"Happy to close?" The relationship between surgical experience and incisional hernia rates following abdominal wall closure in colorectal surgery.

AIM: Incisional hernia (IH) is a common complication of colorectal surgery, affecting up to 30% of patients at 2 years. Given the associated morbidity and high recurrence rates after attempted repair of IH, emphasis should be placed on prevention. There is an association between surgeon volume and outcomes in hernia surgery, yet there is little evidence regarding impact of the seniority of the surgeon performing abdominal wall closure on IH rate. The aim of our study was to assess the rates of IH at 1 year following abdominal wall closure between junior and senior surgeons in patients undergoing elective colorectal surgery. METHODS: This was an exploratory analysis of patients who underwent elective surgery for colorectal cancer between 2014-2018 as part of the Hughes Abdominal Repair Trial (HART), a prospective, multicentre randomised control trial comparing abdominal wall closure methods. Grade of surgeon performing abdominal closure was categorised into "trainee" and "consultant" and compared to IH rate at one year. RESULTS: A total of 663 patients were included in this retrospective analysis of patients in the HART trial. The rate of IH in patients closed by trainees was 20%, compared to 12% in those closed by consultants (p = <0.001). When comparing closure methods, IH rates were significantly higher in the Hughes closure arm between trainees and consultants (20% vs. 12%, p = 0.032), but not high enough in the mass closure arm to reach statistical significance (21% vs. 13%, p = 0.058). On multivariate analysis, age (p = 0.036, OR: 1.02, 95% CI: 1.00-1.04), Male sex (p = 0.049, OR: 1.61, 95% CI: 1.00-2.59) and closure by a trainee (p = 0.006, OR: 1.85, 95% CI: 1.20-2.85) were identified as risk factors for developing IH. CONCLUSION: Patients who undergo abdominal wall closure by a surgeon in training have an increased risk of developing IH when compared to those closed by a consultant. Further work is needed to determine the impact of supervised and unsupervised trainees on IH rates, but abdominal wall closure should be regarded as a training opportunity in its own right.

Dementia Early-Stage Cognitive Aids New Trial (DESCANT) of memory aids and guidance for people with dementia: randomised controlled trial.

BACKGROUND: Common memory aids for people with dementia at home are recommended. However, rigorous evaluation is lacking, particularly what guidance or support is valued. OBJECTIVE: To investigate effects of memory aids and guidance by dementia support practitioners (DSPs) for people in early-stage dementia through a pragmatic, randomised controlled trial. METHODS: Of 469 people with mild-to-moderate dementia and their informal carers, 468 were randomised to a DSP with memory aids or to usual care plus existing dementia guide. Allocation was stratified by Trust/Health Board; time since first attendance at memory service; gender; age; and living with primary carer or not. Primary outcome was Bristol Activities of Daily Living Scale (BADLS) Score at 3 and 6 months (primary end-point). Secondary outcomes for people with dementia: quality of life (CASP-19; DEMQOL); cognition and functioning (Clinical Dementia Rating Scale; S-MMSE); capability (ICECAP-O); social networks (LSNS-R); and instrumental daily living activities (R-IDDD). Secondary outcomes for carers: psychological health (GHQ-12); sense of competence (SSCQ). RESULTS: DSPs were successfully trained, compliance was good and welcomed by participants. Mean 6 months BADLS Score increased to 14.6 (SD: 10.4) in intervention and 12.6 (SD: 8.1) in comparator, indicative of greater dependence in the activities of daily living. Adjusted between-group difference was 0.38 (95% CI: -0.89 to 1.65, p=0.56). Though this suggests greater dependency in the intervention group the difference was not significant. No differences were found in secondary outcomes. CONCLUSIONS: This intervention did not maintain independence in the activities of daily living with no improvement in other outcomes for people with dementia or carers. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN12591717.

A reduced-carbohydrate and lactose-free formulation for stabilization among hospitalized children with severe acute malnutrition: A double-blind, randomized controlled trial.

