The effects of spatially-constrained treatment regions upon a model of wombat mange.

The use of therapeutic agents is a critical option to manage wildlife disease, but their implementation is usually spatially constrained. We seek to expand knowledge around the effectiveness of management of environmentally-transmitted Sarcoptes scabiei on a host population, by studying the effect of a spatially constrained treatment regime on disease dynamics in the bare-nosed wombat Vombatus ursinus. A host population of wombats is modelled using a system of non-linear partial differential equations, a spatially-varying treatment regime is applied to this population and the dynamics are studied over a period of several years. Treatment could result in mite decrease within the treatment region, extending to a lesser degree outside, with significant increases in wombat population. However, the benefits of targeted treatment regions within an environment are shown to be dependent on conditions at the start (endemic vs. disease free), as well as on the locations of these special regions (centre of the wombat population or against a geographical boundary). This research demonstrates the importance of understanding the state of the environment and populations before treatment commences, the effects of re-treatment schedules within the treatment region, and the transient large-scale changes in mite numbers that can be brought about by sudden changes to the environment. It also demonstrates that, with good knowledge of the host-pathogen dynamics and the spatial terrain, it is possible to achieve substantial reduction in mite numbers within the target region, with increases in wombat numbers throughout the environment.

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898.

Socio-economic, demographic, and contextual predictors of malnutrition among children aged 6-59 months in Nigeria.

Malnutrition has remained a global public health issue, particularly in low- and middle-income countries (LMICs). Researchers have committed to studying malnutrition (especially in children under the age of five) to address the nine malnutrition targets, set by the WHO to be achieved by 2025. This study seeks to evaluate the prevalence, the individual and contextual predictors of malnutrition among children aged 6-59 months across Nigeria and its states. Two separates, independently collected, nationally representative cross-sectional surveys, the National Human Development Report (NHDR 2018) and the 2018 Nigeria Demographic and Health Survey (2018 NDHS) were linked for this study. Spatial map was used to describe the prevalence of malnutrition, a 3-level multivariate multilevel logistic regression models were fitted where children/individuals (at level 1) were nested in communities/clusters (at level 2) and nested in states (at level 3). A weighted sample of 7,770 children 6-59 months were considered in this study. The results showed that an estimated 43.6% of children aged 6-59 months are poorly nourished in Nigeria. The proportions of poorly nourished children were generally highest in the Northern Nigeria. Child's gender, age, birth size, preceding birth order, anaemia status, maternal education, work status, body weight, household wealth status, number of bedrooms were among individual/household predictors of malnutrition. On the community level, being from community with high wealth index, distance to nearest health facilities is no big problem. Regional variations and gender inequality index were the state level predictors of malnutrition among children in Nigeria. This study has shown that two-third of children aged 6-59 months in Nigeria were poorly nourished, an indication of a growing concern of double burden of malnutrition in Nigeria.

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

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

A retrospective analysis of conditional power assumptions in clinical trials with continuous or binary endpoints.

BACKGROUND: Adaptive clinical trials may use conditional power (CP) to make decisions at interim analyses, requiring assumptions about the treatment effect for remaining patients. It is critical that these assumptions are understood by those using CP in decision-making, as well as timings of these decisions. METHODS: Data for 21 outcomes from 14 published clinical trials were made available for re-analysis. CP curves for accruing outcome information were calculated using and compared with a pre-specified objective criteria for original and transformed versions of the trial data using four future treatment effect assumptions: (i) observed current trend, (ii) hypothesised effect, (iii) 80% optimistic confidence limit, (iv) 90% optimistic confidence limit. RESULTS: The hypothesised effect assumption met objective criteria when the true effect was close to that planned, but not when smaller than planned. The opposite was seen using the current trend assumption. Optimistic confidence limit assumptions appeared to offer a compromise between the two, performing well against objective criteria when the end observed effect was as planned or smaller. CONCLUSION: The current trend assumption could be the preferable assumption when there is a wish to stop early for futility. Interim analyses could be undertaken as early as 30% of patients have data available. Optimistic confidence limit assumptions should be considered when using CP to make trial decisions, although later interim timings should be considered where logistically feasible.

