The Risk Factors Associated with the Prevalence of Multimorbidity of Anaemia, Malaria, and Malnutrition among Children Aged 6-59 Months in Nigeria.

In the last ten years, multimorbidity in children under the age of five years has become an emerging health issue in developing countries. The study of multimorbidity of anaemia, malaria, and malnutrition (MAMM) among children in Nigeria has not received significant attention. This study aims to investigate what risk factors are associated with the prevalence of multimorbidity among children aged 6 to 59 months in Nigeria. This study used two nationally representative cross-sectional surveys, the 2018 Nigeria Demographic and Health Survey and the 2018 National Human Development Report. A series of multilevel mixed-effect ordered logistic regression models were used to investigate the associations between child/parent/household variables (at level 1), community-related variables (at level 2) and area-related variables (at level 3), and the multimorbidity outcome (no disease, one disease only, two or more diseases). The results show that 48.3% (4917/10,184) of the sample of children aged 6-59 months display two or more of the disease outcomes. Being a female child, the maternal parent having completed higher education, the mother being anaemic, the household wealth quintile being in the richest category, the proportion of community wealth status being high, the region being in the south, and place of residence being rural were among the significant predictors of MAMM (p < 0.05). The prevalence of MAMM found in this study is unacceptably high. If suitable actions are not urgently taken, Nigeria's ability to actualise SDG-3 will be in grave danger. Therefore, suitable policies are necessary to pave the way for the creation/development of integrated care models to ameliorate this problem.

The Intersection of a Child's Demographics and Household Socioeconomic Status in the Multimorbidity of Malaria, Anaemia, and Malnutrition among Children Aged 6-59 Months in Nigeria.

Multimorbidity of malaria, anemia, and malnutrition (MAMM) is a condition in which an individual has two or more of these health conditions, and is becoming an emergent public health concern in sub-Saharan African countries. The independent associations of a child's demographic variables and household socioeconomic (HSE) disparities with a child's health outcomes have been established in the literature. However, the effects of the intersection of these factors on MAMM, while accounting for other covariates, have not been studied. Therefore, this study aimed to determine how children's sex, age, and household socioeconomic status interact to explain the variations in MAMM among children aged 6-59 months in Nigeria. Data from the 2018 Nigeria Demographic and Health Survey and the 2018 National Human Development Report (NHDR) were used. This study included weighted samples of 10,184 children aged 6-59 months in Nigeria. A three-level multilevel mixed effect ordinal logistic regression model was used, such that individual characteristics at level 1 were nested in communities at level 2 and nested in states at level 3. Subsequently, predictive probability charts and average adjusted probability tables were used to interpret the intersectional effects. Five models were created in this scenario. Model 1 is the interaction between the child's sex and household wealth status; model 2 is the interaction between the child's sex and age; model 3 is the interaction between the child's age and household wealth status; model 4 has the three two-way interactions of the child's sex, age, and household wealth status; and model 5 includes model 4 and the three-way interactions between a child's sex, age, and household wealth quintiles; while accounting for other covariates in each of the models. The prevalence of children with a 'none of the three diseases' outcome was 17.3% (1767/10,184), while 34.4% (3499/10,184) had 'only one of the diseases', and 48.3% (4918/10,184) had 'two or more' MAMMs. However, in the multivariate analyses, model 3 was the best fit compared with other models, so the two-way interaction effects of a child's age and household wealth status are significant predictors in the model. Children aged 36-47 months living in the poorest households had a probability of 0.11, 0.18, and 0.32 of existing with MAMM above the probability of children of the same age who live in the middle class, more prosperous, and richest households, respectively, while all other covariates were held constant. Thus, the variation in the prevalence of MAMM in children of different ages differs depending on the household wealth quintile. In other words, in older children, the variations in MAMM become more evident between the richer and the poorer household quintiles. Therefore, it is recommended that policies that are geared toward economic redistribution will help bridge the disparities observed in the prevalence of multiple diseases among children aged 6-59 months in Nigeria.

Analysing cluster randomised controlled trials using GLMM, GEE1, GEE2, and QIF: results from four case studies.

