control group (treatment as usual + DIALOG scale). Clinicians in the intervention group are trained and asked to deliver the intervention regularly for 12 months. Active control participants receive treatment as usual and are asked to rate their satisfaction with areas of life and treatment on the DIALOG scale at the end of the clinical session. Approximately 112 clinician clusters will be recruited to reach a total patient sample size of 376. Clinical and social outcomes including costs are assessed at baseline and 3, 6 and 12 months post randomisation. The primary outcome will be subjective quality of life at 12 months. DISCUSSION: This definitive multi-site, cluster RCT aims to evaluate the clinical- and cost-effectiveness of DIALOG+ for people with chronic depression. If shown to be effective for this patient population it could be used to improve outcomes of mental health care on a larger scale, ensuring that patients with complex and co-morbid diagnoses can benefit. TRIAL REGISTRATION: ISRCTN11301686 . Registered on 13 Jun 2019.

Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19.

Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T-cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T-cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.

A case of severe refractory Darier's disease of the feet in which management with carbon dioxide (CO2) laser therapy demonstrated superior outcomes to surgical excision.

Darier's disease is a rare genodermatosis typically characterized by scaly or crusted papules. Usual management comprises topical and oral treatments, however medical therapy may be inadequate in cases of severe disease. For these patients, further treatment options may include the use of carbon dioxide (CO2) laser therapy or surgical excision with skin grafting. We describe a unique situation in which both CO2 laser therapy and surgical excision were trialed in comparable areas within a single patient. Superior outcomes over a 7-year follow up period have been seen with the use of CO2 laser therapy.

Demonstration of a Fair Level of Agreement Between Escalation Scores Reported by Hospital Managers and Analysis of Stress-Related Hospital Metrics.

BACKGROUND: The National Health System in Wales has developed a novel national electronic dashboard which reports a daily "escalation score," reflecting management's opinion of the pressure each hospital is facing, primarily due to unscheduled care. The aim of this study was to examine the possibility of replacing human scores with a quantitative model, based on the relationship between reported escalation scores and selected hospital metrics. METHODS: Generalized linear mixed models were used to model the association between hospital metrics and escalation scores between October one year and October the next year utilizing hospital bed occupancy rate, ambulance hours lost waiting outside emergency departments, number of "boarded out" patients in the hospital, and the daily ratio of admissions to discharges in the hospital. These models were tested against a subsequent period (December unto May the following year), using three models: "general," "hospital-specific," and "group-specific." The model generated by the initial time frame was tested against data from the subsequent time frame using weighted κ. RESULTS: Across 16 hospitals, using 3343 escalation scores, the rates of agreement and weighted κ were: general model (48.8%; 0.16), hospital-specific model (45.0%; 0.25), and group-specific model (43.1%; 0.25). A 17th small hospital was excluded due to missing data. CONCLUSIONS: This is novel research as no similar studies were identified, although the topic is important as it addresses a major current health-care challenge. Automated scores can be derived which have the advantage of being derived objectively, avoiding human inter- and intraindividual variation. Prospective testing is recommended to assess potential service planning benefit.

The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic ß cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs. METHODS: DILfrequency is a nonrandomized, open-label, response-adaptive study of participants, aged 18-70 years, with T1D. The initial learning phase allocated 12 participants to 6 different predefined regimens. Then, 3 cohorts of 8 participants were sequentially allocated dose frequencies, based on repeated interim analyses of all accumulated trial data. The coprimary endpoints were percentage change in Tregs and Teffs and CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. RESULTS: Thirty-eight participants were enrolled, with thirty-six completing treatment. The optimal regimen to maintain a steady-state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI -0.007 to 0.485) every 3 days. Tregs and CD25 were dose-frequency responsive, Teffs were not. The commonest adverse event was injection site reaction (464 of 694 events). CONCLUSIONS: Using a response-adaptive design, aldesleukin treatment can be optimized. Our methodology can generally be employed to immediately access proof of mechanism, thereby leading to more efficient and safe drug development. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register, ISRCTN40319192; ClinicalTrials.gov, NCT02265809. FUNDING: Sir Jules Thorn Trust, the Swiss National Science Foundation, Wellcome, JDRF, and NIHR Cambridge Biomedical Research Centre.

Challenges of Capacity and Development for Health System Sustainability.

To achieve sustainability, remote and rural communities require health service models that are designed in and for these settings and are responsive to local population health needs. This paper draws on a panel discussion at the Rural and Indigenous Health Symposium held in Toronto, ON, on September 21, 2017. Active community participation is an important contributor to success in rural health system transformation, as well as health workforce recruitment and retention. Increasingly, communication technology is contributing to the quality and effectiveness of healthcare in remote rural community settings, particularly by ensuring that specialist expertise is accessible to and supportive of the local providers of care. Recent medical graduates bring life experiences and work expectations to rural primary care that are different from their senior colleagues. Successful recruitment and retention of the rural primary care workforce depend increasingly on offering a "turnkey" clinic work supported by a functioning electronic medical record. Rural health system sustainability occurs most frequently through ongoing collaboration and partnerships, partnerships, partnerships. It is through partnerships with communities, health services and healthcare providers that the Northern Ontario School of Medicine (NOSM) has been successful in producing medical graduates who provide care responsive to population health needs in previously underserved communities of northern Ontario. Sustainable healthcare in remote and rural communities is enhanced by active community participation and clustering these communities in local networks. An important key to success is shifting from hospital-centric to community-centric care.

Better governance, better access: practising responsible data sharing in the METADAC governance infrastructure.

BACKGROUND: Genomic and biosocial research data about individuals is rapidly proliferating, bringing the potential for novel opportunities for data integration and use. The scale, pace and novelty of these applications raise a number of urgent sociotechnical, ethical and legal questions, including optimal methods of data storage, management and access. Although the open science movement advocates unfettered access to research data, many of the UK's longitudinal cohort studies operate systems of managed data access, in which access is governed by legal and ethical agreements between stewards of research datasets and researchers wishing to make use of them. Amongst other things, these agreements aim to respect the reasonable expectations of the research participants who provided data and samples, as expressed in the consent process. Arguably, responsible data management and governance of data and sample use are foundational to the consent process in longitudinal studies and are an important source of trustworthiness in the eyes of those who contribute data to genomic and biosocial research. METHODS: This paper presents an ethnographic case study exploring the foundational principles of a governance infrastructure for Managing Ethico-social, Technical and Administrative issues in Data ACcess (METADAC), which are operationalised through a committee known as the METADAC Access Committee. METADAC governs access to phenotype, genotype and 'omic' data and samples from five UK longitudinal studies. FINDINGS: Using the example of METADAC, we argue that three key structural features are foundational for practising responsible data sharing: independence and transparency; interdisciplinarity; and participant-centric decision-making. We observe that the international research community is proactively working towards optimising the use of research data, integrating/linking these data with routine data generated by health and social care services and other administrative data services to improve the analysis, interpretation and utility of these data. The governance of these new complex data assemblages will require a range of expertise from across a number of domains and disciplines, including that of study participants. Human-mediated decision-making bodies will be central to ensuring achievable, reasoned and responsible decisions about the use of these data; the METADAC model described in this paper provides an example of how this could be realised.

An examination of user costs in relation to smokers using a cessation service based in the UK.

BACKGROUND: Smoking cessation services provide support to smokers who desire to quit. Published studies to date have looked at the cost and benefit of service provision but typically focus on clinical trial data. Using routinely collected observational data, this study examined the costs involved in providing a service in terms of average health care expenditure per successful quit attempt in addition to population - level cost-effectiveness measures. METHODS: Data were analysed from Quit-51 smoking cessation service across five English regions between March 2013 and March 2016 (n = 9116). For each user, costs were estimated in relation to: (i) time spent with advisers; (ii) prescription of pharmacotherapy. The total costs compared against self-reported quit at 12 weeks, which represents the time period for which the service is offered. Cost per quit (CPQ), with 95% confidence interval (CI), was calculated by relating total expenditure to the number of quitters, firstly for the whole dataset and then by subgroups of key categorical variables, namely; gender, age group, the Fagerstrom test for nicotine dependence (FTND) and Index of Multiple Deprivation (IMD). Confidence intervals (CIs) for the mean estimates were derived using a non-parametric bootstrap procedure. Parameters derived from the calculation in relation to treatment were used to estimate potential long-term population outcomes under a scenario where the Quit 51 prescription was rolled out nationally. RESULTS: The overall mean CPQ for this sample as estimated at 12 weeks was £403.51 (95% CI = £393.36 to £413.76). The estimated CPQs at this time point were comparable for those aged 12-19 (£423.56, 95% CI = £369.45 to £492.60) and those aged 20-29 (£430.76, 95% CI = £395.95 to £470.56). Differences were also seen in relation to other subgroups considered. The treatment parameters translated to a projected increase of 1.5 quality-adjusted life years (QALYs) per 1000 smokers in the short-term and 23.4 QALYS per 1000 smokers based on a lifetime horizon. CONCLUSIONS: These figures throw light on service expenditure for each successful quit over the timeframe for which the service is offered in addition to highlighting variability in these costs across different subgroups of the user population.

The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age.

AIMS/HYPOTHESIS: The genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease process. METHODS: Using ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD. RESULTS: Two regions were convincingly associated with AAD (p < 5 × 10-8): the MHC on 6p21, and 6q22.33. Fine-mapping of 6q22.33 identified two AAD-associated haplotypes in the region nearest to the genes encoding protein tyrosine phosphatase receptor kappa (PTPRK) and thymocyte-expressed molecule involved in selection (THEMIS). We examined the susceptibility to type 1 diabetes at these SNPs by performing a meta-analysis including 19,510 control participants. Although these SNPs were not associated with type 1 diabetes overall (p > 0.001), the SNP most associated with AAD, rs72975913, was associated with susceptibility to type 1 diabetes in those individuals diagnosed at less than 5 years old (p = 2.3 × 10-9). CONCLUSION/INTERPRETATION: PTPRK and its neighbour THEMIS are required for early development of the thymus, which we can assume influences the initiation of autoimmunity. Non-HLA genes may only be detectable as risk factors for the disease in individuals diagnosed under the age 5 years because, after that period of immune development, their role in disease susceptibility has become redundant.