Risk Factors Associated with Multimorbidity among Children Aged Under-Five Years in Sub-Saharan African Countries: A Scoping Review.

BACKGROUND/PURPOSE: Globally, the prevalence of multimorbidity (defined as the cooccurrence of two or more diseases in an individual without reference to an index disease) is greater than 33%. Consequently, childhood multimorbidity, a growing public health concern in Low- and Middle-Income-Countries (LMICs), frequently has an impact on children's health. Therefore, the aim of this scoping review was to locate and describe studies that investigate the association between socioeconomic, demographic, and environmental factors and the prevalence of multimorbidity among children aged under five years in Sub-Saharan Africa (SSA). METHODS/DESIGN: We searched MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Scopus, and Web of Science for papers written in English, and published between January 1990 and March 2022. The search included papers that focused on children aged under five years with multimorbidity from Sub-Saharan Africa and used classical regression methods in their analysis. RESULTS: A total of 261 articles were identified. Out of the 66 articles selected for full-text reading, 60 were removed for various reasons. Therefore, data from a sample of six articles were finally extracted and reported in this study. The sample size for the 6 studies included ranged from 2343 to 193,065 children under five years of age. There were six distinct disease conditions (Pneumonia, diarrhoea, malaria, being overweight, stunting, and anaemia) analysed in the included studies. One of the studies had three concurrent diseases, while the other five studies had two current diseases as their multimorbidity outcome of interest. The prevalence of multimorbidity in these six studies ranged from 1.2% to 24.8%. CONCLUSIONS: The relatively few studies found in this research area is an indication of an evidence deficit/knowledge gap yearning to be filled to help policymakers in coming up with integrated multimorbidity care for children in SSA.

Individual, household and area predictors of anaemia among children aged 6-59 months in Nigeria.

Objectives: This study aims to determine the prevalence of anaemia among children aged 6-59 months in all states of Nigeria, including the Federal Capital Territory (FCT), and to quantify the predicted probabilities by individual, household and area factors. Study design: This study is a secondary analysis of data sets from two national representative cross-sectional surveys in Nigeria: the Nigeria Demographic and Health Survey (2018 NDHS) and the National Human Development Index (2018 NHDR). The state human development index (HDI) and the state multidimensional poverty index (MPI) from the 2018 NHDR were incorporated into the 2018 NDHS. Methods: The study included a weighted sample of 10,222 children aged 6-59 months. Both univariate and bivariate analyses were computed to determine the prevalence and factors associated with anaemia status, respectively. Multiple binary logistic regression analyses with adjusted predicted probabilities (APPs) were performed to quantify the predictors' probabilities. Results: The prevalence of anaemia among children aged 6-59 months in Nigeria was 68.1% (6962/10,222). Zamfara state had the highest prevalence (84.0% [266/317]), while Kaduna state recorded the lowest (50.0% [283/572]). The APPs of being anaemic decreased from 82.9% (95% confidence interval [CI]: 80.0-85.8) for children aged 6-18 months to 60.6% (95% CI: 56.8-64.4) for children aged 43-59 months, when other predictors were held constant. The APP for a child of an anaemic mother is 10.2% points higher than the APP for a child whose mother is not anaemic. In addition, the APPs for children decreased as the age group of their mothers increased. A child from a state that is mildly deprived in the MPI has a lower APP (67.2% [95% CI: 62.2-72.2]) compared with a child from highly deprived MPI state (79.0% [95% CI: 73.4-84.5]). Conclusions: Health strategies, including supplementation programmes, should be carried out at both ante-natal and post-natal clinics to reduce the prevalence of anaemia, especially in vulnerable population groups.

The Journeying through Dementia psychosocial intervention versus usual care study: a single-blind, parallel group, phase 3 trial.

BACKGROUND: There is an urgent clinical need for evidence-based psychosocial interventions for people with mild dementia. We aimed to determine the clinical benefits and cost-effectiveness of Journeying through Dementia (JtD), an intervention designed to promote wellbeing and independence in people with mild dementia. METHODS: We did a single-blind, parallel group, individually randomised, phase 3 trial at 13 National Health Service sites across England. People with mild dementia (Mini-Mental State Examination score of ≥18) who lived in the community were eligible for inclusion. Patients were centrally randomly assigned (1:1) to receive the JtD intervention plus standard care (JtD group) or standard care only (standard care group). Randomisation was stratified by study site. The JtD intervention included 12 group and four one-to-one sessions, delivered in the community at each site. The primary endpoint was Dementia Related Quality of Life (DEMQOL) 8 months after randomisation, assessed according to the intention-to-treat principle. Only outcome assessors were masked to group assignment. A cost-effectiveness analysis reported cost per quality-adjusted life-year (QALY) from a UK NHS and social care perspective. The study is registered with ISRCTN, ISRCTN17993825. FINDINGS: Between Nov 30, 2016, and Aug 31, 2018, 1183 patients were screened for inclusion, of whom 480 (41%) participants were randomly assigned: 241 (50%) to the JtD group and 239 (50%) to the standard care group. Intervention adherence was very good: 165 (68%) of 241 participants in the JtD group attended at least ten of the 16 sessions. Mean DEMQOL scores at 8 months were 93·3 (SD 13·0) for the JtD group and 91·9 (SD 14·6) for the control group. Difference in means was 0·9 (95% CI -1·2 to 3·0; p=0·38) after adjustment for covariates, lower than that identified as clinically meaningful. Incremental cost per QALY ranged from £88 000 to -£205 000, suggesting that JtD was not cost-effective. Unrelated serious adverse events were reported by 40 (17%) patients in the JtD group and 35 (15%) patients in the standard care group. INTERPRETATION: In common with other studies, the JtD intervention was not proven effective. However, this complex trial successfully recruited and retained people with dementia without necessarily involving carers. Additionally, people with dementia were actively involved as participants and study advisers throughout. More research into methods of measuring small, meaningful changes in this population is needed. Questions remain regarding how services can match the complex, diverse, and individual needs of people with mild dementia, and how interventions to meet such needs can be delivered at scale. FUNDING: UK National Institute of Health Research Health Technology Assessment Programme.

Symptom burden according to dialysis day of the week in three times a week haemodialysis patients.

BACKGROUND: Haemodialysis patients experience significant symptom burden and effects on health-related quality of life. Studies have shown increases in fluid overload, hospitalization and mortality immediately after the long interdialytic interval in thrice weekly in-centre haemodialysis patients, however the relationship between the dialytic interval and patient reported outcome measures (PROMs) has not been quantified and the extent to which dialysis day of PROM completion needs to be standardised is unknown. METHODS: Three times a week haemodialysis patients participating in a stepped wedge trial to increase patient participation in haemodialysis tasks completed PROMs (POS-S Renal symptom score and EQ-5D-5L) at recruitment, six, 12 and 18 months. Time from the long interdialytic interval, HD day of the week, and HD days vs non-HD days were included in mixed effects Linear Regression, estimating severity (none to overwhelming treated as 0 to 4) of 17 symptoms and EQ-5D-5L, adjusting for age, sex, time on HD, control versus intervention and Charlson Comorbidity Score. RESULTS: 517 patients completed 1659 YHS questionnaires that could be assigned HD day (510 on Mon/Tue/Sun, 549 on Wed/Thu/Tue, 308 on Fri/Sat/Thu and 269 on non-HD days). With the exception of restless legs and skin changes, there was no statistically significant change in symptom severity or EQ-5D-5L with increasing time from the long interdialytic interval. Patients who responded on non-HD days had higher severity of poor appetite, constipation, difficulty sleeping, poor mobility and depression (approximately 0.2 severity level), and lower EQ-5D-5L (-0.06, CI -0.09 to -0.03) compared to HD days. CONCLUSIONS: Measuring symptom severity and EQ-5D-5L in haemodialysis populations does not need to account for dialysis schedule, but completion either on HD or non-HD days could introduce bias that may impact evaluation of interventions. Researchers should ensure completion of these instruments are standardized on either dialysis or non-dialysis days.

Varicose veins treatment in England: population-based study of time trends and disparities related to demographic, ethnic, socioeconomic, and geographical factors.

BACKGROUND: Varicose vein (VV) treatments have changed significantly in recent years leading to potential disparities in service provision. The aim of this study was to examine the trends in VV treatment in England and to identify disparities in the provision of day-case and inpatient treatments related to deprivation, ethnicity, and other demographic, and geographical factors. METHOD: A population-based study using linked hospital episode statistics for England categorized VV procedures and compared population rates and procedure characteristics by ethnicity, deprivation quintile, and geographical area. RESULTS: A total of 311 936 people had 389 592 VV procedures between 2006/07 and 2017/18, with a further 63 276 procedures between 2018/19 and 2020/21. Procedure rates have reduced in all but the oldest age groups, whereas endovenous procedures have risen to more than 60 per cent of the total in recent years. In younger age groups there was a 20-30 per cent reduction in procedure rates for the least-deprived compared with the most-deprived quintiles. Non-white ethnicity was associated with lower procedure rates. Large regional and local differences were identified in standardized rates of VV procedures. In the most recent 5-year interval, the North-East region had a three-fold higher rate than the South-East region with evidence of greater variation between commissioners in overall rates, the proportion of endovenous procedures, and policies regarding bilateral treatments. CONCLUSIONS: There are substantial geographical variations in the provision of treatment for VVs, which are not explained by demographic differences. These have persisted, despite the publication of guidelines from the National Institute for Health and Care Excellence, and many commissioners, and providers would seem to implement policies that are contrary to this guidance. Lower rates of procedures in less-deprived areas may reflect treatments carried out in private practice, which are not included in these data.

NMR spectroscopy of live human asthenozoospermic and normozoospermic sperm metabolism.

Sperm motility varies between ejaculates from different men and from individual men. We studied normozoospermic and asthenozoospermic ejaculates after density-gradient centrifugation washing (DCG, 80/40%) and compared high- (80%) and low (40%)-motility sperm populations within the same sample. Our objective was to identify differences in endogenous metabolomes and energy metabolism in relation to sperm motility. 1H-Nuclear Magnetic Resonance spectroscopy (NMR) measured the endogenous metabolome of live human sperm. Incubating sperm with 13C-labelled substrates detected energy metabolism by 13C-NMR. The study examined 850 ejaculates and diagnosed asthenozoospermia in 6.1%. DGC was used to wash 160 normozoospermic (N) and 52 asthenozoospermic (A) ejaculates to recover high-motility sperm from the pellet (80N/80A) and low motility from the interface (40N/40A). 1H-NMR spectra, 45(N) and 15(A), were binned and the integrals normalised by sperm concentration. Sperm from 126(N) and 36(A) ejaculates were incubated with either 13C-glucose, 13C-fructose or 13C-pyruvate. 13C-NMR lactate and bicarbonate integrals were normalised by motile or vital sperm concentrations. 1H-NMR spectra choline integrals from the 80A population were significantly lower than the 80N, P < 0.0001. 13C-substrate conversion to lactate was significantly higher for 40A sperm than 80A sperm when normalised by motile sperm concentration. Bicarbonate integrals were sporadically observed. Sperm from asthenozoospermic ejaculates had similar glycolytic requirements to normozoospermic ones, with larger differences observed between 40 and 80% sperm populations. Higher lactate levels produced by 40% sperm may indicate that impaired sperm motility is due to dysregulated energy metabolism. The alteration in choline metabolism provides opportunities to understand the aetiology of asthenozoospermia. Lay summary: How well sperm swim (motility) varies between ejaculates from different men? Normal sperm motility is beneficial to conception and some men diagnosed with infertility have low sperm motility. Sperm metabolise molecules to produce the energy required for motility. We measured concentrations of molecules within sperm and metabolism of molecules given to sperm and related these to the proportion of motile sperm. The study examined 850 sperm samples and found low motility in 6.1%. Metabolism of molecules given to sperm was similar between low and normal motility sperm samples. However, when the most motile sperm were separated from the rest, they were more efficient in metabolising these molecules to achieve motility. Lower concentrations of a molecule called choline were found in low-motility sperm samples compared to normal samples. Choline is associated with cell membranes, energy metabolism and oxidative stress, which may give opportunities to understand the causes of low motility.

Patients' expectations and experiences of accelerated access to physiotherapy for sciatica: qualitative findings from a mixed-methods study.

OBJECTIVES: Physiotherapy is often utilised in the management of sciatica and yet little research has been undertaken to examine patient expectations and experiences of physiotherapy and its timing. This study reports patient expectations and experiences of accelerated access to physiotherapy for sciatica. SETTING & PARTICIPANTS: Participants with clinically diagnosed sciatica (n=33) were recruited for individual interviews (n=46) from 14 National Health Service (NHS) primary care general practices, and one physiotherapy service provider in the same city in England. DESIGN: This was a nested qualitative study within a pilot randomised controlled trial evaluating accelerated access to physiotherapy for sciatica. Interviews with consenting participants were undertaken with some participants prior to randomisation and again after completion of physiotherapy (n=13), some before treatment commencement (n=7) and others only after cessation of treatment (n=13). All interviews were audio recorded and thematically analysed. RESULTS: Three themes emerged from the interviews: participants' expectations of physiotherapy, with negative expectations of physiotherapy being associated with experiences of previous unhelpful physiotherapy. Secondly, the perceived therapeutic value of accelerated physiotherapy in managing sciatica and preventing physical and psychological deterioration. Finally, the value of a personalised approach, with a physiotherapist who actively listened in partnership, and who provided a bespoke multimodal regimen. CONCLUSION: Findings from this study suggest that accelerated access to physiotherapy has value in terms of aiding perceived recovery and/or halting further physical and psychological decline. An individualised patient approach alongside accelerated access to physiotherapy should be considered for patients with sciatica.

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

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

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

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

Self-management intervention to reduce pulmonary exacerbations by supporting treatment adherence in adults with cystic fibrosis: a randomised controlled trial.

INTRODUCTION: Recurrent pulmonary exacerbations lead to progressive lung damage in cystic fibrosis (CF). Inhaled medications (mucoactive agents and antibiotics) help prevent exacerbations, but objectively measured adherence is low. We investigated whether a multi-component (complex) self-management intervention to support adherence would reduce exacerbation rates over 12 months. METHODS: Between October 2017 and May 2018, adults with CF (aged ≥16 years; 19 UK centres) were randomised to the intervention (data-logging nebulisers, a digital platform and behavioural change sessions with trained clinical interventionists) or usual care (data-logging nebulisers). Outcomes included pulmonary exacerbations (primary outcome), objectively measured adherence, body mass index (BMI), lung function (FEV1) and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Analyses were by intent to treat over 12 months. RESULTS: Among intervention (n=304) and usual care (n=303) participants (51% female, median age 31 years), 88% completed 12-month follow-up. Mean exacerbation rate was 1.63/year with intervention and 1.77/year with usual care (adjusted ratio 0.96; 95% CI 0.83 to 1.12; p=0.64). Adjusted mean differences (95% CI) were in favour of the intervention versus usual care for objectively measured adherence (9.5% (8.6% to 10.4%)) and BMI (0.3 (0.1 to 0.6) kg/m2), with no difference for %FEV1 (1.4 (-0.2 to 3.0)). Seven CFQ-R subscales showed no between-group difference, but treatment burden reduced for the intervention (3.9 (1.2 to 6.7) points). No intervention-related serious adverse events occurred. CONCLUSIONS: While pulmonary exacerbations and FEV1 did not show statistically significant differences, the intervention achieved higher objectively measured adherence versus usual care. The adherence difference might be inadequate to influence exacerbations, though higher BMI and lower perceived CF treatment burden were observed.

Individual and Contextual Factors Associated with Malaria among Children 6-59 Months in Nigeria: A Multilevel Mixed Effect Logistic Model Approach.

BACKGROUND/PURPOSE: Over the last two decades, malaria has remained a major public health concern worldwide, especially in developing countries leading to high morbidity and mortality among children. Nigeria is the world most burdened malaria endemic nation, contributing more than a quarter of global malaria cases. This study determined the prevalence of malaria among children at 6-59 months in Nigeria, and the effects of individual and contextual factors. METHODS: This study utilized data from 2018 Nigeria Demographic and Health Survey (NDHS) involving a weighted sample size of 10,185 children who were tested for malaria using rapid diagnostic test (RDT). Given the hierarchical structure of the data set, such that children at Level-1 were nested in communities at Level-2, and nested in states and Federal Capital Territory (FCT) at Level-3, multilevel mixed effect logistic regression models were used for the analysis. RESULTS: The proportion of children 6-59 months of age in Nigeria that had malaria fever positive as assessed by RDTs was 35.5% (3418/10,185), (CI: 33.9-37.1). Kebbi State had 77.7%, (CI: 70.2-83.5), which was the highest proportion of 6-59 months who were malaria positive, next in line was Katsina State with 55.5%, (CI: 47.7-63.1). The Federal Capital Territory (FCT), Abuja had the proportion of 29.6%, (CI: 21.6-39.0), malaria positive children of 6-59 months of age. Children between the age of 48 and 59 months were 2.68 times more likely to have malaria fever than children of ages 6-11 months (AOR = 2.68, 95% CI: 2.03-3.54). In addition, children from the rural area (AOR = 2.12, 95% CI: 1.75-2.57), were more likely to suffer from malaria infection compared to children from urban area. CONCLUSION: The study identified some individual and contextual predictors of malaria among children in Nigeria. These factors identified in this study are potential areas that need to be considered for policy designs and implementations toward control and total elimination of malaria-related morbidity and mortality among children in Nigeria.

Comprehensive review of statistical methods for analysing patient-reported outcomes (PROs) used as primary outcomes in randomised controlled trials (RCTs) published by the UK's Health Technology Assessment (HTA) journal (1997-2020).

OBJECTIVES: To identify how frequently patient-reported outcomes (PROs) are used as primary and/or secondary outcomes in randomised controlled trials (RCTs) and to summarise what statistical methods are used for the analysis of PROs. DESIGN: Comprehensive review. SETTING: RCTs funded and published by the United Kingdom's (UK) National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme. DATA SOURCES AND ELIGIBILITY: HTA reports of RCTs published between January 1997 and December 2020 were reviewed. DATA EXTRACTION: Information relating to PRO use and analysis methods was extracted. PRIMARY AND SECONDARY OUTCOME MEASURES: The frequency of using PROs as primary and/or secondary outcomes; statistical methods that were used for the analysis of PROs as primary outcomes. RESULTS: In this review, 37.6% (114/303) of trials used PROs as primary outcomes, and 82.8% (251/303) of trials used PROs as secondary outcomes from 303 NIHR HTA reports of RCTs. In the 114 RCTs where the PRO was the primary outcome, the most used PRO was the Short-Form 36 (8/114); the most popular methods for multivariable analysis were linear mixed model (45/114), linear regression (29/114) and analysis of covariance (13/114); logistic regression was applied for binary and ordinal outcomes in 14/114 trials; and the repeated measures analysis was used in 39/114 trials. CONCLUSION: The majority of trials used PROs as primary and/or secondary outcomes. Conventional methods such as linear regression are widely used, despite the potential violation of their assumptions. In recent years, there is an increasing trend of using complex models (eg, with mixed effects). Statistical methods developed to address these violations when analysing PROs, such as beta-binomial regression, are not routinely used in practice. Future research will focus on evaluating available statistical methods for the analysis of PROs.

Feasibility and benefits of a structured prehabilitation programme prior to autologous stem cell transplantation (ASCT) in patients with myeloma; a prospective feasibility study.

Evidence supports the benefits of exercise-based rehabilitation in promoting recovery in myeloma patients following autologous stem-cell transplantation (ASCT). However, 'prehabilitation' has never been evaluated prior to ASCT, despite evidence of effectiveness in other cancers. Utilising a mixed method approach the authors investigated the feasibility of a mixed strength and cardiovascular exercise intervention pre-ASCT. Quantitative data were collected to determine feasibility targets; rates of recruitment, adherence and adverse events, including 6minute walking distance (6MWD) test and patient reported outcome measures (PROMs). Qualitative interviews were undertaken with a purposive sample of patients to capture their experiences of the study and the intervention. The authors recruited 23 patients who attended a mean percentage of 75% scheduled exercise sessions. However, retention rates were limited, with only 14/23 (62%) completing the programme. In these patients, the 6MWD increased from a mean of 346 to 451m (i.e. by 105m, 95% CI 62 to 148m) with no serious adverse events. Whist participants found the exercise programme acceptable and reported improvement in their physical fitness and overall mental health and wellbeing prior to ASCT, the study identified challenges in hospital attendance for the prehabilitation schedule whilst receiving induction or re-induction chemotherapy. Evaluation of digitally-enhanced directed but remote prehabilitation models for this patient group is warranted. Trial registration number NCT03135925.

A breakthrough series collaborative to increase patient participation with hemodialysis tasks: A stepped wedge cluster randomised controlled trial.

BACKGROUND: Compared to in-centre, home hemodialysis is associated with superior outcomes. The impact on patient experience and clinical outcomes of consistently providing the choice and training to undertake hemodialysis-related treatment tasks in the in-centre setting is unknown. METHODS: A stepped-wedge cluster randomised trial in 12 UK renal centres recruited prevalent in-centre hemodialysis patients with sites randomised into early and late participation in a 12-month breakthrough series collaborative that included data collection, learning events, Plan-Study-Do-Act cycles, and teleconferences repeated every 6 weeks, underpinned by a faculty, co-production, materials and a nursing course. The primary outcome was the proportion of patients undertaking five or more hemodialysis-related tasks or home hemodialysis. Secondary outcomes included independent hemodialysis, quality of life, symptoms, patient activation and hospitalisation. ISRCTN Registration Number 93999549. RESULTS: 586 hemodialysis patients were recruited. The proportion performing 5 or more tasks or home hemodialysis increased from 45.6% to 52.3% (205 to 244/449, difference 6.2%, 95% CI 1.4 to 11%), however after analysis by step the adjusted odds ratio for the intervention was 1.63 (95% CI 0.94 to 2.81, P = 0.08). 28.3% of patients doing less than 5 tasks at baseline performed 5 or more at the end of the study (69/244, 95% CI 22.2-34.3%, adjusted odds ratio 3.71, 95% CI 1.66-8.31). Independent or home hemodialysis increased from 7.5% to 11.6% (32 to 49/423, difference 4.0%, 95% CI 1.0-7.0), but the remaining secondary endpoints were unaffected. CONCLUSIONS: Our intervention did not increase dialysis related tasks being performed by a prevalent population of centre based patients, but there was an increase in home hemodialysis as well as an increase in tasks among patients who were doing fewer than 5 at baseline. Further studies are required that examine interventions to engage people who dialyse at centres in their own care.