BACKGROUND: Using four case studies, we aim to provide practical guidance and recommendations for the analysis of cluster randomised controlled trials. METHODS: Four modelling approaches (Generalized Linear Mixed Models with parameters estimated by maximum likelihood/restricted maximum likelihood; Generalized Linear Models with parameters estimated by Generalized Estimating Equations (1st order or second order) and Quadratic Inference Function, for analysing correlated individual participant level outcomes in cluster randomised controlled trials were identified after we reviewed the literature. We systematically searched the online bibliography databases of MEDLINE, EMBASE, PsycINFO (via OVID), CINAHL (via EBSCO), and SCOPUS. We identified the above-mentioned four statistical analytical approaches and applied them to four case studies of cluster randomised controlled trials with the number of clusters ranging from 10 to 100, and individual participants ranging from 748 to 9,207. Results were obtained for both continuous and binary outcomes using R and SAS statistical packages. RESULTS: The intracluster correlation coefficient (ICC) estimates for the case studies were less than 0.05 and are consistent with the observed ICC values commonly reported in primary care and community-based cluster randomised controlled trials. In most cases, the four methods produced similar results. However, in a few analyses, quadratic inference function produced different results compared to the generalized linear mixed model, first-order generalized estimating equations, and second-order generalized estimating equations, especially in trials with small to moderate numbers of clusters. CONCLUSION: This paper demonstrates the analysis of cluster randomised controlled trials with four modelling approaches. The results obtained were similar in most cases, however, for trials with few clusters we do recommend that the quadratic inference function should be used with caution, and where possible a small sample correction should be used. The generalisability of our results is limited to studies with similar features to our case studies, for example, studies with a similar-sized ICC. It is important to conduct simulation studies to comprehensively evaluate the performance of the four modelling approaches.

Catheter insertion techniques for improving catheter function and clinical outcomes in peritoneal dialysis patients.

BACKGROUND: Peritoneal dialysis (PD) relies on the optimal functionality of the flexible plastic PD catheter present within the peritoneal cavity to enable effective treatment. As a result of limited evidence, it is uncertain if the PD catheter's insertion method influences the rate of catheter dysfunction and, thus, the quality of dialysis therapy. Numerous variations of four basic techniques have been adopted in an attempt to improve and maintain PD catheter function. This review evaluates the association between PD catheter insertion technique and associated differences in  PD catheter function and post-PD catheter insertion complications OBJECTIVES: Our aims were to 1) evaluate if a specific technique used for PD catheter insertion has lower rates of PD catheter dysfunction (early and late) and technique failure; and 2) examine if any of the available techniques results in a reduction in post-procedure complication rates including postoperative haemorrhage, exit-site infection and peritonitis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 24 November 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) examining adults and children undergoing PD catheter insertion. The studies examined any two PD catheter insertion techniques, including laparoscopic, open-surgical, percutaneous and peritoneoscopic insertion. Primary outcomes of interest were PD catheter function and technique survival.  DATA COLLECTION AND ANALYSIS: Two authors independently performed data extraction and assessed the risk of bias for all included studies. Main outcomes in the Summary of Findings tables include primary outcomes - early PD catheter function, long-term PD catheter function, technique failure and postoperative complications. A random effects model was used to perform meta-analyses; risk ratios (RRs) were calculated for dichotomous outcomes, and mean differences (MD) were calculated for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. The certainty of the evidence was evaluated using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach.  MAIN RESULTS: Seventeen studies were included in this review. Nine studies were suitable for inclusion in quantitative meta-analysis (670 randomised participants). Five studies compared laparoscopic with open PD catheter insertion, and four studies compared a 'medical' insertion technique with open surgical PD catheter insertion: percutaneous (2) and peritoneoscopic (2). Random sequence generation was judged to be at low risk of bias in eight studies. Allocation concealment was reported poorly, with only five studies judged to be at low risk of selection bias. Performance bias was judged to be high risk in 10 studies. Attrition bias and reporting bias were judged to be low in 14 and 12 studies, respectively. Six studies compared laparoscopic PD catheter insertion with open surgical insertion. Five studies could be meta-analysed (394 participants). For our primary outcomes, data were either not reported in a format that could be meta-analysed (early PD catheter function, long-term catheter function) or not reported at all (technique failure). One death was reported in the laparoscopic group and none in the open surgical group. In low certainty evidence, laparoscopic PD catheter insertion may make little or no difference to the risk of peritonitis (4 studies, 288 participants: RR 0.97, 95% CI 0.63 to 1.48; I² = 7%), PD catheter removal (4 studies, 257 participants: RR 1.15, 95% CI 0.80 to 1.64; I² = 0%), and dialysate leakage (4 studies, 330 participants: RR 1.40, 95% CI 0.49 to 4.02; I² = 0%), but may reduce the risk of haemorrhage (2 studies, 167 participants: RR 1.68, 95% CI 0.28 to 10.31; I² = 33%) and catheter tip migration (4 studies, 333 participants: RR 0.43, 95% CI 0.20 to 0.92; I² = 12%). Four studies compared a medical insertion technique with open surgical insertion (276 participants). Technique failure was not reported, and no deaths were reported (2 studies, 64 participants). In low certainty evidence, medical insertion may make little or no difference to early PD catheter function (3 studies, 212 participants: RR 0.73, 95% CI 0.29 to 1.83; I² = 0%), while one study reported long-term PD function may improve with peritoneoscopic insertion (116 participants: RR 0.59, 95% CI 0.38 to 0.92). Peritoneoscopic catheter insertion may reduce the episodes of early peritonitis (2 studies, 177 participants: RR 0.21, 95% CI 0.06 to 0.71; I² = 0%) and dialysate leakage (2 studies, 177 participants: RR 0.13, 95% CI 0.02 to 0.71; I² = 0%). Medical insertion had uncertain effects on catheter tip migration (2 studies, 90 participants: RR 0.74, 95% CI 0.15 to 3.73; I² = 0%). Most of the studies examined were small and of poor quality, increasing the risk of imprecision. There was also a significant risk of bias therefore cautious interpretation of results is advised. AUTHORS' CONCLUSIONS: The available studies show that the evidence needed to guide clinicians in developing their PD catheter insertion service is lacking. No PD catheter insertion technique had lower rates of PD catheter dysfunction. High-quality, evidence-based data are urgently required, utilising multi-centre RCTs or large cohort studies, in order to provide definitive guidance relating to PD catheter insertion modality.

