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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.

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 studied 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), 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

Background\ud \ud 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.\ud \ud \ud \ud Methods\ud \ud 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.\ud \ud \ud \ud Findings\ud \ud 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.\ud \ud \ud \ud Interpretation\ud \ud 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.\ud \ud \ud \ud Funding\ud \ud UK National Institute of Health Research Health Technology Assessment Programme.

Objectives \ud \ud 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.\ud \ud \ud \ud Design \ud \ud Comprehensive review.\ud \ud \ud \ud Setting \ud \ud RCTs funded by the NIHR and published in the NIHR Journals Library.\ud \ud \ud \ud Data extraction \ud \ud Information relating to the trial characteristics, sample size, recruitment and retention.\ud \ud \ud \ud Primary and secondary outcome measures \ud \ud 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).\ud \ud \ud \ud Results \ud \ud 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%).\ud \ud \ud \ud Conclusions \ud \ud 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.

Background\ud \ud 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.\ud \ud \ud \ud Methods\ud \ud 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.\ud \ud \ud \ud Results\ud \ud 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.\ud \ud \ud \ud Conclusions\ud \ud 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.

Adherence to medication in long-term conditions is around 50%. The key components of successful interventions to improve medication adherence remain unclear, particularly when examined over prolonged follow-up periods. Behaviour change theories are increasingly interested in the utility of habit formation for the maintenance of health behaviour change, but there is no documentation on how habit has been conceptualised in the medication adherence intervention literature, or what effect the key technique identified in habit formation theory (context dependent repetition) has in these studies. . To examine this, a machine-learning assisted review was conducted. Searches of MEDLINE, EMBASE and PSYCInfo and the reference list of a comprehensive systematic review of medication adherence interventions yielded 5973 articles. Machine learning-assisted title and abstract screening identified 15 independent RCTs published between 1976 and 2021, including 18 intervention comparisons of interest. Key findings indicate that conceptualisations of habit in the medication adherence literature are varied and intervention behaviour change techniques were diverse among these studies. Behaviour change technique coding identified only six studies which explicitly described using habit formation. Conclusions indicate that despite the potential utility of habits as a technique to support maintenance in medication adherence, randomised controlled trials of habit formation interventions are few. Future work should aim to develop this evidence base, drawing on contemporary habit theory and with explicit demonstration of what techniques have been used to promote habit formation.

Purpose\ud \ud The Dementia-Related Quality of Life (DEMQOL) measure and the DEMQOL-Utility Score (DEMQOL-U) are validated tools for measuring quality of life (QOL) in people with dementia. What score changes translate to a clinically significant impact on patients’ lives was unknown. This study establishes the minimal important differences (MID) for these two instruments.\ud \ud \ud Methods\ud \ud Anchor-based and distribution-based methods were used to estimate the MID scores from patients enrolled in a randomised controlled trial. For the anchor-based method, the global QOL (Q29) item from the DEMQOL was chosen as the anchor for DEMQOL and both Q29 and EQ-5D for DEMQOL-U. A one category difference in Q29, and a 0.07 point difference in EQ-5D score, were used to classify improvement and deterioration, and the MID scores were calculated for each category. These results were compared with scores obtained by the distribution-based methods.\ud \ud \ud Results\ud \ud A total of 490 people with dementia had baseline DEMQOL data, of these 386 had 8-month data, and 344 had 12-month DEMQOL data. The absolute change in DEMQOL for a combined 1-point increase or decrease in the Q29 anchor was 5.2 at 8 months and 6.0 at 12 months. For the DEMQOL-U, the average absolute change at 8 and 12 months was 0.032 and 0.046 for the Q29 anchor and 0.020 and 0.024 for EQ-5D anchor.\ud \ud \ud Conclusion\ud \ud We present MID scores for the DEMQOL and DEMQOL-U instruments obtained from a large cohort of patients with dementia. An anchored-based estimate of the MID for the DEMQOL is around 5 to 6 points; and 0.02 to 0.05 points for the DEMQOL-U. The results of this study can guide clinicians and researchers in the interpretation of these instruments comparisons between groups or within groups of people with dementia.\ud \ud \ud Trial Registration Number and date of registration:\ud \ud ISRCTN17993825 on 11th October 2016.

Background Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. Methods A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. Results Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19–0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20–0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08–0.49];BCSS: HR 0.12 [95% CI 0.03–0.44]).Transient negative quality-of-life impacts were observed. Conclusions Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. Trial Registration ISRCTN 46099296

Background\ud \ud Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy.\ud \ud \ud Methods\ud \ud A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage.\ud \ud \ud Results\ud \ud Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19–0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20–0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08–0.49];BCSS: HR 0.12 [95% CI 0.03–0.44]).Transient negative quality-of-life impacts were observed.\ud \ud \ud Conclusions\ud \ud Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient.\ud \ud \ud Trial Registration\ud \ud ISRCTN 46099296

Background\ud \ud Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice.\ud \ud \ud Methods\ud \ud A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice.\ud \ud \ud Results\ud \ud A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference –0.20, 95 per cent confidence interval (C.I.) –2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference –4.5 (C.I. –8.0 to 0) per cent; P = 0.013). Survival was similar in both arms.\ud \ud \ud Conclusion\ud \ud The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection.\ud \ud \ud Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com).

A pilot study of cognitive analytic therapy (CAT) plus treatment as usual (TAU), versus TAU in stressed pregnant women with anxiety and depression was undertaken as an essential preliminary to any definitive, randomised controlled trial (RCT). The trial was pragmatic, multicentre, parallel, randomised, controlled, and unblinded. Participants were pregnant woman screened using the Hospital Anxiety and Depression Scale (HADS). Treatment was standard 16 session CAT. Main outcome measures: Spielberger State/Trait Anxiety Inventory (STAI) (primary outcome measure) at 24 weeks post‐randomisation, therefore one month post‐therapy for the CAT group; HADS; CORE‐OM, EPDS; SF36, and a brief ‘experience of therapy’ questionnaire, completed at baseline, and on average at 12, 24, 40 and 82 weeks post‐randomisation. 39 patients (CAT + TAU n=20: TAU =19) were randomised with mean baseline STAI‐STATE scores of 50.8 (SD 11.4) and 51.1 (13.3) respectively. 16 patients had missing primary outcome data leaving 23 (n=11, n=12) patients for analysis. The mean STAI‐STATE score was 38.5 (SD 13.8) and 45.7 (16.8) in the CAT and TAU groups respectively at 24 weeks post‐randomisation; an adjusted difference in means of 7.2 (95% CI: ‐7.9 to 20.6). No safety issues were reported. Patient retention for the CAT group was high (18/20; 90% of patients completed therapy). 10/11 (90.9%) respondents ‘agreed’ or ‘strongly agreed’ that having CAT had been ‘very helpful’. The study demonstrated the feasibility of safely undertaking CAT in this setting. Outcomes showed positive trends compatible with a clinically important effect although statistically‐definitive conclusions cannot be drawn in such a study.

