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Patient-reported outcomes (PROs) that aim to measure patients' subjective attitudes towards their health or health-related conditions in various fields have been increasingly used in randomised controlled trials (RCTs). PRO data is likely to be bounded, discrete, and skewed. Although various statistical methods are available for the analysis of PROs in RCT settings, there is no consensus on what statistical methods are the most appropriate for use. This study aims to use simulation methods to compare the performance (in terms of bias, empirical standard error, coverage of the confidence interval, Type I error, and power) of three different statistical methods, multiple linear regression (MLR), Tobit regression (Tobit), and median regression (Median), to estimate a range of predefined treatment effects for a PRO in a two-arm balanced RCT. We assumed there was an underlying latent continuous outcome that the PRO was measuring, but the actual scores observed were equally spaced and discrete. This study found that MLR was associated with little bias of the estimated treatment effect, small standard errors, and appropriate coverage of the confidence interval under most scenarios. Tobit performed worse than MLR for analysing PROs with a small number of levels, but it had better performance when analysing PROs with more discrete values. Median showed extremely large bias and errors, associated with low power and coverage for most scenarios especially when the number of possible discrete values was small. We recommend MLR as a simple and universal statistical method for the analysis of PROs in RCT settings., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.

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.

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., (© 2023. The Author(s).)

The genomic data generated from next-generation sequencing (NGS) provides nucleotide-level resolution of bacterial genomes which is critical for disease surveillance and the implementation of prevention strategies to interrupt the spread of antimicrobial resistance (AMR) bacteria. Infection with AMR bacteria, including Gram-negative Carbapenem-Resistant Organisms (CRO), may be acute and recurrent-once they have colonized a patient, they are notoriously difficult to eradicate. Through phylogenetic tools that assess the single nucleotide polymorphisms (SNPs) within a pathogen genome dataset, public health scientists can estimate the genetic identity between isolates. This information is used as an epidemiologic proxy of a putative outbreak. Pathogens with minimal to no differences in SNPs are likely to be the same strain attributable to a common source or transmission between cases. These genomic comparisons enhance public health response by prompting targeted intervention and infection control measures. This methodology overview demonstrates the utility of phenotypic and molecular assays, antimicrobial susceptibility testing (AST), NGS, publicly available genomics databases, and open-source bioinformatics pipelines for a tiered workflow to detect resistance genes and potential clusters of illness. These methods, when used in combination, facilitate a genomic surveillance workflow for detecting potential AMR bacterial outbreaks to inform epidemiologic investigations. Use of this workflow helps to target and focus epidemiologic resources to the cases with the highest likelihood of being related., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gali, St. Jacques, Daniels, O'Rourke and Turner.)

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., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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 chromatography–tandem 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.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: RMJ, RMS and SJW received funding across various projects from the National Institute for Health Research (NIHR)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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., (© 2022. The Author(s).)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: We examined the effect of spontaneous hyperglycaemia in adults with type 1 diabetes mellitus (T1DM) and without history of cardiovascular disease on heart rate variability (HRV), cardiac repolarisation and incidence of cardiac arrhythmias., Methods: Thirty-seven individuals with T1DM (age 17-50 years, 19 males, mean duration of diabetes 19.3 SD(9.6) years) underwent 96 h of simultaneous ambulatory 12-lead Holter ECG and blinded continuous interstitial glucose (IG) monitoring (CGM). HRV, QT interval and cardiac repolarisation were assessed during hyperglycaemia (IG ≥ 15 mmol/l) and compared with matched euglycaemia (IG 5-10 mmol/l) on a different day, separately during the day and night. Rates of arrhythmias were assessed by calculating incidence rate differences., Results: Simultaneous ECG and CGM data were recorded for 2395 hours. During daytime hyperglycaemia vs euglycaemia the mean QT c interval duration was 404 SD(21)ms vs 407 SD(20)ms, P = 0.263. T-peak to T-end interval duration corrected for heart rate (T p T end c) shortened: 74.8 SD(16.1)ms vs 79.0 SD(14.8)ms, P = 0.033 and T-wave symmetry increased: 1.62 SD(0.33) vs 1.50 SD(0.39), P = 0.02. During night-time hyperglycaemia vs euglycaemia, the mean QT c interval duration was 401 SD(26)ms vs 404 SD(27)ms, P = 0.13 and T p T end shortened: 62.4 SD(12.0)ms vs 67.1 SD(11.8)ms, P = 0.003. The number of cardiac arrhythmias was low and confined to bradycardia and isolated ectopic beats. A considerable inter-subject and diurnal variability was observed., Conclusions: Hyperglycaemia in individuals with T1DM without known cardiovascular disease was not associated with clinically important cardiac arrhythmias., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

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., Competing Interests: JSW declares grants from the NIHR during the conduct of the study; and personal fees from Mereo and Sandoz, personal fees and non-financial support from Eli Lilly, grants from Alexion, and non-financial support from Consilient, outside the submitted work. RMJ declares grants from the NIHR during the conduct of the study. LS declares shares in selenOmed, outside the submitted work. TRH declares speaker fees from DSM, outside the submitted work. JCM declares grants from the NIHR during the conduct of the study. RE declares grants from Amgen, Alexion, and Roche; grants and personal fees from IDS; personal fees from GSK Nutrition, Mereo, Sandoz, AbbiVie, Samsung, Haoma Medica, Elsevier, CL Bio, the Foundation for the National Institutes of Health, Viking, the University of California San Francisco, Biocon, and Lyramid; and grants and personal fees from Nittobo, outside the submitted work. GRW declares no competing interests., (© 2021 The Authors. Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

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., (© 2020 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

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., (© Endocrine Society 2020.)

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., Competing Interests: The authors have declared that no competing interests exist.

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.

Bone markers may be useful to monitor response to treatment withdrawal in osteoporosis. We used two criteria for investigating the change in BTMs after withdrawal of bisphosphonate treatment. A larger increase in BTMs was associated with greater bone loss. Bone markers may be useful in monitoring of patients taking a pause from treatment., Introduction: Measurement of bone turnover markers (BTMs) may be useful to monitor offset of treatment with bisphosphonates (BP) in osteoporosis. We assessed the effect of withdrawal of BP treatment by comparing the changes in BTMs and total hip (TH) bone density (BMD)., Methods: We studied postmenopausal osteoporotic women who had completed a randomised study of three oral BPs. After 2 years of treatment, participants with BMD T-score > - 2.5 and in whom it was considered clinically appropriate to discontinue treatment, were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs (CTX and PINP) with offset being defined by two criteria: (1) an increase greater than the least significant change (LSC) and (2) an increase above the reference mean value., Results: Fifty women completed the study. At 48 weeks after stopping BPs, CTX was greater than the LSC for 66% of women and PINP 72%; CTX was above the reference mean for 64% of women and PINP 42%. The decrease in THBMD was greater for women with the largest increase in BTM compared to those with continued suppression (mean difference for CTX was - 2.98%, 95%CI - 4.75 to - 1.22, P < 0.001, PINP - 2.25%, 95% CI - 4.46 to - 0.032, P = 0.046)., Conclusion: The measurement of BTM after withdrawal of BPs is potentially useful to evaluate patients that are taking a pause from treatment. An increase in BTMs more than the LSC and/or reference mean reflects loss of treatment effect and identifies patients that are likely to have a decrease in BMD. Such changes could provide an indication for reintroduction of treatment.

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.

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., Competing Interests: Competing interests: The authors report grants from NIHR, inside and outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Hypoglycaemia causes QT-interval prolongation and appears pro-arrhythmogenic. Salbutamol, a β 2 -adrenoreceptor agonist also causes QT-interval prolongation. We hypothesized that the magnitude of electrophysiological changes induced by salbutamol and hypoglycaemia might relate to each other and that salbutamol could be used as a non-invasive screening tool for predicting an individual's electrophysiological response to hypoglycaemia., Methods: Eighteen individuals with Type 1 diabetes were administered 2.5 mg of nebulized salbutamol. Participants then underwent a hyperinsulinaemic-hypoglycaemic clamp (2.5 mmol/l for 1 h). During both experiments, heart rate and serum potassium (and catecholamines during the clamp) were measured and a high-resolution electrocardiogram (ECG) was recorded at pre-set time points. Cardiac repolarization was measured by QT-interval duration adjusted for heart rate (QT c ), T-wave amplitude (T amp ), T-peak to T-end interval duration (T p T end ) and T-wave area symmetry (T sym ). The maximum changes vs. baseline in both experiments were assessed for their linear dependence., Results: Salbutamol administration caused QT c and T p T end prolongation and a decrease in T amp and T sym . Hypoglycaemia caused increased plasma catecholamines, hypokalaemia, QT c and T p T end prolongation, and a decrease in T amp and T sym . No significant correlations were found between maximum changes in QT c [r = 0.15, 95% confidence interval (95% CI) -0.341 to 0.576; P = 0.553), T p T end (r = 0.075, 95% CI -0.406 to 0.524; P = 0.767), T sym (r = 0.355, 95% CI -0.132 to 0.706; P = 0.149) or T amp (r = 0.148, 95% CI -0.347 to 0.572; P = 0.558) in either experiment., Conclusions: Both hypoglycaemia and salbutamol caused pro-arrhythmogenic electrophysiological changes in people with Type 1 diabetes but were not related in any given individual. Salbutamol does not appear useful in assessing an individual's electrophysiological response to hypoglycaemia., (© 2018 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Objective: Hypoglycemia may exert proarrhythmogenic effects on the heart via sympathoadrenal stimulation and hypokalemia. Hypoglycemia-induced cardiac dysrhythmias are linked to the "dead-in-bed syndrome," a rare but devastating condition. We examined the effect of nocturnal and daytime clinical hypoglycemia on electrocardiogram (ECG) in young people with type 1 diabetes., Research Design and Methods: Thirty-seven individuals with type 1 diabetes underwent 96 h of simultaneous ambulatory ECG and blinded continuous interstitial glucose monitoring (CGM) while symptomatic hypoglycemia was recorded. Frequency of arrhythmias, heart rate variability, and cardiac repolarization were measured during hypoglycemia and compared with time-matched euglycemia during night and day., Results: A total of 2,395 h of simultaneous ECG and CGM recordings were obtained; 159 h were designated hypoglycemia and 1,355 h euglycemia. A median duration of nocturnal hypoglycemia of 60 min (interquartile range 40-135) was longer than daytime hypoglycemia of 44 min (30-70) ( P = 0.020). Only 24.1% of nocturnal and 51.0% of daytime episodes were symptomatic. Bradycardia was more frequent during nocturnal hypoglycemia compared with matched euglycemia (incident rate ratio [IRR] 6.44 [95% CI 6.26, 6.63], P < 0.001). During daytime hypoglycemia, bradycardia was less frequent (IRR 0.023 [95% CI 0.002, 0.26], P = 0.002) and atrial ectopics more frequent (IRR 2.29 [95% CI 1.19, 4.39], P = 0.013). Prolonged QTc, T-peak to T-end interval duration, and decreased T-wave symmetry were detected during nocturnal and daytime hypoglycemia., Conclusions: Asymptomatic hypoglycemia was common. We identified differences in arrhythmic risk and cardiac repolarization during nocturnal versus daytime hypoglycemia in young adults with type 1 diabetes. Our data provide further evidence that hypoglycemia is proarrhythmogenic., (© 2017 by the American Diabetes Association.)

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Introduction: Women diagnosed with cancer and facing potentially sterilising cancer treatment have to make time-pressured decisions regarding fertility preservation with specialist fertility services while undergoing treatment of their cancer with oncology services. Oncologists identify a need for resources enabling them to support women's fertility preservation decisions more effectively; women report wanting more specialist information to make these decisions. The overall aim of the 'Cancer, Fertility and Me' study is to develop and evaluate a new evidence-based patient decision aid (PtDA) for women with any cancer considering fertility preservation to address this unmet need., Methods and Analysis: This is a prospective mixed-method observational study including women of reproductive age (16 years +) with a new diagnosis of any cancer across two regional cancer and fertility centres in Yorkshire, UK. The research involves three stages. In stage 1, the aim is to develop the PtDA using a systematic method of evidence synthesis and multidisciplinary expert review of current clinical practice and patient information. In stage 2, the aim is to assess the face validity of the PtDA. Feedback on its content and format will be ascertained using questionnaires and interviews with patients, user groups and key stakeholders. Finally, in stage 3 the acceptability of using this resource when integrated into usual cancer care pathways at the point of cancer diagnosis and treatment planning will be evaluated. This will involve a quantitative and qualitative evaluation of the PtDA in clinical practice. Measures chosen include using count data of the PtDAs administered in clinics and accessed online, decisional and patient-reported outcome measures and qualitative feedback. Quantitative data will be analysed using descriptive statistics, paired sample t-tests and CIs; interviews will be analysed using thematic analysis., Ethics and Dissemination: Research Ethics Committee approval (Ref: 16/EM/0122) and Health Research Authority approval (Ref: 194751) has been granted. Findings will be published in open access peer-reviewed journals, presented at conferences for academic and health professional audiences, with feedback to health professionals and program managers. The Cancer, Fertility and Me patient decision aid (PtDA) will be disseminated via a diverse range of open-access media, study and charity websites, professional organisations and academic sources. External endorsement will be sought from the International Patient Decision Aid Standards (IPDAS) Collaboration inventory of PtDAs and other relevant professional organisations, for example, the British Fertility Society., Trial Registration Number: NCT02753296; pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Induction of immune tolerance by an increase in regulatory T (Treg) cells after extracorporeal photopheresis (ECP) is thought to contribute to how ECP exerts its therapeutic effect in patients with chronic graft-versus-host disease (cGvHD). We investigated whether percentages and absolute counts of Treg cells changed post-ECP, and examined correlation with response., Methods: Absolute counts and % of CD4+ T cells and Treg cells (CD4 + CD25 + FOXP3 + CD127dim/-) were evaluated using flow cytometry in 32 patients with cGvHD treated by ECP for a minimum of 3 months, and up to 12 months. CD4+ or Treg cells at baseline to 12 months post-ECP were compared with changes in skin disease scores or global organ involvement, or the ability to taper steroids, at 14, 28, and 56 weeks., Results: Regulatory T cells % increased significantly above any overall changes in CD4+ % at 6, 9, and 12 months post-ECP. There was no statistically significant association between Treg cells and skin or steroid response, whereas a larger increase in CD4+ count from baseline to 1 to 3 months corresponded to increased odds of being able to reduce steroid dose by 50% or greater at 14 weeks. Skin and global organ responders at 28 weeks had higher median Treg cell counts 3 months post-ECP than nonresponders, as did steroid responders at 56 weeks who were 12 months post-ECP., Conclusions: Regulatory T cell counts and % varied greatly among cGvHD patients, and the increase post-ECP was not significant until 6 months. No clear correlation was found between Treg cells and clinical improvement, suggesting that increases in Treg cell numbers and/or proportions are not driving the mechanism leading to a response after ECP.

Unlabelled: We used two methods of identifying women who reached the target for raloxifene treatment with bone turnover markers. Both approaches identified women that responded to treatment but did not fully agree and may be complementary., Introduction: The change in bone turnover markers (BTMs) in response to osteoporosis therapy can be assessed by a decrease beyond the least significant change (LSC) or below the mean of the reference interval (RI). We compared the performance of these two approaches in women treated with raloxifene., Methods: Fifty postmenopausal osteopenic women (age 51-72 years) were randomised to raloxifene or no treatment for 2 years. Blood samples were collected for the measurement of BTM. The LSC for each marker was calculated from the untreated women and the RI obtained from healthy premenopausal women (age 35-40 years). Bone mineral density (BMD) was measured at the spine and hip., Results: There was a decrease in BTM in response to raloxifene treatment, percentage change at 12 weeks: C terminal telopeptide of type I collagen (CTX) -39 % (95 % CI -48 to -28) and N terminal propeptide of type I procollagen (PINP) -32 % (95 % CI -40 to -23) P < 0.001. The proportion of women classified as responding to treatment using LSC at 12 weeks was as follows: CTX 38 % and PINP 52 % and at 48 weeks CTX 60 % and PINP 65 %. For the RI approach, the proportion of women classified as responding to treatment at 12 weeks was CTX and PINP 38 % and at 48 weeks CTX 40 % and PINP 45 %. There was a significant difference in the change in spine BMD in the raloxifene-treated group compared to the no-treatment group at week 48: difference 0.031 g/cm(2) (95 % CI 0.016 to 0.046, P < 0.001)., Conclusions: The two approaches identified women that reached the target for treatment using BTM. Both LSC and RI criteria appear useful in identifying treatment response, but the two approaches do not fully overlap and may be complementary.

Objective: To measure the long-term impact of surgical treatment for vulval cancer upon health-related quality of life and pelvic floor outcomes during the first year of therapy., Methods: Prospective, longitudinal, mixed-methods study. Twenty-three women aged >18 years with a new diagnosis of vulval cancer were recruited. The EORTC QLQ C30, SF-36 and an electronic pelvic floor assessment questionnaire (ePAQ-PF) were administered at baseline (pre-treatment) and 3, 6, 9 and 12 months post-treatment. Mixed effects repeated measures models (all adjusted for age and BMI) were used to investigate changes over time and differences between cancer stage. Qualitative interviews were carried out with 11 of the women and analysed using a thematic approach., Results: Mean age was 59.9 years (SD = 15.3; range = 23.8-86.6 yrs). Mean BMI was 30.0 (SD = 4.5; range = 24.4-38.2). Sixteen women had early (Stage 1 to 2B), and seven women had advanced stage disease (Stage 3 to 4B). Questionnaire scores revealed that physical and social functioning, fatigue, pain and general sex life were significantly worse at 12 months than pre-treatment (p = < 0.05). Qualitative analysis revealed multiple treatment side effects which were perceived as severe and enduring. Women with advanced vulval cancer had significantly worse SF-36 mental health scores at 12 months compared to women with early stage disease (p = 0.037)., Conclusions: Surgery for vulval cancer has long-term implications which can be persistent 12 months post-treatment. High rates of morbidity relating to lymphoedema and sexual function re-enforce the need for specialist clinics to support women who suffer these complications. © 2015 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd., (© 2015 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

Background: The mechanism and clinical significance of low circulating 25-hydroxyvitamin D [25(OH)D] in obese people are unknown. Low total 25(OH)D may be due to low vitamin D-binding proteins (DBPs) or faster metabolic clearance. However, obese people have a higher bone mineral density (BMD), which suggests that low 25(OH)D may not be associated with adverse consequences for bone., Objective: We sought to determine whether 1) vitamin D metabolism and 2) its association with bone health differ by body weight., Design: We conducted a cross-sectional observational study of 223 normal-weight, overweight, and obese men and women aged 25-75 y in South Yorkshire, United Kingdom, in the fall and spring. A subgroup of 106 subjects was also assessed in the winter. We used novel techniques, including an immunoassay for free 25(OH)D, a stable isotope for the 25(OH)D3 half-life, and high-resolution quantitative tomography, to make a detailed assessment of vitamin D physiology and bone health., Results: Serum total 25(OH)D was lower in obese and overweight subjects than in normal-weight subjects in the fall and spring (geometric means: 45.0 and 40.8 compared with 58.6 nmol/L, respectively; P < 0.001) but not in the winter. Serum 25(OH)D was inversely correlated with body mass index (BMI) in the fall and spring and in the winter. Free 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] were lower in obese subjects. DBP, the DBP genotype, and the 25(OH)D3 half-life did not differ between BMI groups. Bone turnover was lower, and bone density was higher, in obese people., Conclusions: Total and free 25(OH)D and 1,25(OH)2D are lower at higher BMI, which cannot be explained by lower DBP or the shorter half-life of 25(OH)D3 We speculate that low 25(OH)D in obesity is due to a greater pool of distribution. Lower 25(OH)D may not reflect at-risk skeletal health in obese people, and BMI should be considered when interpreting serum 25(OH)D as a marker of vitamin D status., (© 2016 American Society for Nutrition.)

Unlabelled: We used bone turnover markers to identify women who responded to bisphosphonate treatment for osteoporosis. Response was more likely with alendronate and ibandronate than risedronate. There was a greater decrease in bone markers if baseline bone turnover markers were higher and if the patient took more than 80 % of her medication., Introduction: Biochemical response to bisphosphonate therapy can be assessed using either a decrease in bone turnover marker beyond the least significant change (LSC) or a reduction to within a reference interval (RI). We compared the performance of these target responses and determined whether response was related to the type of bisphosphonate, compliance and baseline bone turnover markers., Methods: Biochemical responses to three oral bisphosphonates were assessed in an open, controlled trial comprising 172 postmenopausal osteoporotic women (age 53-84 years), randomised to alendronate, ibandronate or risedronate, plus calcium and vitamin D supplementation for 2 years. The LSC for each marker was derived within the study population, whereas RIs were obtained from a control group of healthy premenopausal women (age 35-40 years)., Results: Over 70 % of women achieved a target response for serum CTX and PINP, irrespective of the approach used. The percentage decrease at 12 weeks was greater for women with baseline PINP above the RI -63 % (difference 13 %, 95 % CI 0 to 27.1, P = 0.049) and good compliance -67 % (difference 15.9 %, 95 % CI 6.3 to 25.5, P = 0.001). Responders had a greater increase in spine bone density compared to nonresponders; for example 6.2 vs. 2.3 % (difference 3.9 %, 95 % CI 1.6 to 6.3, P = 0.0011) for PINP LSC. The magnitude of change in bone markers was greater with ibandronate and alendronate than risedronate., Conclusions: Both approaches to response identified similar proportions of women as responders. Nonresponders had smaller increases in BMD, and we suggest that biochemical assessment of response is a useful tool for the management of women with postmenopausal osteoporosis.

Aim: This study investigates the relationship between basal insulin regimen and glycaemic outcomes 12 months after skills-based structured education in the UK Dose Adjustment for Normal Eating (DAFNE) programme for Type 1 diabetes mellitus., Method: Retrospective analysis of data from 892 DAFNE participants from 11 UK centres., Results: Mean HbA1c 12 months after DAFNE was lower in those using twice- rather than once-daily basal insulin after correcting for differences in baseline HbA1c , age and duration of diabetes; difference -2 (95% CI -3 to -1) mmol/mol [-0.2 (-0.3 to -0.1)%], P = 0.009. The greatest fall in HbA1c of -5 (-7 to -3) mmol/mol [-0.4 (-0.6 to -0.3)%], P < 0.001 occurred in those with less good baseline control, HbA1c  ≥ 58 mmol/mol, who switched from once- to twice-daily basal insulin. There was no difference in the 12-month HbA1c between users of glargine, detemir and NPH insulin after correcting for other variables. Relative risk of severe hypoglycaemia fell by 76% and ketoacidosis by 63% 12 months after DAFNE. The rate of severe hypoglycaemia fell from 0.82 to 0.23 events/patient year in twice-daily basal insulin users. In the group with greatest fall in HbA1c , the estimated relative risk for severe hypoglycaemia in twice-daily basal insulin users versus once daily at 12 months was 1.72 (0.88-3.36, P = 0.110)., Conclusion: After structured education in adults with Type 1 diabetes mellitus, use of basal insulin twice rather than once daily was associated with lower HbA1c , independent of insulin type, with significant reductions in severe hypoglycaemia and ketoacidosis in all groups., (© 2015 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aims: To compare, in a randomized controlled non-inferiority trial, the outcomes of the traditional format for Dose Adjustment for Normal Eating structured education courses; that is, one delivered over 5 consecutive days (1-week course) with a variant of this format delivered 1 day a week for 5 consecutive weeks (5-week course)., Methods: Adults with Type 1 diabetes, from seven UK Dose Adjustment For Normal Eating training centres, were individually randomized, stratified by centre, to receive either a 1-week or 5-week course. A qualitative study was embedded within the trial to explore patients' experiences., Results: In total, 213 patients were randomized and 160 completed the study procedures. In the per-protocol analysis, the difference in HbA1c levels (95% CI) between the arms at 6 months was 0.4 mmol/mol (-2.4, 3.1) or 0.03% (-0.22, 0.28) and -0.9 mmol/mol (-3.9, 2.2) or -0.08% (-0.36, 0.20) at 12 months. All confidence limits were within the non-inferiority margin of ± 5.5 mmol/mol (0.5%) for HbA1c %. For those patients with a baseline HbA1c of ≥ 58 mmol/mol (≥ 7.5%) the mean change (95% CI) in HbA1c was -2.2 mmol/mol (-4.0, -0.4) or -0.20% (-0.37, -0.04) at 6 months (P = 0.016), and -2.0 mmol/mol (-4.1, 0.04) or -0.18% (-0.37 to 0.004) at 12 months (P = 0.055). Episodes of severe hypoglycaemia were decreased by 82% [relative risk 0.18 (95% CI 0.03-0.936); P = 0.042], psychosocial outcomes improved significantly, and the difference between arms was not significant. Qualitative interviews showed that patients overwhelmingly favoured the format of course that they attended., Conclusions: In summary, 5-week and 1-week Dose Adjustment for Normal Eating courses are equivalent in terms of biomedical and psychosocial outcomes, and we were persuaded that both course formats should be made available in routine care., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Context: Bone mass is low and fracture risk is higher in obese children. Hormonal changes in relation to skeletal microstructure and biomechanics have not been studied in obese children., Objective: The objective of the study was to ascertain the relationships of obesity-related changes in hormones with skeletal microstructure and biomechanics., Design: High resolution peripheral quantitative computed tomography (HR-pQCT) was used to compare three-dimensional cortical and trabecular microstructure and biomechanics at load-bearing and nonload bearing sites in obese and lean children. The relationship between leptin, adiponectin, testosterone, estrogen, osteocalcin and sclerostin and skeletal microstructure was also determined., Setting: The study was conducted at a tertiary pediatric endocrine unit in the United Kingdom., Participants: Obese and lean children were matched by gender and pubertal stage., Results: Radial cortical porosity (mean difference -0.01 [95% CI: -0.02, -0.004], P = .003) and cortical pore diameter (mean difference -0.005 mm [95% CI: -0.009, -0.001], P = .011) were lower in obese children. Tibial trabecular thickness was lower (mean difference -0.009 mm [95% CI: -0.014, -0.004], P = .003), and trabecular number was higher (mean difference 0.23 mm(-1) [95% CI: 0.08, 0.38], P = .004) in obese children. At the radius, fat mass percentage negatively correlated with cortical porosity (r = -0.57, P < .001) and pore diameter (r = -0.38, P = .02) and negatively correlated with trabecular thickness (r = -0.62, P < .001) and trabecular von Mises stress (r = -0.39, P = .019) at the tibia. No difference was observed in the other biomechanical parameters of the radius and tibia. Leptin was higher in obese children (805.3 ± 440.6 pg/ml vs 98.1 ± 75.4 pg/ml, P < .001) and was inversely related to radial cortical porosity (r = 0.60, 95% CI: [-0.80, -0.30], P < .001), radial cortical pore diameter (r = 0.51, 95% CI [-0.75, -0.16], P = .002), tibial trabecular thickness (r = 0.55, 95% CI: [-0.78, -0.21], P = .001) and tibial trabecular von Mises stress (r = -0.39, 95% CI: -0.65, 0.04, P = .02)., Conclusion: Childhood obesity alters radial and tibial microstructure. Leptin may direct these changes. Despite this, the biomechanical properties of the radius and tibia do not adapt sufficiently in obese children to withstand the increased loading potential from a fall. This may explain the higher incidence of fracture in obese children.

Aims: To determine the impact of structured education promoting flexible intensive insulin therapy on rates of diabetic ketoacidosis, and the costs associated with emergency treatment for severe hypoglycaemia and ketoacidosis in adults with Type 1 diabetes., Methods: Using the Dose Adjustment For Normal Eating research database we compared the rates of ketoacidosis and severe hypoglycaemia during the 12 months preceding Dose Adjustment For Normal Eating training with the rates during the 12-month follow-up after this training. Emergency treatment costs were calculated for associated paramedic assistance, Accident and Emergency department attendance and hospital admissions., Results: Complete baseline and 1-year data were available for 939/1651 participants (57%). The risk of ketoacidosis in the 12 months after Dose Adjustment For Normal Eating training, compared with that before training, was 0.39 (95% CI: 0.23 to 0.65, P < 0.001), reduced from 0.07 to 0.03 episodes/patient/year. For every 1 mmol/mol unit increase in HbA1c concentration, the risk of a ketoacidosis episode increased by 6% (95% CI: 5 to 7%; 88% for a 1% increase), and for each 5-year increase in diabetes duration, the relative risk reduced by 20% (95% CI: 19 to 22%). The number of emergency treatments decreased for ketoacidosis (P < 0.001), and also for severe hypoglycaemia, including paramedic assistance (P < 0.001), Accident and Emergency department attendance (P = 0.029) and hospital admission (P = 0.001). In the study cohort, the combined cost of emergency treatment for ketoacidosis and severe hypoglycaemia fell by 64%, from £119,470 to £42,948., Conclusions: Structured training in flexible intensive insulin therapy is associated with a 61% reduction in the risk of ketoacidosis and with 64% lower emergency treatment costs for ketoacidosis and severe hypoglycaemia., (© 2014 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: In an evaluation of a new health technology, a pilot trial may be undertaken prior to a trial that makes a definitive assessment of benefit. The objective of pilot studies is to provide sufficient evidence that a larger definitive trial can be undertaken and, at times, to provide a preliminary assessment of benefit., Methods: We describe significance thresholds, confidence intervals and surrogate markers in the context of pilot studies and how Bayesian methods can be used in pilot trials. We use a worked example to illustrate the issues raised., Results: We show how significance levels other than the traditional 5% should be considered to provide preliminary evidence for efficacy and how estimation and confidence intervals should be the focus to provide an estimated range of possible treatment effects. We also illustrate how Bayesian methods could also assist in the early assessment of a health technology., Conclusions: We recommend that in pilot trials the focus should be on descriptive statistics and estimation, using confidence intervals, rather than formal hypothesis testing and that confidence intervals other than 95% confidence intervals, such as 85% or 75%, be used for the estimation. The confidence interval should then be interpreted with regards to the minimum clinically important difference. We also recommend that Bayesian methods be used to assist in the interpretation of pilot trials. Surrogate endpoints can also be used in pilot trials but they must reliably predict the overall effect on the clinical outcome.

Background: Unadjusted survival on renal replacement therapy (RRT) varies widely from centre to centre in England. Until now, missing data on case mix have made it impossible to determine whether this variation reflects genuine differences in the quality of care. Data linkage has the capacity to reduce missing data., Methods: Modelling of survival using Cox proportional hazards of data returned to the UK Renal Registry on patients starting RRT for established renal failure in England. Data on ethnicity, socioeconomic status and comorbidity were obtained by linkage to the Hospital Episode Statistics database, using data from hospitalizations prior to starting RRT., Results: Patients with missing data were reduced from 61 to 4%. The prevalence of comorbid conditions was remarkably similar across centres. When centre-specific survival was compared after adjustment solely for age, survival was below the 95% limit for 6 of 46 centres. The addition of variables into the multivariable model altered the number of centres that appeared to be 'outliers' with worse than expected survival as follows: ethnic origin four outliers, socioeconomic status eight outliers and year of the start of RRT four outliers. The addition of a combination of 16 comorbid conditions present at the start of RRT reduced the number of centres with worse than expected survival to one., Conclusions: Linked data between a national registry and hospital admission dramatically reduced missing data, and allowed us to show that nearly all the variation between English renal centres in 3-year survival on RRT was explained by demographic factors and by comorbidity.

Patients with monoclonal gammopathy of undetermined significance (MGUS) are at increased fracture risk, and we have previously shown that MGUS patients have altered trabecular bone microarchitecture compared with controls. However, there are no data on whether the porosity of cortical bone, which may play a greater role in bone strength and the occurrence of fractures, is increased in MGUS. Thus, we studied cortical porosity and bone strength (apparent modulus) using high-resolution peripheral quantitative computed tomography imaging of the distal radius in 50 MGUS patients and 100 age-, gender-, and body mass index-matched controls. Compared with controls, MGUS patients had both significantly higher cortical porosity (+16.8%; P < .05) and lower apparent modulus (-8.9%; P < .05). Despite their larger radial bone size, MGUS patients have significantly increased cortical bone porosity and reduced bone strength relative to controls. This increased cortical porosity may explain the increased fracture risk seen in MGUS patients.

Background: Comparison of outcomes between populations or centres may be confounded by any casemix differences and standardisation is carried out to avoid this. However, when the casemix adjustment models are large and complex, direct standardisation has been described as "practically impossible", and indirect standardisation may lead to unfair comparisons. We propose a new method of directly standardising for risk rather than standardising for casemix which overcomes these problems., Methods: Using a casemix model which is the same model as would be used in indirect standardisation, the risk in individuals is estimated. Risk categories are defined, and event rates in each category for each centre to be compared are calculated. A weighted sum of the risk category specific event rates is then calculated. We have illustrated this method using data on 6 million admissions to 146 hospitals in England in 2007/8 and an existing model with over 5000 casemix combinations, and a second dataset of 18,668 adult emergency admissions to 9 centres in the UK and overseas and a published model with over 20,000 casemix combinations and a continuous covariate., Results: Substantial differences between conventional directly casemix standardised rates and rates from direct risk standardisation (DRS) were found. Results based on DRS were very similar to Standardised Mortality Ratios (SMRs) obtained from indirect standardisation, with similar standard errors., Conclusions: Direct risk standardisation using our proposed method is as straightforward as using conventional direct or indirect standardisation, always enables fair comparisons of performance to be made, can use continuous casemix covariates, and was found in our examples to have similar standard errors to the SMR. It should be preferred when there is a risk that conventional direct or indirect standardisation will lead to unfair comparisons.

Background and Aim: On the basis of retrospective studies, hysterectomy has been considered a risk factor for functional bowel disorders. The aim of this study was to prospectively evaluate the patients' bowel function and general health-related quality of life (QoL) before and after hysterectomy. Our hypothesis was that hysterectomy in properly selected patients can impact positively on the patients' self-reporting of their general health and bowel function., Materials and Methods: A prospective longitudinal observational study was conducted in a university-based teaching hospital. Eighty-five patients who were scheduled for total abdominal hysterectomy for a nonmalignant cause completed the study. The main outcome measure was the patient's perception of her bowel function, which was assessed preoperatively and at 6, 12, 26 and 52 weeks postoperatively using the gastrointestinal quality of life questionnaire. The patient's general health was also assessed using a generic general health questionnaire (EQ5D and EQVAS). The effect of time on change in questionnaire score was assessed using mixed model repeated measures at a significance level of 0.05., Results: The scores in the three questionnaires declined significantly at 6 weeks postoperatively as compared with those obtained preoperatively. However, there was a subsequent increase in the scores up to 12 months postoperatively. Smoking and use of laxative were identified as potential confounding variables., Conclusion: Apart from a transient negative effect, total abdominal hysterectomy improves the patient's gastrointestinal-related QoL, probably as part of general improvement in their QoL.

Background: There is some evidence that hospital performance in England measured by the Dr Foster Hospital Standardised Mortality Ratio (HSMR) has improved substantially over the last 10 years. This study explores mortality in-hospital and up to 30 days post-discharge over a five year period to determine whether there have been improvements in case-mix adjusted mortality, to examine if any changes are due to changes in case-mix adjustment variables such as age, sex, method of admission and comorbidity, and to compare changes between hospital trusts., Methods: Using Hospital Episode Statistics linked to mortality data from the Office for National Statistics the Summary Hospital-Level Mortality Index (SHMI) was calculated for all patients who were discharged or died in general acute hospital trusts in England for the period 01/04/2005 to 30/09/2010., Results: During this five year period the number of admissions rose by 8% but deaths fell by 5%. The SHMI fell by 24% from 112 to 85 over the period, partly due to fewer deaths but partly due to increasing numbers predicted by the SHMI model. Excluding comorbidities from the model the SHMI fell by 18% from 108 to 89 over this period. The reduction was similar in emergency and elective admissions and in all other sub-groups examined. The average quarterly change in SHMI varied considerably between trusts (range: -4.4 to -0.2)., Conclusions: As measured by the SHMI there has been a 24% improvement in mortality in acute general trusts in England over a period of five and a half years. Part of this improvement is an artificial effect caused by changes in the depth of coding of comorbidities and other effects due to change in case-mix or non-constant risk.

Measurements of change in bone mineral density (BMD) are thought to be weak predictors of treatment effect on the reduction of fracture risk. In this study we report an alternative year-on-year approach for the estimation of treatment effect explained by BMD in which we examine the relationship between fracture risk and the most recent change in BMD. We studied 7736 postmenopausal women (ages 65 to 89 years) who were participants in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and were randomized to either intravenous administration of zoledronic acid or placebo. The percentage of treatment effect explained by change in total hip BMD was estimated using the alternative year-on-year approach and the standard approach of looking at change over 3 years. We also studied a subset of 1132 women in whom procollagen type 1 amino-terminal propeptide (PINP) was measured at baseline and 12 months, to estimate the percentage of treatment effect explained by change in PINP. Regardless of the method used, the change in total hip BMD explained a large percentage of the effect of zoledronic acid in reducing new vertebral fracture risk (40%; 95% CI, 30% to 54%; for the 3-year analysis). The treatment effects for nonvertebral fracture were not statistically significant for the year-on-year analysis but 3-year change in BMD explained 61% (95% CI, 24% to 156%) of treatment effect. Change in PINP explained 58% (95% CI, 15% to 222%) of the effect of zoledronic acid in reducing new vertebral fracture risk. We conclude that our estimates of the percentage of treatment effect explained may be higher than in previous studies because of high compliance with zoledronic acid (due to its once-yearly intravenous administration). Previous studies may have underestimated the relationship between BMD change and the effect of treatment on fracture risk., (Copyright © 2012 American Society for Bone and Mineral Research.)

Objectives: To develop a transparent and reproducible measure for hospitals that can indicate when deaths in hospital or within 30 days of discharge are high relative to other hospitals, given the characteristics of the patients in that hospital, and to investigate those factors that have the greatest effect in changing the rank of a hospital, whether interactions exist between those factors, and the stability of the measure over time., Design: Retrospective cross sectional study of admissions to English hospitals., Setting: Hospital episode statistics for England from 1 April 2005 to 30 September 2010, with linked mortality data from the Office for National Statistics., Participants: 36.5 million completed hospital admissions in 146 general and 72 specialist trusts., Main Outcome Measures: Deaths within hospital or within 30 days of discharge from hospital., Results: The predictors that were used in the final model comprised admission diagnosis, age, sex, type of admission, and comorbidity. The percentage of people admitted who died in hospital or within 30 days of discharge was 4.2% for males and 4.5% for females. Emergency admissions comprised 75% of all admissions and 5.5% died, in contrast to 0.8% who died after an elective admission. The percentage who died with a Charlson comorbidity score of 0 was 2% in contrast with 15% who died with a score greater than 5. Given these variables, the relative standardised mortality rates of the hospitals were not noticeably changed by adjusting for the area level deprivation and number of previous emergency visits to hospital. There was little evidence that including interaction terms changed the relative values by any great amount. Using these predictors the summary hospital mortality index (SHMI) was derived. For 2007/8 the model had a C statistic of 0.911 and accounted for 81% of the variability of between hospital mortality. A random effects funnel plot was used to identify outlying hospitals. The outliers from the SHMI over the period 2005-10 have previously been identified using other mortality indicators., Conclusion: The SHMI is a relatively simple tool that can be used in conjunction with other information to identify hospitals that may need further investigation.

Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary phenotype data with quantitative x-ray microradiography, micro-computed tomography, statistical approaches and biomechanical testing in 100 unselected knockout mouse strains identified nine new genetic determinants of bone mass and strength. These nine new genes include five whose deletion results in low bone mass and four whose deletion results in high bone mass. None of the nine genes have been implicated previously in skeletal disorders and detailed analysis of the biomechanical consequences of their deletion revealed a novel functional classification of bone structure and strength. The organ-specific and disease-focused strategy described in this study can be applied to any biological system or tractable polygenic disease, thus providing a general basis to define gene function in a system-specific manner. Application of the approach to diseases affecting other physiological systems will help to realize the full potential of the International Mouse Phenotyping Consortium., Competing Interests: The authors have declared that no competing interests exist.

Group B Streptococcus (GBS) is a major cause of newborn sepsis and meningitis and induces systemic release of tumor necrosis factor alpha (TNF-alpha), believed to play a role in morbidity and mortality. While previous studies have shown that GBS can induce TNF-alpha release from monocytes and macrophages, little is known about the potential modulating effect of plasma or serum on GBS-induced TNF-alpha release, and there are conflicting reports as to the host receptors involved. In a human whole-blood assay system, GBS type III COH-1 potently induced substantial monocyte TNF-alpha release in adult peripheral blood and, due to a higher concentration of monocytes, 10-fold-greater TNF-alpha release in newborn cord blood. Remarkably, GBS-induced TNF-alpha release from human monocytes was enhanced approximately 1000-fold by heat-labile serum components. Experiments employing C2-, C3-, or C7-depleted serum demonstrated that C3 activation via the alternative pathway is crucial for potent GBS-induced TNF-alpha release. Accordingly, whole blood from C3-deficient mice demonstrated significantly reduced GBS-induced TNF-alpha release. Preincubation with human serum enhanced the TNF-alpha-inducing activity of GBS in a C3- and factor B-dependent manner, implying deposition of complement components via the alternative pathway. GBS-induced TNF-alpha release was inhibited by monoclonal antibodies directed against each of the components of CR3 and CR4: the common integrin beta subunit CD18 and the alpha subunits CD11b (of CR3) and CD11c (of CR4). Blood derived from CR3 (CD11b/CD18)-deficient mice demonstrated a markedly diminished TNF-alpha response to GBS. We conclude that the ability of plasma and serum to greatly amplify GBS-induced TNF-alpha release reflects the activity of the alternative complement pathway that deposits fragments on GBS and thereby enhances CR3- and CR4-mediated monocyte activation.