Home Waking Salivary Cortisone to Screen for Adrenal Insufficiency.

BACKGROUND: Worldwide, adults and children are at risk of adrenal insufficiency as a result of adrenal suppression from use of anti-inflammatory glucocorticoids and opiates, as well as infectious diseases. The adrenocorticotropin (ACTH) stimulation test is the reference standard for diagnosis of adrenal insufficiency but requires clinic attendance and venesection. Salivary cortisone reflects free serum cortisol, and samples can be collected at home and posted to a laboratory. We tested whether home waking salivary cortisone level could be used to screen for adrenal insufficiency. METHODS: A prospective, diagnostic accuracy study was performed in patients at high risk of adrenal insufficiency. Patients collected a home salivary sample on waking and then attended the clinical facility for an ACTH stimulation test. Salivary cortisone was measured by liquid chromatography­tandem mass spectrometry. Receiver-operating characteristic curves were computed, and positive and negative predictive values were calculated. RESULTS: Two hundred twenty patients were recruited. As measured by an ACTH stimulation test, the prevalence of adrenal insufficiency was 44%. The area under the receiver-operating characteristic curve for waking salivary cortisone as a predictor of adrenal insufficiency was 0.95 (95% confidence interval [CI], 0.92 to 0.97). Cutoffs to ensure a minimum of 95% sensitivity and specificity gave a negative predictive value of 96% (95% CI, 90 to 99) and a positive predictive value of 95% (95% CI, 87 to 99) to exclude and confirm adrenal insufficiency, respectively. Waking salivary cortisone data provided information similar to that of an ACTH stimulation test in 70% of participants. Eighty-three percent of patients preferred home salivary collection to clinic attendance. CONCLUSIONS: Home waking salivary cortisone sampling has accuracy for the diagnosis of adrenal insufficiency similar to that of a standard ACTH stimulation test. Patients found the at-home test to be more convenient than the hospital-based test. (Funded by the National Institute for Health Research.)

Supporting the ambulance service to safely convey fewer patients to hospital by developing a risk prediction tool: Risk of Adverse Outcomes after a Suspected Seizure (RADOSS)-protocol for the mixed-methods observational RADOSS project.

INTRODUCTION: Ambulances services are asked to further reduce avoidable conveyances to emergency departments (EDs). Risk of Adverse Outcomes after a Suspected Seizure seeks to support this by: (1) clarifying the risks of conveyance and non-conveyance, and (2) developing a risk prediction tool for clinicians to use 'on scene' to estimate the benefits an individual would receive if conveyed to ED and risks if not. METHODS AND ANALYSIS: Mixed-methods, multi-work package (WP) project. For WP1 and WP2 we shall use an existing linked data set that tracks urgent and emergency care (UEC) use of persons served by one English regional ambulance service. Risk tools are specific to clinical scenarios. We shall use suspected seizures in adults as an exemplar.WP1: Form a cohort of patients cared for a seizure by the service during 2019/2020. It, and nested Knowledge Exchange workshops with clinicians and service users, will allow us to: determine the proportions following conveyance and non-conveyance that die and/or recontact UEC system within 3 (/30) days; quantify the proportion of conveyed incidents resulting in 'avoidable ED attendances' (AA); optimise risk tool development; and develop statistical models that, using information available 'on scene', predict the risk of death/recontact with the UEC system within 3 (/30) days and the likelihood of an attendance at ED resulting in an AA.WP2: Form a cohort of patients cared for a seizure during 2021/2022 to 'temporally' validate the WP1 predictive models.WP3: Complete the 'next steps' workshops with stakeholders. Using nominal group techniques, finalise plans to develop the risk tool for clinical use and its evaluation. ETHICS AND DISSEMINATION: WP1a and WP2 will be conducted under database ethical approval (IRAS 307353) and Confidentiality Advisory Group (22/CAG/0019) approval. WP1b and WP3 have approval from the University of Liverpool Central Research Ethics Committee (11450). We shall engage in proactive dissemination and knowledge mobilisation to share findings with stakeholders and maximise evidence usage.