Background\ud \ud frailty is a dynamic condition for which a range of interventions are available. Health state utilities are values that represent the strength of an individual’s preference for specific health states, and are used in economic evaluation. This is a topic yet to be examined in detail for frailty. Likewise, little has been reported on minimally important difference (MID), the extent of change in frailty status that individuals consider to be important.\ud \ud \ud Objectives\ud \ud to examine the relationship between frailty status, for both the frailty phenotype (FP) and frailty index (FI), and utility (preference-based health state), and to determine a MID for both frailty measures.\ud \ud \ud Design and setting\ud \ud population-based cohort of community-dwelling Australians.\ud \ud \ud Participant\ud \ud in total, 874 adults aged ≥65 years (54% female), mean age 74.4 (6.2) years.\ud \ud \ud Measurements\ud \ud frailty was measured using the FP and FI. Utilities were calculated using the short-form 6D health survey, with Australian and UK weighting applied. MID was calculated cross-sectionally.\ud \ud \ud Results\ud \ud for both the FP and FI, frailty was significantly statistically associated (P

Background\ud \ud In the UK there is variation in the treatment of older women with breast cancer, with up to 40% receiving primary endocrine therapy (PET), which is associated with inferior survival. Case mix and patient choice may explain some variation in practice but clinician preference may also be important.\ud \ud \ud \ud Methods\ud \ud A multicentre prospective cohort study of women aged >70 with operable breast cancer. Patient characteristics (health status, age, tumour characteristics, treatment allocation and decision-making preference) were analysed to identify whether treatment variation persisted following case-mix adjustment. Expected case-mix adjusted surgery rates were derived by logistic regression using the variables age, co-morbidity, tumour stage and grade. Concordance between patients’ preferred and actual decision-making style was assessed and associations between age, treatment and decision-making style calculated.\ud \ud \ud \ud Results\ud \ud Women (median age 77, range 70–102) were recruited from 56 UK breast units between 2013 and 2018. Of 2854/3369 eligible women with oestrogen receptor positive breast cancer, 2354 were treated with surgery and 500 with PET. Unadjusted surgery rates varied between hospitals, with 23/56 units falling outside the 95% confidence intervals on funnel plots. Adjusting for case mix reduced, but did not eliminate, this variation between hospitals (10/56 units had practice outside the 95% confidence intervals). Patients treated with PET had more patient-centred decisions compared to surgical patients (42.2% vs 28.4%, p

Background/Purpose: Malnutrition is a significant global public health burden with greater concern among children under five years in Sub-Saharan Africa (SSA). To effectively address the problem of malnutrition, especially in resource-scarce communities, knowing the prevalence, causes and risk factors associated with it are essential steps. This scoping review aimed to identify the existing literature that uses classical regression analysis on nationally representative health survey data sets to find the individual socioeconomic, demographic and contextual risk factors associated with malnutrition among children under five years of age in Sub-Sahara Africa (SSA). Methods: The electronic databases searched include EMBASE (OVID platform), PubMed (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science (WoS) and Cochrane Library. Only papers written in the English language, and for which the publication date was between 1 January 1990 and 31 July 2020, were included. Results: A total of 229 papers were identified, of which 26 were studies that have been included in the review. The risk factors for malnutrition identified were classified as child-related, parental/household-related and community or area-related. Conclusions: Study-interest bias toward stunting over other anthropometric indicators of malnutrition could be addressed with a holistic research approach to equally address the various dimension of the anthropometric indicators of malnutrition in a population.

Background\ud \ud Sciatica is often a painful and disabling condition, with medication routinely the first line of management. It is important to describe patients experiences of taking medication for sciatica, the reasons for commencing and reasons for cessation, the effects of the medication in symptom management and any other potential positive or deleterious effects.\ud \ud \ud \ud Objectives\ud \ud To describe patient experiences of medication for the relief of symptoms of sciatica.\ud \ud \ud \ud Study design\ud \ud Qualitative analysis of data from a mixed-methods randomised controlled pilot study.\ud \ud \ud \ud Methods\ud \ud A total of 46 semi-structured interviews were conducted with 33 consenting participants (19 female) recruited from 14 GP practices. A purposive sampling strategy ensured a range of age, severity of pain and disability. Interviews were recorded and transcribed verbatim prior to thematic analysis, which aimed to identify the important, interesting or divergent views within the data.\ud \ud \ud \ud Findings\ud \ud Participant experiences of pain were often severe with significant disability and fear. The use of a combination of medications was common, including the use of opioids and other medication inconsistent with national (NICE) guidance. Most participants found medication ineffective and reported significant side-effects, often necessitating cessation of the drugs or the use of alternatives. Despite the regularity of participants stopping all medication for sciatica, their pain levels still significantly eased over the 6-month period of the study.\ud \ud \ud \ud Conclusions\ud \ud The study highlighted a lack of perceived effectiveness for prescribed medication, often with concomitant side-effects. Clinicians should be cognisant of the fears that patients hold in terms of the cause and severity of sciatica, as well as fears of prescribed medication.

Background: The National Institute for Health and Care Excellence (NICE) use economic modelling to inform judgements whenever further insight is required for decision-making. Doing so for public health guidance poses several challenges. The study’s objective was to investigate the level of heterogeneity in NICE’s public health economic models with regards to economic evaluation techniques, perspectives on outcomes and the measurement of non-health benefits.\ud \ud Methods: A review of all economic modelling reports published by NICE’s Centre for Public Health (CPH) as part of their guidance.\ud \ud Results: The review identified 56 eligible pieces of public health over the relevant period. Of these, 43 used economic modelling and 13 used no formal economic model. In total 61 economic models were used. Though the CPH specifies a reference case, in practice there is a large amount of variability from one model to the next. The most common perspective used for evaluations was that of the National Health Service (NHS); the most common economic evaluation approach was cost-utility analysis (CUA). 23 of the 56 topics used other combinations of perspective and technique, which allowed them to incorporate non-health effects, such as productivity, the effect on taxes raised and benefits spending, costs to the criminal justice sector, the effect on educational attainment and general wellbeing.\ud \ud Conclusions: NICE regularly updates its reference case, and non-CUA evaluation techniques have become more prominent in recent years. The results highlight the genuine advantages of having a variety of economic evaluation techniques available, which can be matched with the given topic. While it is always necessary to be wary of the possibility of gamesmanship and cherry picking, there is a surprising alignment between many approaches in certain circumstances.

Rationale, aims and objective:\ud \ud We previously demonstrated that annual review %FEV1 under-estimates lung health of adults with CF compared to %FEV1 captured during periods of clinical stability. This has implications in the comparisons against registries with encounter-based FEV1, such as the US. It is uncertain whether this bias affects between-centre comparison within the UK. Previous funnel plot analyses have identified variation in annual review %FEV1 according to centre size, hence we investigated whether paired differences between annual review and best %FEV1 also vary according to centre size.\ud \ud \ud \ud Methods:\ud \ud This registry analysis included 18 adult CF centres in the UK with ≥80% completeness for best FEV1 data in 2014. Mean discrepancy between annual review and best %FEV1 is a surrogate for the extent by which annual review %FEV1 underestimates lung health; and was plotted against centre size. A Local Polynomial Regression (LOESS) curve was used to explore the relationship between the two variables. An appropriate model is fitted based on the LOESS curve to determine the strength of relationship between discrepancies in %FEV1 and centre size.\ud \ud \ud \ud Results:\ud \ud There is an inverted U-shaped relationship between mean discrepancies in %FEV1 and centre size. A regression of the paired mean difference in %FEV1 against centre size showed a significant improvement in the goodness of fit for a quadratic model (R2 = 23.8% for a quadratic model compared with 0.4% for a linear one; p = 0.048 for the quadratic term). \ud \ud \ud \ud Conclusions:\ud \ud Annual review %FEV1 under-estimated lung health of adults from small and large centres in the UK to a greater extent compared to medium-sized centres. A plot of %FEV1 against centre size (e.g. funnel plot comparison) would be affected by systematic bias in annual review %FEV1. Therefore, annual review %FEV1 is an unreliable metric to compare health outcomes of adult CF centres within the UK.

Background\ud \ud Accurate centre-level medication adherence measurement allows identification of highly performing CF centres, drives shared learning and informs quality improvement. Self-reported adherence is unreliable but data-logging nebulisers can capture objective data. However, adherence levels in current literature are limited by the use of agreed prescriptions and convenience sampling. In this single-centre retrospective study, we quantified the differences in centre-level adherence with different methods of calculating adherence (unadjusted vs normative adherence) and different data sampling frames (convenience sampling vs including difficult to obtain data).\ud \ud \ud \ud Methods\ud \ud Adherence data were objectively captured using I-neb® from 2013-2016 in Sheffield Adult CF Centre. Adults on non data-logging devices, on ivacaftor or with previous lung transplantation were excluded. Adherence was calculated based on agreed regimen (‘unadjusted adherence’) or minimum required regimen (‘normative adherence’). I-nebs® not brought to clinic were downloaded during home visits. Adults not on any inhaled therapy but with chronic Pseudomonas aeruginosa infection were included by counting their adherence as “0”.\ud \ud \ud \ud Results\ud \ud Of the 131 included adults, 126 provided I-neb® data. Calculating unadjusted adherence from I-nebs® brought to clinics resulted in the highest centre-level adherence (median 41.8% in 2013). Median adherence reduced after sequentially accounting for minimum required regimen (40.0% in 2013), I-nebs® not brought to clinics (32.9% in 2013) and adults not on any inhaled therapy (31.0% in 2013).\ud \ud \ud \ud Conclusions\ud \ud Different approaches of calculating adherence produced different adherence levels. Adherence levels based only on agreed regimen among adults who readily brought their nebulisers to clinics can over-estimate the effective adherence of CF centres.

Background\ud \ud 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).\ud \ud \ud \ud 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.\ud \ud \ud \ud Methods\ud \ud The Pearson correlation coefficients between the baseline and repeated PROM assessments from 20 RCTs (with 7173 participants at baseline) were calculated and summarised.\ud \ud \ud \ud Results\ud \ud 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).\ud \ud \ud \ud Conclusions\ud \ud 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.

Background: There is currently insufficient evidence for the clinical effectiveness and cost-effectiveness of psychological therapies for post-stroke depression.\ud \ud Objective: To evaluate the feasibility of undertaking a definitive trial to evaluate the clinical effectiveness and cost-effectiveness of behavioural activation (BA) compared with usual stroke care for treating post-stroke depression.\ud \ud Design: Parallel-group, feasibility, multicentre, randomised controlled trial with nested qualitative research and a health economic evaluation.\ud \ud Setting: Acute and community stroke services in three sites in England.\ud \ud Participants: Community-dwelling adults 3 months to 5 years post stroke who are depressed, as determined by the Patient Health Questionnaire-9 (PHQ-9) or the Visual Analogue Mood Scales ‘Sad’ item.\ud \ud Exclusions: patients who are blind and/or deaf, have dementia, are unable to communicate in English, do not have mental capacity to consent, are receiving treatment for depression at the time of stroke onset or are currently receiving psychological intervention.\ud \ud Randomisation and blinding: Participants were randomised (1 : 1 ratio) to BA or usual stroke care. Randomisation was conducted using a computer-generated list with random permuted blocks of varying sizes, stratified by site. Participants and therapists were aware of the allocation, but outcome assessors were blind.\ud \ud Interventions: The intervention arm received up to 15 sessions of BA over 4 months. BA aims to improve mood by increasing people’s level of enjoyable or valued activities. The control arm received usual care only.\ud \ud Main outcome measures: Primary feasibility outcomes concerned feasibility of recruitment to the main trial, acceptability of research procedures and measures, appropriateness of baseline and outcome measures, retention of participants and potential value of conducting the definitive trial. Secondary feasibility outcomes concerned the delivery of the intervention. The primary clinical outcome 6 months post randomisation was the PHQ-9. Secondary clinical outcomes were Stroke Aphasic Depression Questionnaire – Hospital version, Nottingham Leisure Questionnaire, Nottingham Extended Activities of Daily Living, Carer Strain Index, EuroQol-5 Dimensions, five-level version and health-care resource use questionnaire.\ud \ud Results: Forty-eight participants were recruited in 27 centre-months of recruitment, at a recruitment rate of 1.8 participants per centre per month. The 25 participants randomised to receive BA attended a mean of 8.5 therapy sessions [standard deviation (SD) 4.4 therapy sessions]; 23 participants were allocated to usual care. Outcome assessments were completed by 39 (81%) participants (BA, n = 18; usual care, n = 21). Mean PHQ-9 scores at 6-month follow-up were 10.1 points (SD 6.9 points) and 14.4 points (SD 5.1 points) in the BA and control groups, respectively, a difference of –3.8 (95% confidence interval –6.9 to –0.6) after adjusting for baseline PHQ-9 score and centre, representing a reduction in depression in the BA arm. Therapy was delivered as intended. BA was acceptable to participants, carers and therapists. Value-of-information analysis indicates that the benefits of conducting a definitive trial would be likely to outweigh the costs. It is estimated that a sample size of between 580 and 623 participants would be needed for a definitive trial.\ud \ud Limitations: Target recruitment was not achieved, although we identified methods to improve recruitment.\ud \ud Conclusions: The Behavioural Activation Therapy for Depression after Stroke trial was feasible with regard to the majority of outcomes. The outstanding issue is whether or not a sufficient number of participants could be recruited within a reasonable time frame for a definitive trial. Future work is required to identify whether or not there are sufficient sites that are able to deliver the services required for a definitive trial.\ud \ud Trial registration: Current Controlled Trials ISRCTN12715175.\ud \ud Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 47. See the NIHR Journals Library website for further project information.

Introduction\ud In CF, people with higher FEV1 are less aggressively treated with intravenous (IV) antibiotics, with resultant negative impact on their health outcomes. This could be entirely clinician-driven, but patient choice may also influence IV use. In this prospective observational study, we explored IV recommendations by clinicians and IV acceptance by adults with CF to understand how clinical presentations consistent with exacerbations resulted in IV use.\ud \ud Methods\ud Clinical presentations consistent with exacerbations, IV recommendation by clinicians and IV acceptance by patients were prospectively identified for every adult with CF in Sheffield throughout 2016, excluding those who had lung transplantation (n = 7) or on ivacaftor (n = 13). Relevant demographic data, e.g. %FEV1, were extracted from medical records. Multi-level mixed-effects logistic regression models were used to compare IV recommendations vs non-recommendations for all clinical encounters, and IV acceptance vs non-acceptance for all IV recommendations.\ud \ud Results\ud Among 186 adults (median age 27 years, median FEV1 78.5%), there were 434 exacerbation events and 318 IV use episodes following 1010 clinical encounters. Only 254 (58.5%) of exacerbations were IV treated. A diagnosis of exacerbation, higher number of symptoms and lower %FEV1 were independent predictors for IV recommendation by clinicians. Higher number of symptoms and lower %FEV1 were also independent predictors for IV acceptance by adults with CF.\ud \ud Conclusions\ud Lower IV use among adults with higher %FEV1 was influenced by both clinicians' and patients’ decisions. Using IV antibiotics as an exacerbation surrogate could under-estimate exacerbation rates and conceal differential treatment decisions according to varying clinical characteristics.

Background: Habit, a psychological process that automatically generates urges to perform a behavior in associated settings, is potentially an important determinant of medication adherence. Habit is challenging to measure because, as a psychological construct, it cannot be directly observed. We describe a method of using routinely available objective adherence data from electronic data capture (EDC) to generate a behavior-based index of adherence habit and demonstrate how this index can be applied.\ud Methods to generate the habit index: Our proposed habit index is a “frequency in context” measure. It estimates habit as a multiplicative product of behavior frequency (generated from weekly percentage adherence) and context stability (inferred from time of nebulizer use). Although different timescales can be used, we chose to generate weekly habit scores since we believe that this is the most granular level at which context stability can be reasonably calculated.\ud An application of the habit index: A hallmark of habit is to predict future behavior, hence we used time series method to cross-correlate the habit index with nebulizer adherence in the subsequent week among 123 adults with cystic fibrosis (52, 42.3% female; median age 25 years) over a median duration of 153 weeks (IQR 74–198 weeks). The mean cross-correlation coefficient (R) between the habit index and subsequent adherence was 0.40 (95% CI 0.36–0.44). Adjusting for current adherence, the unstandardized regression coefficient (B) for the habit index was 0.30 (95% CI -1.04 to 1.65).\ud Conclusion: We have described a pragmatic method to infer “habit” from adherence data routinely captured with EDC and provided proof-of-principle evidence regarding the feasibility of this concept. The continuous stream of data from EDC allows the habit index to unobtrusively assess “habit” at various time points over prolonged periods, and hence the habit index may be applicable in habit formation studies.

STUDY QUESTION: Can 13C-Magnetic Resonance Spectroscopy (MRS) of selected metabolites provide useful information about human sperm metabolism and how glycolysis or oxidative phosphorylation are used by different sperm populations? SUMMARY ANSWER: Sperm populations, prepared by density gradient centrifugation (DGC) and incubated with either 13Cu-glucose, 13Cu-fructose or 13C1-pyruvate, showed consistent evidence of metabolism generating principally lactate and more intermittently bicarbonate, and significantly more lactate was produced from 13Cu-glucose by vital or motile sperm recovered from the 40/80% interface compared to those from the pellet, which could not be accounted for by differences in the non-sperm cells present. WHAT IS KNOWN ALREADY: Previous studies have focused on CO2 or other specific metabolite production by human sperm and there remains considerable debate about whether glycolysis and/or oxidative phosphorylation is the more important pathway for ATP production in sperm. STUDY DESIGN SIZE, DURATION: Sperm populations were prepared by DGC and subjected to 13C-MRS to answer the following questions. (i) Is it possible to detect human sperm metabolism of 13C substrates implicated in energy generation? (ii) What are the kinetics of such reactions? (iii) Do different sperm populations (e.g. '80%' pellet sperm and '40%' interface sperm) utilise substrates in the same way? Semen samples from 97 men were used in these experiments; 52 were used in parallel for aims (i) and (ii) and 45 were used for aim (iii). PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm populations were prepared from ejaculates of healthy men using a Percoll/Phosphate Buffered Saline (PBS) DGC and then incubated with a range of 13C-labelled substrates (13Cu-glucose, 13Cu-fructose, 13C1-pyruvate, 13C1-butyrate, 13C3-lactate, 13C2,4-D-3-hydroxybutyrate, 13C5-L-glutamate, 13C1,2-glycine or 13Cu-galactose) along with penicillin/streptomycin antibiotic at 37°C for 4 hours, 24 hours or over 48 hours for an estimated rate constant. Sperm concentration, vitality and motility were measured and, for a subset of experiments, non-sperm cell concentration was determined. A 9.4T magnetic resonance spectrometer was used to acquire 1D 13C, inverse gated 1H decoupled, MRS spectra. Spectrum processing was carried out using spectrometer software and Matlab scripts to determine peak integrals for each spectrum. MAIN RESULTS AND THE ROLE OF CHANCE: 13Cu-glucose, 13Cu-fructose and 13C1-pyruvate were consistently converted into lactate and, to a lesser extent, bicarbonate. There was a significant correlation between sperm concentration and lactate peak size for 13Cu-glucose and 13Cu-fructose, which was not observed for 13C1-pyruvate. The lactate peak did not correlate with the non-sperm cell concentration up to 6.9 × 106/ml. The concentration of 13Cu-glucose, 13Cu-fructose or 13C1-pyruvate (1.8, 3.6, 7.2 or 14.4 mM) had no influence on the size of the observed lactate peak over a 4 hour incubation. The rate of conversion of 13C1-pyruvate to lactate was approximately three times faster than for 13Cu-glucose or 13Cu-fructose which were not significantly different from each other. After incubating for 4 hours, the utilisation of 13Cu-glucose, 13Cu-fructose or 13C1-pyruvate by sperm from the '40%' interface of the DGC was no different from those from the pellet when normalised to total sperm concentration. However, after normalising by either the vital or motile sperm concentration, there was a significant increase in conversion of 13Cu-glucose to lactate by '40%' interface sperm compared to pellet sperm (Vital = 3.3 ± 0.30 × 106 vs 2.0 ± 0.21 × 106; p = 0.0049; Motile = 7.0 ± 0.75 × 106 vs 4.8 ± 0.13 × 106; p = 0.0032. Mann-Whitney test p

Randomised controlled trials are considered to be the best method to assess comparative clinical efficacy and effectiveness, and can be a key source of data for estimating cost effectiveness. Central to the design of a randomised controlled trial is an a priori sample size calculation, which ensures that the study has a high probability of achieving its prespecified main objective. Beyond pure statistical or scientific concerns, it is ethically imperative that an appropriate number of study participants be recruited, to avoid imposing the burdens of a clinical trial on more patients than necessary. The scientific concern is satisfied and the ethical imperative is further addressed by the specification of a target difference between treatments that is considered realistic or important by one or more key stakeholder groups. The sample size calculation ensures that the trial will have the required statistical power to identify whether a difference of a particular magnitude exists. In this article, the key messages from the DELTA 2 guidance on determining the target difference and sample size calculation for a randomised controlled trial are presented. Recommendations for the subsequent reporting of the sample size calculation are also provided.

Rationale, aims and objective\ud \ud Cross‐country comparisons of cystic fibrosis (CF) outcomes can potentially identify variation in care but are dependent on data quality. An important assumption is that the UK annual review FEV1 is only collected during periods of clinical stability. If this assumption does not hold, results of FEV1 comparisons may be biased in favour of registries with encounter‐based FEV1. We aimed to test the assumption that CF annual reviews in the UK are only performed during periods of clinical stability.\ud \ud \ud \ud Method\ud \ud Prospective encounter‐based data collected in Sheffield (n = 174) was used to establish whether annual review FEV1 were always collected during periods of clinical stability and to determine the group‐level discrepancy between annual review vs best FEV1. We then went on to quantify the group‐level discrepancy between annual review and best annual FEV1 readings within the UK registry (n = 2995) to determine if the differences observed in Sheffield also apply to the wider UK data.\ud \ud \ud \ud Results\ud \ud Sheffield results showed a group‐level discrepancy between best and annual review FEV1 of −2.5% (95% CI −3.95% to −1.2%) for annual reviews performed during periods of clinical stability (n = 50). The group‐level discrepancy is larger at −8.0% (95% CI −11.2% to −4.9%) among annual reviews performed during periods of clinical instability (n = 13). Therefore, the magnitude of this group‐level discrepancy is a surrogate for the proportion of clinically stable annual reviews—smaller discrepancy indicates a higher proportion of clinically stable annual reviews and vice versa.\ud \ud The overall group‐level discrepancy in the UK registry (−5.6%, 95% CI −5.9 to −5.4%) was similar to Sheffield (−6.1%, 95% CI −7.1 to −5.1%). Around 20% of the clinician reviewed, annual reviews in Sheffield were performed during periods of clinically instability.\ud \ud \ud \ud Conclusions\ud \ud Annual review FEV1 underestimates lung health of adults with CF in the UK and may bias cross‐country comparisons.

BACKGROUND/AIMS: External pilot trials are recommended for testing the feasibility of main or confirmatory trials. However, there is little evidence that progress in external pilot trials actually predicts randomisation and attrition rates in the main trial. To assess the use of external pilot trials in trial design, we compared randomisation and attrition rates in publicly funded randomised controlled trials with rates in their pilots. METHODS: Randomised controlled trials for which there was an external pilot trial were identified from reports published between 2004 and 2013 in the Health Technology Assessment Journal. Data were extracted from published papers, protocols and reports. Bland-Altman plots and descriptive statistics were used to investigate the agreement of randomisation and attrition rates between the full and external pilot trials. RESULTS: Of 561 reports, 41 were randomised controlled trials with pilot trials and 16 met criteria for a pilot trial with sufficient data. Mean attrition and randomisation rates were 21.1% and 50.4%, respectively, in the pilot trials and 16.8% and 65.2% in the main. There was minimal bias in the pilot trial when predicting the main trial attrition and randomisation rate. However, the variation was large: the mean difference in the attrition rate between the pilot and main trial was -4.4% with limits of agreement of -37.1% to 28.2%. Limits of agreement for randomisation rates were -47.8% to 77.5%. CONCLUSION: Results from external pilot trials to estimate randomisation and attrition rates should be used with caution as comparison of the difference in the rates between pilots and their associated full trial demonstrates high variability. We suggest using internal pilot trials wherever appropriate.

PURPOSE: Nelson's syndrome is a challenging condition that can develop following bilateral adrenalectomy for Cushing's disease, with high circulating ACTH levels, pigmentation and an invasive pituitary tumor. There is no established medical therapy. The aim of the study was to assess the effects of pasireotide on plasma ACTH and tumor volume in Nelson's syndrome. METHODS: Open labeled multicenter longitudinal trial in three steps: (1) a placebo-controlled acute response test; (2) 1 month pasireotide 300-600 μg s.c. twice-daily; (3) 6 months pasireotide long-acting-release (LAR) 40-60 mg monthly. RESULTS: Seven patients had s.c. treatment and 5 proceeded to LAR treatment. There was a significant reduction in morning plasma ACTH during treatment (mean ± SD; 1823 ± 1286 ng/l vs. 888.0 ± 812.8 ng/l during the s.c. phase vs. 829.0 ± 1171 ng/l during the LAR phase, p

BACKGROUND: The Epidemiologic Study of Cystic Fibrosis using 1995-1996 and 2003-2005 data found that CF centres with lowest FEV1 tended to use fewer intravenous antibiotics. We repeated the analyses using 2013-2014 UK CF registry data to determine if this was still the case. METHODS: Analysing data for 2013 and 2014 separately, 28 adult CF centres were ranked according to median % age-adjusted FEV1. The top 7 centres were placed in the 'upper quarter' (best FEV1), the bottom 7 centres in 'lower quarter' (lowest FEV1), and the rest in 'middle half'. IV use was stratified according to %FEV1, then compared between the three groups. RESULTS: Centres in the 'upper quarter' and 'middle half' used significantly more IV antibiotics compared to centres in the 'lower quarter' (van Elteren test P-value

BACKGROUND: It is important to quantify the dose response for a drug in phase 2a clinical trials so the optimal doses can then be selected for subsequent late phase trials. In a phase 2a clinical trial of new lead drug being developed for the treatment of rheumatoid arthritis (RA), a U-shaped dose response curve was observed. In the light of this result further research was undertaken to design an efficient phase 2a proof of concept (PoC) trial for a follow-on compound using the lessons learnt from the lead compound. \ud \ud METHODS: The planned analysis for the Phase 2a trial for GSK123456 was a Bayesian Emax model which assumes the dose-response relationship follows a monotonic sigmoid "S" shaped curve. This model was found to be suboptimal to model the U-shaped dose response observed in the data from this trial and alternatives approaches were needed to be considered for the next compound for which a Normal dynamic linear model (NDLM) is proposed. This paper compares the statistical properties of the Bayesian Emax model and NDLM model and both models are evaluated using simulation in the context of adaptive Phase 2a PoC design under a variety of assumed dose response curves: linear, Emax model, U-shaped model, and flat response. \ud \ud RESULTS: It is shown that the NDLM method is flexible and can handle a wide variety of dose-responses, including monotonic and non-monotonic relationships. In comparison to the NDLM model the Emax model excelled with higher probability of selecting ED90 and smaller average sample size, when the true dose response followed Emax like curve. In addition, the type I error, probability of incorrectly concluding a drug may work when it does not, is inflated with the Bayesian NDLM model in all scenarios which would represent a development risk to pharmaceutical company. The bias, which is the difference between the estimated effect from the Emax and NDLM models and the simulated value, is comparable if the true dose response follows a placebo like curve, an Emax like curve, or log linear shape curve under fixed dose allocation, no adaptive allocation, half adaptive and adaptive scenarios. The bias though is significantly increased for the Emax model if the true dose response follows a U-shaped curve. \ud \ud CONCLUSIONS: In most cases the Bayesian Emax model works effectively and efficiently, with low bias and good probability of success in case of monotonic dose response. However, if there is a belief that the dose response could be non-monotonic then the NDLM is the superior model to assess the dose response.

Background and objective: Intravenous (i.v.) antibiotics are needed for rescue when preventative therapy fails to achieve stability among adults with cystic fibrosis (CF). Understanding the distribution of i.v. days can provide insight into the care that adults with CF need. We aim to determine the baseline characteristics that are associated with higher i.v. use, in particular to test the hypothesis that prior-year i.v. use is associated with future-year i.v. use. Methods: This is a cross-sectional analysis of the 2013–2014 UK CF registry data. Stepwise logistic regression was performed using current-year i.v. days as the dependent variable, and demographic variables including prior-year i.v. days as the covariates. Based on these results, study sample was divided into clinically meaningful subgroups using analysis similar to tree-based method. Results: Data were available for 4269 adults in 2013 and 4644 adults in 2014. Prior-year i.v. use was the strongest predictor for current-year i.v. use followed by forced expiratory volume in 1 s (FEV1). Adults with high prioryear i.v. use (>14 days) continued to require high levels of i.v., regardless of FEV1. Those with high prior-year i. v. use and FEV1 ≥70% had higher current-year i.v. days compared to adults with low prior-year i.v. use and FEV1

Introduction\ud \ud Peripheral vascular disease is a major cause of death and disability. The extent to which volume influences outcome of lower limb (LL) vascular surgery remains unclear. This review evaluated the relationship between hospital/surgeon volume and outcome in LL surgery.\ud \ud Methodology\ud \ud Electronic databases; Medline, Embase, the Cochrane Library Databases, Science Citation Index, and CINAHL, proceedings from conferences, citations, and references of included studies were searched. Studies from Europe, of adults undergoing LL vascular surgery reporting outcomes by hospital or surgeon volume were included. Quality of studies was assessed using a modified ACROBAT-NRSI(Robins1) tool. Association between hospital/surgeon volume and outcome were summarised using tables.\ud \ud Results\ud \ud Nine studies from different European countries, comprising 67,445 patients who had undergone diverse LL surgeries were included. Increase in hospital/surgeon volume was associated with a decrease in amputations. The evidence on an association between hospital/surgeon volume and mortality was contradictory, but mortality and amputations may co-vary by hospital volume. There were an insufficient number of studies reporting on the other variables to draw firm conclusions; but their results suggest high volume hospitals may undertake more repeated surgeries/revascularisations and limb salvage. The impact of hospital/surgical volume on adverse events and length of hospitalisation could not be determined.\ud \ud Conclusion\ud \ud High volume hospitals/surgeons may undertake fewer amputations and mortality and amputations may co-vary. The finding that hospital and surgeon volume affected the number of secondary amputations has implications on re-organisation of vascular surgery services. However due to the small number and poor quality of some of the included studies, decisions on reorganisation of LL vascular surgery services should be supplemented by results from clinical audits. There is need for standardisation of definition of volume stratification of outcomes by patient’s clinical conditions.

Objectives\ud In children, radiography is performed to diagnose vertebral fractures and dual energy x-ray absorptiometry (DXA) to\ud assess bone density. In adults, DXA assesses both. We aimed to establish whether\ud DXA can replace spine radiographs in assessment of paediatric vertebral fractures.\ud \ud Methods\ud Prospectively, lateral spine radiographs and lateral spine DXA of 250 children\ud performed on the same day were independently scored by three radiologists using\ud the simplified algorithm based qualitative technique and blinded to results of the\ud other modality. Consensus radiograph read and second read of 100 random images\ud were performed. Diagnostic accuracy, inter/intraobserver and intermodality\ud agreements, patient/carer experience and radiation dose were assessed.\ud \ud Results\ud Average sensitivity and specificity (95% confidence interval) in diagnosing one or\ud more vertebral fractures requiring treatment was 70% (58%-82%) and 97% (94%-\ud 100%) respectively for DXA and 74% (55%-93%) and 96% (95%-98%) for\ud radiographs. Fleiss’ kappa for interobserver and average kappa for intraobserver\ud reliability were 0.371 and 0.631 respectively for DXA and 0.418 and 0.621 for\ud radiographs. Average effective dose was 41.9µSv for DXA and 232.7µSv for\ud radiographs. Image quality was similar.\ud \ud Conclusion\ud Given comparable image quality and non-inferior diagnostic accuracy, lateral spine\ud DXA should replace conventional radiographs for assessment of vertebral fractures\ud in children.

Background: Evidence suggests behavioural interventions may exacerbate health inequalities, potentially due to differences in uptake or effectiveness. We used a physical activity intervention targeting deprived communities to identify neighbourhood-level factors that might explain differences in programme impact.\ud \ud Methods: Individuals aged 40–65 were sent a postal invitation offering a brief intervention to increase physical activity. We used postcodes linkage to determine whether neighbourhood indicators of deprivation, housing, crime and proximity to green spaces and leisure facilities predicted uptake of the initial invitation or an increase in physical activity level in those receiving the brief intervention.\ud \ud Results: A total of 4134 (6.8%) individuals responded to the initial invitation and of those receiving the intervention and contactable after 3 months, 486 (51.6%) reported an increase in physical activity. Area deprivation scores linked to postcodes predicted intervention uptake, but not intervention effectiveness. Neighbourhood indicators did not predict either uptake or intervention effectiveness.\ud \ud Conclusions: The main barrier to using brief intervention invitations to increase physical activity in deprived, middle-aged populations was the low uptake of an intervention requiring significant time and motivation from participants. Once individuals have taken up the intervention offer, neighbourhood characteristics did not appear to be significant barriers to successful lifestyle change.

Background: There is currently insufficient evidence for the clinical and cost-effectiveness of psychological\ud therapies for treating post-stroke depression.\ud \ud Methods/Design: BEADS is a parallel group feasibility multicentre randomised controlled trial with nested\ud qualitative research and economic evaluation. The aim is to evaluate the feasibility of undertaking a full trial\ud comparing behavioural activation (BA) to usual stroke care for 4 months for patients with post-stroke depression.\ud We aim to recruit 72 patients with post-stroke depression over 12 months at three centres, with patients identified\ud from the National Health Service (NHS) community and acute services and from the voluntary sector. They will be\ud randomly allocated to receive behavioural activation in addition to usual care or usual care alone. Outcomes will be\ud measured at 6 months after randomisation for both participants and their carers, to determine their effectiveness.\ud The primary clinical outcome measure for the full trial will be the Patient Health Questionnaire-9 (PHQ-9). Rates of\ud consent, recruitment and follow-up by centre and randomised group will be reported. The acceptability of the\ud intervention to patients, their carers and therapists will also be assessed using qualitative interviews. The economic\ud evaluation will be undertaken from the National Health Service and personal social service perspective, with a\ud supplementary analysis from the societal perspective. A value of information analysis will be completed to identify\ud the areas in which future research will be most valuable.\ud \ud Discussion: The feasibility outcomes from this trial will provide the data needed to inform the design of a\ud definitive multicentre randomised controlled trial evaluating the clinical and cost-effectiveness of behavioural\ud activation for treating post-stroke depression.\ud \ud Trial registration: Current controlled trials ISRCTN12715175

Background: Preventative inhaled treatments in cystic fibrosis will only be effective in maintaining lung health if used appropriately. An accurate adherence index should therefore reflect treatment effectiveness, but the standard method of reporting adherence, that is, as a percentage of the agreed regimen between clinicians and people with cystic fibrosis, does not account for the appropriateness of the treatment regimen. We describe two different indices of inhaled therapy adherence for adults with cystic fibrosis which take into account effectiveness, that is, “simple” and “sophisticated” normative adherence. Methods to calculate normative adherence: Denominator adjustment involves fixing a minimum appropriate value based on the recommended therapy given a person’s characteristics. For simple normative adherence, the denominator is determined by the person’s Pseudomonas status. For sophisticated normative adherence, the denominator is determined by the person’s Pseudomonas status and history of pulmonary exacerbations over the previous year. Numerator adjustment involves capping the daily maximum inhaled therapy use at 100% so that medication overuse does not artificially inflate the adherence level. Three illustrative cases: Case A is an example of inhaled therapy under prescription based on Pseudomonas status resulting in lower simple normative adherence compared to unadjusted adherence. Case B is an example of inhaled therapy under-prescription based on previous exacerbation history resulting in lower sophisticated normative adherence compared to unadjusted adherence and simple normative adherence. Case C is an example of nebulizer overuse exaggerating the magnitude of unadjusted adherence. Conclusion: Different methods of reporting adherence can result in different magnitudes of adherence. We have proposed two methods of standardizing the calculation of adherence which should better reflect treatment effectiveness. The value of these indices can be tested empirically in clinical trials in which there is careful definition of treatment regimens related to key patient characteristics, alongside accurate measurement of health outcomes.

Background\ud \ud Gastrostomy feeding is commonly used to support patients with amyotrophic lateral sclerosis who develop severe dysphagia. Although recommended by both the American Academy of Neurology and the European Federation of Neurological Societies, currently little evidence indicates the optimum method and timing for gastrostomy insertion. We aimed to compare gastrostomy insertion approaches in terms of safety and clinical outcomes.\ud \ud Methods\ud \ud In this large, longitudinal, prospective cohort study (ProGas), we enrolled patients with a diagnosis of definite, probable, laboratory supported, or possible amyotrophic lateral sclerosis who had agreed with their treating clinicians to undergo gastrostomy at 24 motor neuron disease care centres or clinics in the UK. The primary outcome was 30-day mortality after gastrostomy. This study was registered on the UK Clinical Research Network database, identification number 9923.\ud \ud Findings\ud \ud Between Nov 2, 2010, and Jan 31, 2014, 345 patients were recruited of whom 330 had gastrostomy. 163 (49%) patients underwent percutaneous endoscopic gastrostomy, 121 (37%) underwent radiologically inserted gastrostomy, 43 (13%) underwent per-oral image-guided gastrostomy, and three (1%) underwent surgical gastrostomy. 12 patients (4%, 95% CI 2·1–6·2) died within the first 30 days after gastrostomy: five (3%) of 163 after percutaneous endoscopic gastrostomy, four (3%) of 121 after radiologically inserted gastrostomy, and three (7%) of 43 after per-oral image-guided gastrostomy (p=0·46). Including repeat attempts in 14 patients, 21 (6%) of 344 gastrostomy procedures could not be completed: 11 (6%) of 171 percutaneous endoscopic gastrostomies, seven (6%) of 121 radiologically inserted gastrostomies, and three (6%) of 45 per-oral image-guided gastrostomies (p=0·947).\ud \ud Interpretation\ud \ud The three methods of gastrostomy seemed to be as safe as each other in relation to survival and procedural complications. In the absence of data from randomised trials, our findings could inform clinicians and patients in reaching decisions about gastrostomy and will stimulate further research into the nutritional management in patients with amyotrophic lateral sclerosis.\ud \ud

Background\ud Systematic reviews have identified a range of brief interventions which increase physical activity in previously sedentary people. A randomised controlled trial is needed to assess whether providing motivational interviewing, three months after giving initial advice, sustains physical activity levels in those who recently became physically active. This paper reports the results of an internal pilot study designed to test the feasibility of the study in terms of recruitment, per protocol delivery of the intervention and retention at three months.\ud \ud Methods\ud Participants were: aged 40-64 years; resident in deprived areas of Sheffield, UK; and, had recently become physically active as a result of using a brief intervention following an invitation from a mass mailout. Interventions: Motivational Interviewing 'boosters' aimed at sustaining change in physical activity status delivered face-to-face or over the telephone compared with no further intervention. Outcomes of the feasibility study: recruitment of 60 participants from mailout of 3,300; retention of 45 participants with 3-month follow-up accelerometry measurements; 70% of those randomised to boosters receiving intervention per protocol. Sample size and power were recalculated using the accelerometry data collected.\ud \ud Results\ud Forty-seven participants were randomised (78% of the feasibility target); 37 participants were retained at three months, 29 with at least four days of accelerometry data (64% of the feasibility target); 79% of those allocated boosters received them per protocol (surpassing the feasibility target). The proposed sample size of 600 was confirmed as appropriate and power is expected to be sufficient to detect a difference between groups.\ud \ud Conclusions\ud The main study will continue with the original recruitment target of 600 participants but to ensure feasibility, it is necessary to increase recruitment and improve the numbers of those followed-up who have evaluable data. Strategies will include increasing the number of initial invitations sent out and improving the training of research assistants and participants in the positioning of the accelerometer.

This cross-sectional study aimed to investigate the relationship between quality of life (QoL), physical activity (PA), diet and overweight status in children 11 to 15 years old.\ud \ud Participants (N = 1,771) children with self-reported physical activity and QoL outcome data.\ud \ud Cross-sectional survey of four secondary schools, using the PedsQL and EQ-5D QoL instruments; the CAPANS physical activity instrument and a food intake screener questionnaire.\ud \ud The correlational analysis indicates little or no relationship between self-reported QoL, BMI and moderate to vigorous PA. We found no statistically significant differences between the two groups of children, who achieved the recommended PA guidelines and those who did not, on any of the dimensions of the PedsQL and the EQ-5D utility score. Only on the EQ-5D VAS dimensions score was there a statistically significant difference. Children who self-reported a BMI of overweight to obese had significantly lower QoL on both dimensions of the EQ-5D and every dimension of the PedsQL apart from School functioning.\ud \ud Overall this study showed mixed results for pupils achieving the recommended targets for physical activity and diet and their relationship with QoL. Hence, further study into PA and diet and their effects on QoL is needed.\ud

Objectives: To determine which of two methods of case note review – holistic (implicit) and criterion-based (explicit) – provides the most useful and reliable information for quality and safety of care, and the level of agreement within and between groups of health-care professionals when they use the two methods to review the same record. To explore the process–outcome relationship between holistic and criterion-based quality-of-care measures and hospital-level outcome indicators. © 2010 Crown Copyright\ud \ud \ud

Health-Related Quality of Life (HRQoL) measures are becoming increasingly used in clinical trials as primary outcome measures. Investigators are now asking statisticians for advice on how to analyse studies that have used HRQoL outcomes.\ud \ud HRQoL outcomes, like the SF-36, are usually measured on an ordinal scale. However, most investigators assume that there exists an underlying continuous latent variable that measures HRQoL, and that the actual measured outcomes (the ordered categories), reflect contiguous intervals along this continuum.\ud \ud The ordinal scaling of HRQoL measures means they tend to generate data that have discrete, bounded and skewed distributions. Thus, standard methods of analysis such as the t-test and linear regression that assume Normality and constant variance may not be appropriate. For this reason, conventional statistical advice would suggest that non-parametric methods be used to analyse HRQoL data. The bootstrap is one such computer intensive non-parametric method for analysing data.\ud \ud We used the bootstrap for hypothesis testing and the estimation of standard errors and confidence intervals for parameters, in four datasets (which illustrate the different aspects of study design). We then compared and contrasted the bootstrap with standard methods of analysing HRQoL outcomes. The standard methods included t-tests, linear regression, summary measures and General Linear Models.\ud \ud Overall, in the datasets we studied, using the SF-36 outcome, bootstrap methods produce results similar to conventional statistical methods. This is likely because the t-test and linear regression are robust to the violations of assumptions that HRQoL data are likely to cause (i.e. non-Normality). While particular to our datasets, these findings are likely to generalise to other HRQoL outcomes, which have discrete, bounded and skewed distributions. Future research with other HRQoL outcome measures, interventions and populations, is required to confirm this conclusion.\ud