BACKGROUND: Children with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase. METHODS AND FINDINGS: In a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2-5 days), which was similar between randomized groups (0.23 [95% CI -0.13 to 0.60], P = 0.59). There was no evidence of effect modification by diarrhea at admission, age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P = 0.84). Cumulative days with diarrhea (P = 0.27), enteral (P = 0.42) or intravenous fluids (P = 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite. CONCLUSIONS: Empirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM. TRIAL REGISTRATION: ClinicalTrials.gov NCT02246296.

Use of scratchcards for allocation concealment in a prehospital randomised controlled trial.

BACKGROUND: Rapid Analgesia for Prehospital Hip Disruption was a small study designed to determine the feasibility of undertaking a randomised controlled trial (RCT) to test the clinical and cost-effectiveness of paramedics administering Fascia Iliaca Compartment Block as early prehospital pain relief to patients with a fractured hip. The objective was to devise a simple and effective method of random allocation concealment suitable for use by paramedics while in the emergency prehospital setting. METHODS: Scratchcards were produced using scratch-off silver stickers which concealed the trial arm allocation. Paramedics were each allocated a unique range of consecutive numbers, used as both the scratchcard number and the patient's study ID. The cards were designed to allow the paramedic to write on the incident number, date and signature. A small envelope holding the cards was prepared for each paramedic. The study took place between 28 June 2016 and 31 July 2017 in the Swansea area. RESULTS: Nineteen trial paramedics used 71 scratchcards throughout the study and reported no problems randomly allocating patients using the scratchcards. Five protocol deviations were reported in relation to scratchcard use. On auditing the scratchcards, all unused cards were located, and no evidence of tampering with the silver panel was found. CONCLUSION: Paramedics can use scratchcards as a method of randomly allocating patients in trials in prehospital care. In the future, a method that allows only the top card to be selected and a more protective method of storing the cards should be used. Scratchcards can be considered for wider use in RCTs in the emergency prehospital setting. TRIAL REGISTRATION NUMBER: ISRCTN60065373; Post-results.

The impact of rickets on growth and morbidity during recovery among children with complicated severe acute malnutrition in Kenya: A cohort study.

The effects of rickets on children recovery from severe acute malnutrition (SAM) are unknown. Rickets may affect both growth and susceptibility to infectious diseases. We investigated the associations of clinically diagnosed rickets with life-threatening events and anthropometric recovery during 1 year following inpatient treatment for complicated SAM. This was a secondary analysis of clinical trial data among non-human immunodeficiency virus-infected Kenyan children with complicated SAM (2-59 months) followed for 1 year posthospital discharge (ClinicalTrials.gov ID NCT00934492). The outcomes were mortality, hospital readmissions, and growth during 12 months. The main exposure was clinically diagnosed rickets at baseline. Of 1,778 children recruited, 230 (12.9%, 95% CI [11.4, 14 .6]) had clinical signs of rickets at baseline. Enrolment at an urban site, height-for-age and head circumference-for-age z scores were associated with rickets. Rickets at study enrolment was associated with increased mortality (adjusted Hazard Ratio [aHR] 1.61, 95% CI [1.14, 2.27]), any readmission (aHR 1.37, 95% CI [1.09, 1.72]), readmission for severe pneumonia (aHR 1.37, 95% CI [1.05, 1.79]), but not readmission with diarrhoea (aHR 1.05, 95% CI [0.73, 1.51]). Rickets was associated with increased height gain (centimetres), adjusted regression coefficient 0.19 (95% CI [0.10, 0.28]), but not changes in head circumference, mid-upper arm circumference, or weight. Rickets was common among children with SAM at urban sites and associated with increased risks of severe pneumonia and death. Increased height gain may have resulted from vitamin D and calcium treatment. Future work should explore possibility of other concurrent micronutrient deficiencies and optimal treatment of rickets in this high-risk population.

Mortality after Inpatient Treatment for Severe Pneumonia in Children: a Cohort Study.

BACKGROUND: Although pneumonia is a leading cause of inpatient mortality, deaths may also occur after discharge from hospital. However, prior studies have been small, in selected groups or did not fully evaluate risk factors, particularly malnutrition and HIV. We determined 1-year post-discharge mortality and risk factors among children diagnosed with severe pneumonia. METHODS: A cohort study of children aged 1-59 months admitted to Kilifi County Hospital with severe pneumonia (2007-12). The primary outcome was death <1 year after discharge, determined through Kilifi Health and Demographic Surveillance System (KHDSS) quarterly census rounds. RESULTS: Of 4184 children (median age 9 months) admitted with severe pneumonia, 1041 (25%) had severe acute malnutrition (SAM), 267 (6.4%) had a positive HIV antibody test, and 364 (8.7%) died in hospital. After discharge, 2279 KHDSS-resident children were followed up; 70 (3.1%) died during 2163 child-years: 32 (95% confidence interval (CI) 26, 41) deaths per 1000 child years. Post-discharge mortality was greater after admission for severe pneumonia than for other diagnoses, hazard ratio 2.5 (95% CI 1.2, 5.3). Malnutrition, HIV status, age and prolonged hospitalisation, but not signs of pneumonia severity, were associated with post-discharge mortality. Fifty-two per cent (95% CI 37%, 63%) of post-discharge deaths were attributable to low mid-upper arm circumference and 11% (95% CI 3.3%, 18%) to a positive HIV test. CONCLUSIONS: Admission with severe pneumonia is an important marker of vulnerability. Risk stratification and better understanding of the mechanisms underlying post-discharge mortality, especially for undernourished children, are needed to reduce mortality after treatment for pneumonia.

Control of Viremia Enables Acquisition of Resting Memory B Cells with Age and Normalization of Activated B Cell Phenotypes in HIV-Infected Children.

HIV affects the function of all lymphocyte populations, including B cells. Phenotypic and functional defects of B cells in HIV-infected adults have been well characterized, but defects in children have not been studied to the same extent. We determined the proportion of B cell subsets and frequencies of Ag-specific memory B cells in peripheral blood from HIV-infected children and healthy controls, using flow cytometry and B cell ELISPOT, respectively. In addition, we measured the quantities and avidities of plasma Abs against various Ags by ELISA. We also determined plasma levels of BAFF and expression of BAFF receptors on B cells. Children with high HIV viremia had increased proportions of activated mature B cells, tissue-like memory B cells and plasmablasts, and low proportions of naive B cells when compared with community controls and children with low HIV viremia, similar to adults infected with HIV. HIV-infected groups had lower proportions of resting memory B cells than did community controls. Notably, high HIV viremia prevented the age-dependent accumulation of class-switched resting memory B cells. HIV-infected children, regardless of the level of viremia, showed lower quantities and avidities of IgG and lower frequencies of memory B cells against Expanded Program on Immunization vaccines. The HIV-infected children had an altered BAFF profile that could have affected their B cell compartment. Therefore, B cell defects in HIV-infected children are similar to those seen in HIV-infected adults. However, control of HIV viremia is associated with normalization of activated B cell subsets and allows age-dependent accumulation of resting memory B cells.

Umbilical cord bilirubin as a predictor of neonatal jaundice: a retrospective cohort study.

BACKGROUND: Hyperbilirubinaemia is a major cause of neonatal morbidity. Early identification of those infants most at risk might allow the development of targeted primary preventative therapy and follow-up. The objective of this study was to assess whether arterial umbilical cord bilirubin (aUCB) level at delivery predicts the development of neonatal jaundice in term deliveries. METHODS: Retrospective analysis of hospital biochemistry records identified term deliveries with recorded aUCB. Infant medical records were reviewed to identify those who developed neonatal hyperbilirubinaemia (requiring treatment according to UK NICE guidelines) with/without a positive direct antiglobulin test (DAT). RESULTS: Of 1411 term deliveries with a clearly recorded aUCB, 30 infants developed clinically-significant jaundice (2.7%), of whom 8 were DAT + ve (0.6%) mostly due to ABO incompatibility. aUCB strongly predicted the development of DAT + ve jaundice (area under the ROC curve = 0.996), as well as all-cause jaundice (area under the ROC curve = 0.74). However, this effect was critically dependent on maternal blood group. Amongst infants at risk of ABO incompatibility (maternal blood groups O + ve/O-ve, 39.7%) the predictive value of aUCB for all cause jaundice was strengthened (area under the ROC curve = 0.88). Amongst those not at risk (defined maternal blood group not O + ve/O-ve, 51.0%) it disappeared completely (area under the ROC curve = 0.46). A cutoff of 35 µmol/l for mothers with blood group O + ve/O-ve increased the pre-test probability for all-cause jaundice of 4% to a post-test probability of 30%. CONCLUSIONS: For infants of mothers with blood group O, aUCB predicts development of neonatal jaundice. There was no evident utility for infants of mothers with other blood groups. Estimation of aUCB should be considered as a strategy for early identification of those at risk of neonatal haemolytic jaundice.

Pediatric blood transfusion practices at a regional referral hospital in Kenya.

BACKGROUND: Severe anemia in children is a major public health problem in sub-Saharan Africa. In this study we describe clinical and operational aspects of blood transfusion in children admitted to Coast Provincial General Hospital, Kenya. STUDY DESIGN AND METHODS: This was an observational study where over a 2-year period, demographic and laboratory data were collected on all children for whom the hospital blood bank received a transfusion request. Clinical data were obtained by retrospective review of case notes over the first year. RESULTS: There were 2789 requests for blood for children (median age, 1.8 years; interquartile range [IQR], 0.6-6.6 years); 70% (1950) of the samples were crossmatched with 85% (1663/1950) issued. Ninety percent (1505/1663) were presumed transfused. Median time from laboratory receipt of request to collection of blood was 3.6 hours (IQR, 1.4-12.8 hr). Case notes of 590 children were reviewed and median pretransfusion hemoglobin level was 6.0 g/dL (IQR, 4.2-9.1 g/dL). Ninety-four percent (186) were transfused "appropriately" while 52% (120) were transfused "inappropriately." There was significant disagreement between the clinical and laboratory diagnosis of severe anemia (exact McNemar's test; p < 0.0001). Antimalarials were prescribed for 65% (259) of children who received blood transfusions but only 41% (106) of these had a positive blood film. CONCLUSION: In this setting, clinicians often order blood based on the clinical impression of "severe anemia." This has implications for laboratory workload and the blood supply itself. However, the majority of children with severe anemia were appropriately transfused. The use of antimalarials with blood transfusions irrespective of blood film results is common practice.

Comparison of allele frequencies of Plasmodium falciparum merozoite antigens in malaria infections sampled in different years in a Kenyan population.

BACKGROUND: Plasmodium falciparum merozoite antigens elicit antibody responses in malaria-endemic populations, some of which are clinically protective, which is one of the reasons why merozoite antigens are the focus of malaria vaccine development efforts. Polymorphisms in several merozoite antigen-encoding genes are thought to arise as a result of selection by the human immune system. METHODS: The allele frequency distribution of 15 merozoite antigens over a two-year period, 2007 and 2008, was examined in parasites obtained from children with uncomplicated malaria. In the same population, allele frequency changes pre- and post-anti-malarial treatment were also examined. Any gene which showed a significant shift in allele frequencies was also assessed longitudinally in asymptomatic and complicated malaria infections. RESULTS: Fluctuating allele frequencies were identified in codons 147 and 148 of reticulocyte-binding homologue (Rh) 5, with a shift from HD to YH haplotypes over the two-year period in uncomplicated malaria infections. However, in both the asymptomatic and complicated malaria infections YH was the dominant and stable haplotype over the two-year and ten-year periods, respectively. A logistic regression analysis of all three malaria infection populations between 2007 and 2009 revealed, that the chance of being infected with the HD haplotype decreased with time from 2007 to 2009 and increased in the uncomplicated and asymptomatic infections. CONCLUSION: Rh5 codons 147 and 148 showed heterogeneity at both an individual and population level and may be under some degree of immune selection.

Ready-to-use therapeutic food with elevated n-3 polyunsaturated fatty acid content, with or without fish oil, to treat severe acute malnutrition: a randomized controlled trial.

BACKGROUND: Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children's PUFA status during treatment of severe acute malnutrition. METHODS: This randomized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were randomized to receive i) RUTF with standard composition; ii) RUTF with elevated short chain n-3 PUFA; or iii) RUTF with elevated short chain n-3 PUFA plus fish oil capsules. Participants were followed-up for 3 months. The primary outcome was erythrocyte PUFA composition. RESULTS: Erythrocyte docosahexaenoic acid (DHA) content declined from baseline in the two arms not receiving fish oil. Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or standard RUTF alone: 3 months after enrollment, DHA content was 6.3% (interquartile range 6.0-7.3), 4.5% (3.9-4.9), and 3.9% (2.4-5.7) of total erythrocyte fatty acids (P <0.001), respectively, while eicosapentaenoic acid (EPA) content was 2.0% (1.5-2.6), 0.7% (0.6-0.8), and 0.4% (0.3-0.5) (P <0.001). RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers, and there were no significant differences in safety outcomes. CONCLUSIONS: PUFA requirements of children with SAM are not met by current formulations of RUTF, or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA. Clinical and growth implications of revised formulations need to be addressed in large clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT01593969. Registered 4 May 2012.

The Africa Center for Biostatistical Excellence: a proposal for enhancing biostatistics capacity for sub-Saharan Africa.

Sub-Saharan Africa has a shortage of well-trained biomedical research methodologists, in particular, biostatisticians. In July 2014, a group of biostatisticians and researchers from the region attended a brainstorming workshop to identify ways in which to reduce the deficit in this critical skill. The workshop recognized that recommendations from previous workshops on building biostatistics capacity in sub-Saharan Africa had not been implemented. The discussions culminated with a proposal to setup an Africa Center for Biostatistical Excellence, a collaborative effort across academic and researcher institutions within the region, as a vehicle for promoting biostatistics capacity building through specialized academic masters programs as well as regular workshops targeting researchers.

Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial.

BACKGROUND: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy. METHODS: In this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention. RESULTS: Treatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone--insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth. CONCLUSIONS: Intestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust. TRIAL REGISTRATION: Registered at Clinicaltrials.gov NCT01841099.

Evaluation of Kilifi epilepsy education programme: a randomized controlled trial.

OBJECTIVES: The epilepsy treatment gap is largest in resource-poor countries. We evaluated the efficacy of a 1-day health education program in a rural area of Kenya. The primary outcome was adherence to antiepileptic drugs (AEDs) as measured by drug levels in the blood, and the secondary outcomes were seizure frequency and Kilifi Epilepsy Beliefs and Attitudes Scores (KEBAS). METHODS: Seven hundred thirty-eight people with epilepsy (PWE) and their designated supporter were randomized to either the intervention (education) or nonintervention group. Data were collected at baseline and 1 year after the education intervention was administered to the intervention group. There were 581 PWE assessed at both time points. At the end of the study, 105 PWE from the intervention group and 86 from the nonintervention group gave blood samples, which were assayed for the most commonly used AEDs (phenobarbital, phenytoin, and carbamazepine). The proportions of PWE with detectable AED levels were determined using a standard blood assay method. The laboratory technicians conducting the assays were blinded to the randomization. Secondary outcomes were evaluated using questionnaires administered by trained field staff. Modified Poisson regression was used to investigate the factors associated with improved adherence (transition from nonoptimal AED level in blood at baseline to optimal levels at follow-up), reduced seizures, and improved KEBAS, which was done as a post hoc analysis. This trial is registered in ISRCTN register under ISRCTN35680481. RESULTS: There was no significant difference in adherence to AEDs based on detectable drug levels (odds ratio [OR] 1.46, 95% confidence interval [95% CI] 0.74-2.90, p = 0.28) or by self-reports (OR 1.00, 95% CI 0.71-1.40, p = 1.00) between the intervention and nonintervention group. The intervention group had significantly fewer beliefs about traditional causes of epilepsy, cultural treatment, and negative stereotypes than the nonintervention group. There was no difference in seizure frequency. A comparison of the baseline and follow-up data showed a significant increase in adherence-intervention group (36-81% [p < 0.001]) and nonintervention group (38-74% [p < 0.001])-using detectable blood levels. The number of patients with less frequent seizures (≤3 seizures in the last 3 months) increased in the intervention group (62-80% [p = 0.002]) and in the nonintervention group (67-75% [p = 0.04]). Improved therapeutic adherence (observed in both groups combined) was positively associated with positive change in beliefs about risks of epilepsy (relative risk [RR] 2.00, 95% CI 1.03-3.95) and having nontraditional religious beliefs (RR 2.01, 95% CI 1.01-3.99). Reduced seizure frequency was associated with improved adherence (RR 1.72, 95% CI 1.19-2.47). Positive changes in KEBAS were associated with having tertiary education as compared to none (RR 1.09, 95% CI 1.05-1.14). SIGNIFICANCE: Health education improves knowledge about epilepsy, but once only contact does not improve adherence. However, sustained education may improve adherence in future studies.

Improving infant Neurocognitive Development and Growth Outcomes with micronutrients (INDiGO): A protocol for an efficacy trial in rural Gambia.

Background: Undernutrition during the early years of life has a harmful and irreversible impact on child growth and cognitive development. Many of the interventions tested to improve outcomes across infancy have had disappointing or inconsistent impact, a common feature being the absence of any attempt to provide nutritional supplements to infants during the first six months. With increasing evidence of micronutrient deficiencies in this age group, alongside strong evidence that growth and developmental deficits begin before six months, a renewed focus on the micronutrient status of infants is required. Methods: This study is a five-arm, double-blind, placebo-controlled, randomised efficacy trial of micronutrient supplementation to mothers (during pregnancy or pregnancy and lactation) and infants (Day 8 to six months of age) in rural Gambia, where rates of micronutrient deficiencies are high. 600 pregnant women (<20 weeks gestation) will be enrolled into one of five trial arms and followed to 12 months post-partum. The primary outcome will be infant brain development at six months, with micronutrient status, growth and neurocognitive development to 12 months as secondary outcomes. Discussion: This novel research will identify the most efficacious way of improving micronutrient status in infancy, and assess impact on infant developmental outcomes, providing an evidence base for future effectiveness trials and policy recommendations. Trial registration: ISRCTN registry ( ISRCTN15063705, 09/07/2021); Pan African Clinical Trials Registry ( PACTR202201552774601, 21/01/2022).

Deficiencies of micronutrients in infants and young children can have a long-lasting impact on growth and development. This is especially relevant in populations with poor diets. However, little research has focused on interventions to improve micronutrient deficiencies in the first six-months of life, during the period when exclusive breastfeeding is recommended. Here we describe the protocol for a randomised trial among women and infants living in sub-Saharan Africa, to determine whether supplementation with micronutrients to mothers (in pregnancy, or pregnancy and lactation) or supplementation to infants directly (while promoting exclusive breastfeeding) will improve infant development across the first 12 months of life. This trial will test the effect of supplementation on infant brain development, micronutrient status and growth. This novel research will determine the best way to improve infant micronutrient status and developmental outcomes, providing important data for policy considerations.

Evaluation of an electronic clinical decision support algorithm to improve primary care management of acute febrile illness in rural Cambodia: protocol for a cluster-randomised trial.

INTRODUCTION: Acute febrile illness (AFI), traditionally attributed to malaria, is a common reason for seeking primary healthcare in rural South and Southeast Asia. However, malaria transmission has declined while health workers are often poorly equipped to manage non-malarial AFIs. This results in indiscriminate antibiotic prescribing and care escalation, which promotes antibiotic resistance and may increase healthcare costs. To address this problem, an electronic clinical decision support algorithm (eCDSA) called 'Electronic clinical Decision support for Acute fever Management (EDAM)' has been developed for primary health workers which integrates clinical, epidemiological and vital sign data with simple point-of-care tests to produce a diagnosis and management plan. METHODS AND ANALYSIS: This is a pragmatic cluster-randomised trial aiming to assess the effect of EDAM and related training on antibiotic prescribing rates in rural Cambodian primary health centres (PHCs) as the primary outcome, along with a range of secondary outcomes including safety. Patients with AFI are eligible for recruitment if they are aged ≥1 year. A cluster is defined as a PHC and PHCs will be randomised to control (standard of care) and intervention (EDAM and associated training) arms, with 15 PHCs per arm. Patients will be followed up after 7 days to ascertain the safety profile of EDAM. Each PHC will recruit 152 patients (total 4560), based on a baseline antibiotic prescription rate of 25% and expected reduction to 17.5% with EDAM. ETHICS AND DISSEMINATION: Results will be published in international peer-reviewed journals to inform the design of future versions of EDAM and of future trials of similar eCDSAs and other digital health interventions targeted towards rural populations. This study was approved by the Oxford University Tropical Research Ethics Committee (550-23) and the Cambodian National Ethics Committee for Health Research (395-NECHR). TRIAL REGISTRATION NUMBER: International Standard Randomized Controlled Trial Number Registry (ISRCTN15157105).

Did the COVID-19 pandemic affect levels of burnout, anxiety and depression among doctors and nurses in Bangladesh? A cross-sectional survey study.

INTRODUCTION: COVID-19 has caused severe disruption to clinical services in Bangladesh but the extent of this, and the impact on healthcare professionals is unclear. We aimed to assess the perceived levels of anxiety, depression and burnout among doctors and nurses during COVID-19 pandemic. METHODS: We undertook an online survey using RedCap, directed at doctors and nurses across four institutions in Bangladesh (The Sheikh Russel Gastro Liver Institute & Hospital (SRNGIH), Dhaka Medical College Hospital (DMCH), Mugda Medical College Hospital (MMCH) and M Abdur Rahim Medical College (MARMC) Hospital). We collected information on demographics, awareness of well-being services, COVID-19-related workload, as well as anxiety, depression and burnout using two validated questionnaires: the Hospital Anxiety and Depression Scale (HADS) and the Maslach Burnout Inventory (MBI). RESULTS: Of the 3000 participants approached, we received responses from 2705 (90.2%). There was a statistically significant difference in anxiety, depression and burnout scores across institutions (p<0.01). Anxiety, depression and burnout scores were statistically worse in COVID-19 active staff compared with those not working on COVID-19 activities (p<0.01 for HADS anxiety and depression and MBI emotional exhaustion (EE), depersonalisation (DP) and personal accomplishment (PA)). Over half of the participants exhibited some level of anxiety (SRNGIH: 52.2%; DMCH: 53.9%; MMCH: 61.3%; MARMC: 68%) with a high proportion experiencing depression (SRNGIH: 39.5%; DMCH: 38.7%; MMCH: 53.7%; MARMC: 41.1%). Although mean burnout scores were within the normal range for each institution, a high proportion of staff (almost 20% in some instances) were shown to be classified as experiencing burnout by their EE, DP and PA scores. CONCLUSION: We identified a high prevalence of perceived anxiety, depression and burnout among doctors and nurses during the COVID-19 pandemic. This was worse in staff engaged in COVID-19-related activities. These findings could help healthcare organisations to plan for future similar events.

Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial.

Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of ß-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12-18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, ß-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte-macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in ß-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380).

The effect of an anti-malarial subsidy programme on the quality of service provision of artemisinin-based combination therapy in Kenya: a cluster-randomized, controlled trial.

BACKGROUND: Many patients with suspected malaria in sub-Saharan Africa seek treatment from private providers, but this sector suffers from sub-standard medicine dispensing practices. To improve the quality of care received for presumptive malaria from the highly accessed private retail sector in western Kenya, subsidized pre-packaged artemether-lumefantrine (AL) was provided to private retailers, together with a one day training for retail staff on malaria diagnosis and treatment, job aids and community engagement activities. METHODS: The intervention was assessed using a cluster-randomized, controlled design. Provider and mystery-shopper cross-sectional surveys were conducted at baseline and eight months post-intervention to assess provider practices. Data were analysed based on cluster-level summaries, comparing control and intervention arms. RESULTS: On average, 564 retail outlets were interviewed per year. At follow-up, 43% of respondents reported that at least one staff member had attended the training in the intervention arm. The intervention significantly increased the percentage of providers knowing the first line treatment for uncomplicated malaria by 24.2% points (confidence interval (CI): 14.8%, 33.6%; adjusted p=0.0001); the percentage of outlets stocking AL by 31.7% points (CI: 22.0%, 41.3%; adjusted p=0.0001); and the percentage of providers prescribing AL for presumptive malaria by 23.6% points (CI: 18.7%, 28.6%; adjusted p=0.0001). Generally outlets that received training and job aids performed better than those receiving one or none of these intervention components. CONCLUSION: Overall, subsidizing ACT and retailer training can significantly increase the percentage of outlets stocking and selling AL for the presumptive treatment of malaria, but further research is needed on strategies to improve the provision of counselling advice to retail customers.

Are Health Facility Management Committees in Kenya ready to implement financial management tasks: findings from a nationally representative survey.

BACKGROUND: Community participation in peripheral public health facilities has in many countries focused on including community representatives in Health Facility Management Committees (HFMCs). In Kenya, HFMC roles are being expanded with the phased implementation of the Health Sector Services Fund (HSSF). Under HSSF, HFMCs manage facility funds which are dispersed directly from central level into facility bank accounts. We assessed how prepared HFMCs were to undertake this new role in advance of HSSF roll out, and considered the implications for Kenya and other similar settings. METHODS: Data were collected through a nationally representative sample of 248 public health centres and dispensaries in 24 districts in 2010. Data collection included surveys with in-charges (n = 248), HFMC members (n = 464) and facility users (n = 698), and record reviews. These data were supplemented by semi-structured interviews with district health managers in each district. RESULTS: Some findings supported preparedness of HFMCs to take on their new roles. Most facilities had bank accounts and HFMCs which met regularly. HFMC members and in-charges generally reported positive relationships, and HFMC members expressed high levels of motivation and job satisfaction. Challenges included users' low awareness of HFMCs, lack of training and clarity in roles among HFMCs, and some indications of strained relations with in-charges. Such challenges are likely to be common to many similar settings, and are therefore important considerations for any health facility based initiatives involving HFMCs. CONCLUSION: Most HFMCs have the basic requirements to operate. However to manage their own budgets effectively and meet their allocated roles in HSSF implementation, greater emphasis is needed on financial management training, targeted supportive supervision, and greater community awareness and participation. Once new budget management roles are fully established, qualitative and quantitative research on how HFMCs are adapting to their expanded roles, especially in financial management, would be valuable in informing similar financing mechanisms in Kenya and beyond.