Measuring the impact introducing NHS 111 online had on the NHS 111 telephone service and the wider NHS urgent care system: an observational study.

OBJECTIVES: To explore what impact introducing the National Health Service (NHS) 111 online service had on the number of phone calls to the NHS 111 telephone service and the NHS urgent care system. DESIGN: Observational study using a dose-response interrupted time series model and random-effects meta- analysis to estimate the average effect. SETTING AND PARTICIPANTS: NHS 111 telephone and online contacts for 18 NHS 111 area codes in England. NHS 111 telephone and online contacts data were collected between October 2010 to December 2019 and January 2018 to December 2019, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome: the number of triaged calls to the NHS 111 telephone service following the introduction of NHS 111 online. SECONDARY OUTCOMES: total calls to the NHS 111 telephone service, total number of emergency ambulance referrals or advice to contact 999, total number of advice to attend an emergency department or other urgent care treatment facility, and total number of advice to contact primary care. RESULTS: For triaged calls, the overall incidence rate ratio (IRR) per 1000 online contacts was 1.013 (95% CI: 0.996 to 1.029, p=0.127). For total calls, the overall IRR per 1000 online contacts was 1.008 (95% CI: 0.992 to 1.025, p=0.313). For emergency ambulance referrals or advice to contact 999, the overall IRR per 1000 online contacts was 1.067 (95% CI: 1.035 to 1.100, p<0.001). For advice to attend an emergency department or other urgent care treatment facility, the overall IRR per 1000 online contacts is 1.050 (95% CI: 1.010 to 1.092, p=0.014). And finally, for those advised to contact primary care, the overall IRR per 1000 online contacts is 1.051 (95% CI: 1.027 to 1.076, p<0.001). CONCLUSIONS: It was found that the NHS 111 online service has little impact on the number of triaged and total calls, suggesting that the workload for the NHS 111 telephone service has not increased or decreased as a result of introducing NHS 111 online. However, there was evidence to suggest an increase in the overall number of disposition recommendations (ambulance, emergency department and primary care) for NHS 111 telephone and online services combined following the introduction of the NHS 111 online service.

Recruitment, consent and retention of participants in randomised controlled trials: a review of trials published in the National Institute for Health Research (NIHR) Journals Library (1997-2020).

OBJECTIVES: To review the consent, recruitment and retention rates for randomised controlled trials (RCTs) funded by the UK's National Institute for Health Research (NIHR) and published in the online NIHR Journals Library between January 1997 and December 2020. DESIGN: Comprehensive review. SETTING: RCTs funded by the NIHR and published in the NIHR Journals Library. DATA EXTRACTION: Information relating to the trial characteristics, sample size, recruitment and retention. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the recruitment rate (number of participants recruited per centre per month). Secondary outcomes were the target sample size and whether it was achieved; consent rates (percentage of eligible participants who consented and were randomised) and retention rates (percentage of randomised participants retained and assessed with valid primary outcome data). RESULTS: This review identified 388 individual RCTs from 379 reports in the NIHR Journals Library. The final recruitment target sample size was achieved in 63% (245/388) of the RCTs. The original recruitment target was revised in 30% (118/388) of trials (downwards in 67% (79/118)). The median recruitment rate (participants per centre per month) was found to be 0.95 (IQR: 0.42-2.60); the median consent rate was 72% (IQR: 50%-88%) and the median retention rate was estimated at 88% (IQR: 80%-97%). CONCLUSIONS: There is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs. Although the majority of (6 out of 10) trials in this review achieved their final target sample; 3 out of 10 trials revised their original target sample size (downwards in 7 out of 10 trials). Investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections.

Statistical analysis of publicly funded cluster randomised controlled trials: a review of the National Institute for Health Research Journals Library.