BACKGROUND: \ud \ud The SF-6D is a new single summary preference-based measure of health derived from the SF-36. Empirical work is required to determine what is the smallest change in SF-6D scores that can be regarded as important and meaningful for health professionals, patients and other stakeholders.\ud \ud OBJECTIVES: \ud \ud To use anchor-based methods to determine the minimally important difference (MID) for the SF-6D for various datasets.\ud \ud METHODS: \ud \ud All responders to the original SF-36 questionnaire can be assigned an SF-6D score provided the 11 items used in the SF-6D have been completed. The SF-6D can be regarded as a continuous outcome scored on a 0.29 to 1.00 scale, with 1.00 indicating "full health".\ud \ud Anchor-based methods examine the relationship between an health-related quality of life (HRQoL) measure and an independent measure (or anchor) to elucidate the meaning of a particular degree of change. One anchor-based approach uses an estimate of the MID, the difference in the QoL scale corresponding to a self-reported small but important change on a global scale. Patients were followed for a period of time, then asked, using question 2 of the SF-36 as our global rating scale, (which is not part of the SF-6D), if there general health is much better (5), somewhat better (4), stayed the same (3), somewhat worse (2) or much worse (1) compared to the last time they were assessed. We considered patients whose global rating score was 4 or 2 as having experienced some change equivalent to the MID. In patients who reported a worsening of health (global change of 1 or 2) the sign of the change in the SF-6D score was reversed (i.e. multiplied by minus one). The MID was then taken as the mean change on the SF-6D scale of the patients who scored (2 or 4).\ud \ud RESULTS: \ud \ud This paper describes the MID for the SF-6D from seven longitudinal studies that had previously used the SF-36.\ud \ud CONCLUSIONS: \ud \ud From the seven reviewed studies (with nine patient groups) the MID for the SF-6D ranged from 0.010 to 0.048, with a weighted mean estimate of 0.033 (95% CI: 0.029 to 0.037). The corresponding Standardised Response Means (SRMs) ranged from 0.11 to 0.48, with a mean of 0.30 and were mainly in the "small to moderate" range using Cohen's criteria, supporting the MID results. Using the half-standard deviation (of change) approach the mean effect size was 0.051 (range 0.033 to 0.066). Further empirical work is required to see whether or not this holds true for other patient groups and populations.\ud

OBJECTIVES: To assess the practicality and validity of using the SF-36 in a community-dwelling population over 65 years old, and obtain population scores in this age group.\ud \ud DESIGN: \ud Postal survey, using a questionnaire booklet containing the SF-36 and other health related items, of all those aged 65 or over registered with twelve general practices. Non-respondents received up to two reminders at three-weekly intervals.\ud \ud SETTING: \ud Twelve randomly selected general practices in Sheffield.\ud \ud SAMPLE: \ud 9897 subjects aged 65 to 104.\ud \ud MAIN OUTCOME MEASURES: \ud Scores for the eight dimensions of the SF-36 and a modified version of the physical functioning dimension.\ud \ud RESULTS: \ud The SF-36 achieved a response rate of 82% (n=8117) and dimension completion rates of 86.4% to 97.7%. Internal consistency measured by Cronbach’s a exceeded 0.80 for all dimensions except social functioning. These results compare favourably with postal surveys of younger adults. Scores for older adults were calculated by age and sex. Comparison with data from younger people showed how physical health declines steeply with age, in marked contrast with mental health.\ud \ud CONCLUSIONS: \ud The SF-36 is a practical and valid instrument to use in postal surveys of older people living in the community. The population scores provided here may facilitate its use in future surveys of older adults.\ud

BACKGROUND: To assist clinicians and researchers in choosing outcome measures for patients with chronic obstructive pulmonary disease attending routine outpatient clinics, a comparative assessment was undertaken of four questionnaires designed to reflect the patients' perception of their physical and emotional health in terms of their feasibility, validity, reliability, and responsiveness to health change. METHODS: Two condition specific questionnaires, the St George's Respiratory Questionnaire (SGRQ) and Guyatt's Chronic Respiratory Questionnaire (CRQ), and two generic questionnaires, the Short Form-36 Health Survey (SF-36) and Euroqol (EQ), were compared for their discriminative and evaluative properties. Spirometric tests and a walking test were also performed. One hundred and fifty six adults who were clinically judged to have COPD and who attended an outpatient chest clinic were assessed at recruitment and six and 12 months later. Patients were also asked whether their health had changed since their last assessment. RESULTS: Completion rates and consistency between items for dimensions of the SGRQ were lower than for dimensions of the other questionnaires. The distributions of responses were skewed for certain dimensions in all questionnaires except the CRQ. Validity was supported for all instruments insofar as patients' scores were associated with differences in disease severity. The generic questionnaires better reflected other health problems. All instruments were reliable over time. The condition specific questionnaires were more responsive between baseline and first follow up visit but this difference did not persist. While certain dimensions of the SF-36 were responsive to patient perceived changes, this did not apply to the derived single index of the EQ. The rating scale of the EQ, however, provided a quick and easy indicator of change. CONCLUSIONS: Evidence from this study supports the CRQ and the SF-36 as comprehensive outcome measures for patients with longstanding COPD. \ud

Background\ud Health Related Quality of Life (HRQoL) measures are becoming more frequently used in clinical trials and health services research, both as primary and secondary endpoints. Investigators are now asking statisticians for advice on how to plan and analyse studies using HRQoL measures, which includes questions on sample size. Sample size requirements are critically dependent on the aims of the study, the outcome measure and its summary measure, the effect size and the method of calculating the test statistic. The SF-6D is a new single summary preference-based measure of health derived from the SF-36 suitable for use clinical trials and in the economic evaluation of health technologies.\ud \ud Objectives\ud To describe and compare two methods of calculating sample sizes when using the SF-6D in comparative clinical trials and to give pragmatic guidance to researchers on what method to use.\ud \ud Methods\ud We describe two main methods of sample size estimation. The parametric (t-test) method assumes the SF-6D data is continuous and normally distributed and that the effect size is the difference between two means. The non-parametric (Mann-Whitney MW) method assumes the data are continuous and not normally distributed and the effect size is defined in terms of the probability that an observation drawn at random from population Y would exceed an observation drawn at random from population X. We used bootstrap computer simulation to compare the power of the two methods for detecting a shift in location.\ud \ud Results\ud This paper describes the SF-6D and retrospectively calculated parametric and nonparametric effect sizes for the SF-6D from a variety of studies that had previously used the SF-36. Computer simulation suggested that if the distribution of the SF-6D is reasonably symmetric then the t-test appears to be more powerful than the MW test at detecting differences in means. Therefore if the distribution of the SF-6D is symmetric or expected to be reasonably symmetric then parametric methods should be used for sample size calculations and analysis. If the distribution of the SF-6D is skewed then the MW test appears to be more powerful at detecting a location shift (difference in means) than the t-test. However the differences in power (between the t and MW tests) are small and decrease as the sample size increases.\ud \ud Conclusions\ud We have provided a clear description of the distribution of the SF-6D and believe that the mean is an appropriate summary measure for the SF-6D when it is to be used in clinical trials and the economic evaluation of new health technologies. Therefore pragmatically we would recommend that parametric methods be used for sample size calculation and analysis when using the SF-6D.