BACKGROUND: In cluster randomised controlled trials (cRCTs), groups of individuals (rather than individuals) are randomised to minimise the risk of contamination and/or efficiently use limited resources or solve logistic and administrative problems. A major concern in the primary analysis of cRCT is the use of appropriate statistical methods to account for correlation among outcomes from a particular group/cluster. This review aimed to investigate the statistical methods used in practice for analysing the primary outcomes in publicly funded cluster randomised controlled trials, adherence to the CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines for cRCTs and the recruitment abilities of the cluster trials design. METHODS: We manually searched the United Kingdom's National Institute for Health Research (NIHR) online Journals Library, from 1 January 1997 to 15 July 2021 chronologically for reports of cRCTs. Information on the statistical methods used in the primary analyses was extracted. One reviewer conducted the search and extraction while the two other independent reviewers supervised and validated 25% of the total trials reviewed. RESULTS: A total of 1942 reports, published online in the NIHR Journals Library were screened for eligibility, 118 reports of cRCTs met the initial inclusion criteria, of these 79 reports containing the results of 86 trials with 100 primary outcomes analysed were finally included. Two primary outcomes were analysed at the cluster-level using a generalized linear model. At the individual-level, the generalized linear mixed model was the most used statistical method (80%, 80/100), followed by regression with robust standard errors (7%) then generalized estimating equations (6%). Ninety-five percent (95/100) of the primary outcomes in the trials were analysed with appropriate statistical methods that accounted for clustering while 5% were not. The mean observed intracluster correlation coefficient (ICC) was 0.06 (SD, 0.12; range, - 0.02 to 0.63), and the median value was 0.02 (IQR, 0.001-0.060), although 42% of the observed ICCs for the analysed primary outcomes were not reported. CONCLUSIONS: In practice, most of the publicly funded cluster trials adjusted for clustering using appropriate statistical method(s), with most of the primary analyses done at the individual level using generalized linear mixed models. However, the inadequate analysis and poor reporting of cluster trials published in the UK is still happening in recent times, despite the availability of the CONSORT reporting guidelines for cluster trials published over a decade ago.

Non-urgent emergency department attendances in children: a retrospective observational analysis.

INTRODUCTION: A significant proportion of ED attendances in children may be non-urgent attendances (NUAs), which could be better managed elsewhere. This study aimed to quantify NUAs and urgent attendances (UAs) in children to ED and determine which children present in this way and when. METHODS: Dataset extracted from the CUREd research database containing linked data on the provision of care in Yorkshire and Humber. Analysis focused on children's ED attendances (April 2014-March 2017). Summary statistics and odds ratios (OR) comparing NUAs and UAs were examined by: age, mode and time of arrival and deprivation alongside comparing summary statistics for waiting, treatment and total department times. RESULTS: NUAs were more likely in younger children: OR for NUA in children aged 1-4 years, 0.82 (95% CI: 0.80 to 0.83), age 15 years, 0.39 (95% CI: 0.38 to 0.40), when compared with those under 1 year. NUAs were more likely to arrive out of hours (OOHs) compared with in hours: OR 1.19 (95% CI 1.18 to 1.20), and OOHs arrivals were less common in older children compared with those under 1 year: age 1-4 years, 0.87 (95% CI: 0.84 to 0.89) age 15 years, 0.66 (95% CI: 0.63 to 0.69). NUAs also spent less total time in the ED, with a median (IQR) of 98 min (60-147) compared with 127 min (80-185) for UAs. CONCLUSION: A substantial proportion of ED attendances in children are NUAs. Our data suggest there are particular groups of children for whom targeted interventions would be most beneficial. Children under 5 years would be such a group, particularly in providing accessible, timely care outside of usual community care opening hours.

Effect of selenium supplementation on musculoskeletal health in older women: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Observational and preclinical studies show associations between selenium status, bone health, and physical function. Most adults in Europe have serum selenium below the optimum range. We hypothesised that selenium supplementation could reduce pro-resorptive actions of reactive oxygen species on osteoclasts and improve physical function. METHODS: We completed a 6-month randomised, double-blind, placebo-controlled trial. We recruited postmenopausal women older than 55 years with osteopenia or osteoporosis at the Northern General Hospital, Sheffield, UK. Participants were randomly assigned 1:1:1 to receive selenite 200 µg, 50 µg, or placebo orally once per day. Medication was supplied to the site blinded and numbered by a block randomisation sequence with a block size of 18, and participants were allocated medication in numerical order. All participants and study team were masked to treatment allocation. The primary endpoint was urine N-terminal cross-linking telopeptide of type I collagen (NTx, expressed as ratio to creatinine) at 26 weeks. Analysis included all randomly assigned participants who completed follow-up. Groups were compared with analysis of covariance with Hochberg testing. Secondary endpoints were other biochemical markers of bone turnover, bone mineral density, short physical performance battery, and grip strength. Mechanistic endpoints were glutathione peroxidase, highly sensitive C-reactive protein, and interleukin-6. This trial is registered with EU clinical trials, EudraCT 2016-002964-15, and ClinicalTrials.gov, NCT02832648, and is complete. FINDINGS: 120 participants were recruited between Jan 23, 2017, and April 11, 2018, and randomly assigned to selenite 200 µg, 50 µg, or placebo (n=40 per group). 115 (96%) of 120 participants completed follow-up and were included in the primary analysis (200 µg [n=39], 50 µg [n=39], placebo [n=37]). Median follow-up was 25·0 weeks (IQR 24·7-26·0). In the 200 µg group, mean serum selenium increased from 78·8 (95% CI 73·5-84·2) to 105·7 µg/L (99·5-111·9). Urine NTx to creatinine ratio (nmol bone collagen equivalent:mmol creatinine) did not differ significantly between treatment groups at 26 weeks: 40·5 (95% CI 34·9-47·0) for placebo, 43·4 (37·4-50·5) for 50 µg, and 42·2 (37·5-47·6) for 200 µg. None of the secondary or mechanistic endpoint measurements differed between treatment groups at 26 weeks. Seven (6%) of 120 participants were withdrawn from treatment at week 13 due to abnormal thyroid-stimulating hormone concentrations (one in the 200 µg group, three in the 50 µg group, and three in the placebo group) and abnormal blood glucose (one in the 50 µg group). There were three serious adverse events: a non-ST elevation myocardial infarction at week 18 (in the 50 µg group), a diagnosis of bowel cancer after routine population screening at week 2 (in the placebo group), and a pulmonary embolus due to metastatic bowel cancer at week 4 (in the 200 µg group). All severe adverse events were judged by the principal investigator as unrelated to trial medication. INTERPRETATION: Selenium supplementation at these doses does not affect musculoskeletal health in postmenopausal women. FUNDING: UK National Institute for Health Research Efficacy and Mechanism Evaluation programme.

The prevalence and natural history of normocalcaemic hypoparathyroidism in a United Kingdom referral population.

CONTEXT: Normocalcaemic hypoparathyroidism (NHYPO) is characterized by low levels of parathyroid hormone (PTH) with normal levels of calcium. There is little in the current literature on this disease, with only two studies published on its prevalence, while its natural history remains relatively unknown. OBJECTIVES: To identify the prevalence of NHYPO in a UK referral population and to study the natural history of the disorder. DESIGN: Retrospective study. Five-year follow-up. PATIENTS: 6280 patients referred for a BMD measurement in a Metabolic Bone referral centre. MEASUREMENTS: Prevalence of NHYPO and variability of calcium. RESULTS: Based on laboratory results on the index day, 22 patients with NHYPO were identified. Four patients were excluded due to non-PTH-induced hypocalcaemia and unconfirmed data. The final prevalence was 0.29%. Only 67% had persistent normocalcaemia, and the rest had intermittent hypocalcaemia. Two of these patients also had persistently low PTH on two occasions. Most of the patients had one PTH measurement available. No patient developed permanent hypoparathyroidism. CONCLUSIONS: The prevalence calculated from this UK referral population is lower when compared to results from previous studies. NHYPO patients often have episodes of hypocalcaemia with some cases having no apparent reason for calcium levels below the reference range.

Paediatric emergency department utilisation rates and maternal migration status in the Born in Bradford cohort: A cross-sectional study.

BACKGROUND: Globally, international migration is increasing. Population growth, along with other demographic changes, may be expected to put new pressures on healthcare systems. Some studies across Europe suggest that emergency departments (EDs) are used more, and differently, by migrants compared to non-migrant populations, which may be a result of unfamiliarity with the healthcare systems and difficulties accessing primary healthcare. However, little evidence exists to understand how migrant parents, who are typically young and of childbearing age, utilise EDs for their children. This study aimed to examine the association between paediatric ED utilisation in the first 5 years of life and maternal migration status in the Born in Bradford (BiB) cohort study. METHODS AND FINDINGS: We analysed linked data from the BiB study-an ongoing, multi-ethnic prospective birth cohort study in Bradford. Bradford is a large, ethnically diverse city in the north of England. In 2017, more than a third of births in Bradford were to mothers who were born outside the UK. Between March 2007 and December 2010, pregnant women were recruited to BiB during routine antenatal care, and the children born to these mothers have been, and continue to be, followed over time to assess how social, genetic, environmental, and behavioural factors impact on health from childhood to adulthood. Data analysed in this study included baseline questionnaire data from BiB mothers, and Bradford Royal Infirmary ED episode data for their children. Main outcomes were likelihood of paediatric ED use (no visits versus at least 1 ED visit in the first 5 years of life) and ED utilisation rates (number and frequency of ED visits) for children who have accessed the ED. The main explanatory variable was mother's migrant status (foreign-born versus UK/Irish-born). Multivariable analyses (logistic and zero-truncated negative binomial regression) were conducted adjusting for socio-demographic and socio-economic factors. The final dataset included 10,168 children born between April 2007 and June 2011, of whom 35.6% were born to migrant mothers. Foreign-born mothers originated from South Asia (28.6%), Europe/Central Asia (3.2%), Africa (2.1%), East Asia/Pacific (1.1%), and the Middle East (0.6%). At recruitment the mothers ranged in age from 15 to 49 years old. Overall, 3,104 (30.5%) children had at least 1 ED visit in the first 5 years of life, with the highest proportion of visits being in the first year of life (36.7%). The proportion of children who visited the ED at least once was lower for children of migrant mothers as compared to children of non-migrant mothers (29.4% versus 31.2%). Children of migrant mothers were found to be less likely to visit the ED (odds ratio 0.88 [95% CI 0.80 to 0.97], p = 0.012). However, among children who visited the ED, the utilisation rate was significantly higher for children of migrant mothers (incidence rate ratio [IRR] 1.19 [95% CI 1.01 to 1.40], p = 0.040). Utilisation rates were higher for children born to mothers from Europe (IRR 1.71 [95% CI 1.07 to 2.71], p = 0.024) and established migrants (≥5 years living in UK) (IRR 1.24 [95% CI 1.02 to 1.51], p = 0.032) compared to UK/Irish-born mothers. Important limitations include being unable to measure children's underlying health status and the urgency of ED attendance, as well as the analysis being limited by missing data. CONCLUSIONS: In this study we observed that there is no higher likelihood of first paediatric ED attendance in the first 5 years of life for children in the BiB cohort for migrant mothers. However, among ED users, children of migrant mothers attend the service more frequently than children of UK/Irish-born mothers. Our findings show that patterns of ED utilisation differ by mother's region of origin and time since arrival in the UK.

Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History.

CONTEXT: Normocalcemic hyperparathyroidism (NPHPT) is characterized by persistently normal calcium levels and elevated parathyroid hormone (PTH) values, after excluding other causes of secondary hyperparathyroidism. The prevalence of the disease varies greatly and the data on the natural history of this disease are sparse and inconclusive. OBJECTIVES: The objectives of this study are to describe the prevalence of NPHPT and its natural history in a referral population and to compare the variability of serum calcium with a group of patients with primary hyperparathyroidism (PHPT). DESIGN: A retrospective study was conducted over 5 years. SETTING: The setting for this study was a metabolic bone referral center. PATIENTS: A total of 6280 patients were referred for a bone mineral density measurement (BMD). MAIN OUTCOME MEASURES: The prevalence and natural history of NPHPT and variability of calcium were the main outcome measures. RESULTS: We identified NPHPT patients using data from the day of the BMD measurement. We excluded patients with low estimated glomerular filtration rate (eGFR) or vitamin D, or with no measurements available. Based on the evaluation of their medical files, we identified 11 patients with NPHPT (prevalence 0.18%). Only 4 patients had consistent normocalcemia throughout their follow-up, with only 2 also having consistently high PTH. None had consistently normal eGFR or vitamin D.Intermittent hypercalcemia was present in 7 of the 11 NPHPT patients. The mean adjusted calcium was found to be significantly lower in the NPHPT group compared with the PHPT group but higher than the control group. PTH was similar for NPHPT and PHPT. These 2 groups had similar variability in serum calcium. CONCLUSIONS: NPHPT patients often have episodes of hypercalcemia. We believe that NPHPT is a mild form of PHPT.

Correction to: Sample size estimation for randomised controlled trials with repeated assessment of patient-reported outcomes: what correlation between baseline and follow-up outcomes should we assume?

Following publication of the original article [1], we have been notified that one of an error in the Conclusions section of the Abstract.

Sample size estimation for randomised controlled trials with repeated assessment of patient-reported outcomes: what correlation between baseline and follow-up outcomes should we assume?

BACKGROUND: Patient-reported outcome measures (PROMs) are now frequently used in randomised controlled trials (RCTs) as primary endpoints. RCTs are longitudinal, and many have a baseline (PRE) assessment of the outcome and one or more post-randomisation assessments of outcome (POST). With such pre-test post-test RCT designs there are several ways of estimating the sample size and analysing the outcome data: analysis of post-randomisation treatment means (POST); analysis of mean changes from pre- to post-randomisation (CHANGE); analysis of covariance (ANCOVA). Sample size estimation using the CHANGE and ANCOVA methods requires specification of the correlation between the baseline and follow-up measurements. Other parameters in the sample size estimation method being unchanged, an assumed correlation of 0.70 (between baseline and follow-up outcomes) means that we can halve the required sample size at the study design stage if we used an ANCOVA method compared to a comparison of POST treatment means method. So what correlation (between baseline and follow-up outcomes) should be assumed and used in the sample size calculation? The aim of this paper is to estimate the correlations between baseline and follow-up PROMs in RCTs. METHODS: The Pearson correlation coefficients between the baseline and repeated PROM assessments from 20 RCTs (with 7173 participants at baseline) were calculated and summarised. RESULTS: The 20 reviewed RCTs had sample sizes, at baseline, ranging from 49 to 2659 participants. The time points for the post-randomisation follow-up assessments ranged from 7 days to 24 months; 464 correlations, between baseline and follow-up, were estimated; the mean correlation was 0.50 (median 0.51; standard deviation 0.15; range - 0.13 to 0.91). CONCLUSIONS: There is a general consistency in the correlations between the repeated PROMs, with the majority being in the range of 0.4 to -0.6. The implications are that we can reduce the sample size in an RCT by 25% if we use an ANCOVA model, with a correlation of 0.50, for the design and analysis. There is a decline in correlation amongst more distant pairs of time points.

Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans.

CONTEXT: Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. OBJECTIVE: To determine whether hypoglycemia modifies subsequent innate immune system responses. DESIGN AND SETTING: Single-blinded, prospective study of three independent parallel groups. PARTICIPANTS AND INTERVENTIONS: Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. MAIN OUTCOME MEASURES: We studied in-vivo monocyte mobilization and monocyte-platelet interactions. RESULTS: Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/µL vs euglycemia 20.66 ± 3.43/µL, P < 0.01; vs sham-saline 26.20 ± 3.86/µL, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/µL vs euglycemia 12.72 ± 2.42/µL, P < 0.001; vs sham-saline 19.05 ± 3.81/µL, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/µL vs 49.32 ± 6.41/µL, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/µL vs euglycemia 4.19 ± 1.08/µL, P < 0.05; vs sham-saline 3.81± 1.42/µL, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/µL vs euglycemia 2.86 ± 0.72/µL, P < 0.01; vs sham-saline 3.08 ± 1.01/µL, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P < 0.05). CONCLUSIONS: Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.

Urgent care axis for the older adult: where is best to target interventions?

BACKGROUND: We explored the urgent care axis across EDs in Yorkshire and Humber (Y&H) for patients aged ≥75 years to identify where interventions could be targeted to prevent ED attendances and inpatient admissions. METHODS: Hospital Episode Statistics (HES) data for attendances across 18 EDs in Y&H from April 2011 to March 2014 were retrospectively analysed. HES A&E and Admitted Patient Care patient records data were linked to describe the entire patient pathway. The population studied was adult patients attending type 1 EDs, comparing those ≥75 years with those under 75. Data analysed included arrival mode, presentation time, time in ED, outcome (admitted/discharged), admission length of stay, International Classification of Diseases 10th Revision (ICD-10) and cause codes related to admission. Short-stay admissions and admissions with potentially avoidable conditions (identified by ICD-10 codes and cause codes) were identified. Comparative analysis was undertaken between sites. RESULTS: There were 3 736 541 ED attendances, of which 625 772 (16.7%) were ≥75 years. Older patients were significantly more likely to attend via ambulance than the younger cohort (OR 7.7, 95% CI 7.6 to 7.7), and had significantly longer median stays within ED (195 vs 136 min, p<0.001) and increased likelihood of admission (OR 4.5, 95% CI 4.5 to 4.6). Short-stay admissions accounted for 28.3% of older adult admissions. 37.3% of older adult admissions were with conditions that were potentially avoidable, accounting for 42.3% of short-stay admissions. There was regional variation in the proportions of older adults admitted (between 34.3% and 40.9%). DISCUSSION: Large numbers of older adults present to EDs mainly by ambulance. Significant proportions are admitted for short periods with conditions that might potentially be managed outside of hospital. Variation across the region warrants further study.

Recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the United Kingdom Health Technology Assessment Programme.

BACKGROUND: Substantial amounts of public funds are invested in health research worldwide. Publicly funded randomised controlled trials (RCTs) often recruit participants at a slower than anticipated rate. Many trials fail to reach their planned sample size within the envisaged trial timescale and trial funding envelope. OBJECTIVES: To review the consent, recruitment and retention rates for single and multicentre randomised control trials funded and published by the UK's National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme. DATA SOURCES AND STUDY SELECTION: HTA reports of individually randomised single or multicentre RCTs published from the start of 2004 to the end of April 2016 were reviewed. DATA EXTRACTION: Information was extracted, relating to the trial characteristics, sample size, recruitment and retention by two independent reviewers. MAIN OUTCOME MEASURES: Target sample size and whether it was achieved; recruitment rates (number of participants recruited per centre per month) and retention rates (randomised participants retained and assessed with valid primary outcome data). RESULTS: This review identified 151 individually RCTs from 787 NIHR HTA reports. The final recruitment target sample size was achieved in 56% (85/151) of the RCTs and more than 80% of the final target sample size was achieved for 79% of the RCTs (119/151). The median recruitment rate (participants per centre per month) was found to be 0.92 (IQR 0.43-2.79) and the median retention rate (proportion of participants with valid primary outcome data at follow-up) was estimated at 89% (IQR 79-97%). CONCLUSIONS: There is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs. Investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections.