Laparoscopic cholecystectomy versus conservative management for adults with uncomplicated symptomatic gallstones: the C-GALL RCT.

Background: Gallstone disease is a common gastrointestinal disorder in industrialised societies. The prevalence of gallstones in the adult population is estimated to be approximately 10-15%, and around 80% remain asymptomatic. At present, cholecystectomy is the default option for people with symptomatic gallstone disease. Objectives: To assess the clinical and cost-effectiveness of observation/conservative management compared with laparoscopic cholecystectomy for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones in secondary care. Design: Parallel group, multicentre patient randomised superiority pragmatic trial with up to 24 months follow-up and embedded qualitative research. Within-trial cost-utility and 10-year Markov model analyses. Development of a core outcome set for uncomplicated symptomatic gallstone disease. Setting: Secondary care elective settings. Participants: Adults with symptomatic uncomplicated gallstone disease referred to a secondary care setting were considered for inclusion. Interventions: Participants were randomised 1: 1 at clinic to receive either laparoscopic cholecystectomy or observation/conservative management. Main outcome measures: The primary outcome was quality of life measured by area under the curve over 18 months using the Short Form-36 bodily pain domain. Secondary outcomes included the Otago gallstones' condition-specific questionnaire, Short Form-36 domains (excluding bodily pain), area under the curve over 24 months for Short Form-36 bodily pain domain, persistent symptoms, complications and need for further treatment. No outcomes were blinded to allocation. Results: Between August 2016 and November 2019, 434 participants were randomised (217 in each group) from 20 United Kingdom centres. By 24 months, 64 (29.5%) in the observation/conservative management group and 153 (70.5%) in the laparoscopic cholecystectomy group had received surgery, median time to surgery of 9.0 months (interquartile range, 5.6-15.0) and 4.7 months (interquartile range 2.6-7.9), respectively. At 18 months, the mean Short Form-36 norm-based bodily pain score was 49.4 (standard deviation 11.7) in the observation/conservative management group and 50.4 (standard deviation 11.6) in the laparoscopic cholecystectomy group. The mean area under the curve over 18 months was 46.8 for both groups with no difference: mean difference -0.0, 95% confidence interval (-1.7 to 1.7); p-value 0.996; n = 203 observation/conservative, n = 205 cholecystectomy. There was no evidence of differences in quality of life, complications or need for further treatment at up to 24 months follow-up. Condition-specific quality of life at 24 months favoured cholecystectomy: mean difference 9.0, 95% confidence interval (4.1 to 14.0), p < 0.001 with a similar pattern for the persistent symptoms score. Within-trial cost-utility analysis found observation/conservative management over 24 months was less costly than cholecystectomy (mean difference -£1033). A non-significant quality-adjusted life-year difference of -0.019 favouring cholecystectomy resulted in an incremental cost-effectiveness ratio of £55,235. The Markov model continued to favour observation/conservative management, but some scenarios reversed the findings due to uncertainties in longer-term quality of life. The core outcome set included 11 critically important outcomes from both patients and healthcare professionals. Conclusions: The results suggested that in the short term (up to 24 months) observation/conservative management may be a cost-effective use of National Health Service resources in selected patients, but subsequent surgeries in the randomised groups and differences in quality of life beyond 24 months could reverse this finding. Future research should focus on longer-term follow-up data and identification of the cohort of patients that should be routinely offered surgery. Trial registration: This trial is registered as ISRCTN55215960. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/71) and is published in full in Health Technology Assessment; Vol. 28, No. 26. See the NIHR Funding and Awards website for further award information.

The C-GALL study assessed the benefits, in terms of symptoms, quality of life and costs, of cholecystectomy versus observation (conservative management: by the patient and general practitioner that might include dietary advice and pain management and surgery if needed). Four hundred and thirty-four patients with symptomatic gallstones were randomly allocated surgery or conservative management. The main symptom of ongoing bodily pain and some other quality-of-life measures were assessed over the next 2 years using postal questionnaires. After 2 years, 70% of those allocated to surgery had been operated on and 37% of the observation group either had an operation or were waiting for one. There was no difference in bodily pain or overall quality of life between the groups. However, participants in the surgery group reported fewer ongoing problems related to their gallstone disease or after surgery than those in the conservative management group. Surgery was, however, more costly than conservative management. The C-GALL study has shown that for some patients, a conservative management approach may be a sufficient and less costly way of managing their gallstone symptoms rather than going straight on the waiting list for surgery. More research is needed to identify which patients benefit most from surgery.

Effectiveness of conservative management versus laparoscopic cholecystectomy in the prevention of recurrent symptoms and complications in adults with uncomplicated symptomatic gallstone disease (C-GALL trial): pragmatic, multicentre randomised controlled trial.

OBJECTIVE: To assess the clinical and cost effectiveness of conservative management compared with laparoscopic cholecystectomy for the prevention of symptoms and complications in adults with uncomplicated symptomatic gallstone disease. DESIGN: Parallel group, pragmatic randomised, superiority trial. SETTING: 20 secondary care centres in the UK. PARTICIPANTS: 434 adults (>18 years) with uncomplicated symptomatic gallstone disease referred to secondary care, assessed for eligibility between August 2016 and November 2019, and randomly assigned (1:1) to receive conservative management or laparoscopic cholecystectomy. INTERVENTIONS: Conservative management or surgical removal of the gallbladder. MAIN OUTCOME MEASURES: The primary patient outcome was quality of life, measured by area under the curve, over 18 months using the short form 36 (SF-36) bodily pain domain, with higher scores (range 0-100) indicating better quality of life. Other outcomes included costs to the NHS, quality adjusted life years (QALYs), and incremental cost effectiveness ratio. RESULTS: Of 2667 patients assessed for eligibility, 434 were randomised: 217 to the conservative management group and 217 to the laparoscopic cholecystectomy group. By 18 months, 54 (25%) participants in the conservative management arm and 146 (67%) in the cholecystectomy arm had received surgery. The mean SF-36 norm based bodily pain score was 49.4 (standard deviation 11.7) in the conservative management arm and 50.4 (11.6) in the cholecystectomy arm. The SF-36 bodily pain area under the curve up to 18 months did not differ (mean difference 0.0, 95% confidence interval -1.7 to 1.7; P=1.00). Conservative management was less costly (mean difference -£1033, (-$1334; -€1205), 95% credible interval -£1413 to -£632) and QALYs did not differ (mean difference -0.019, 95% credible interval -0.06 to 0.02). CONCLUSIONS: In the short term (≤18 months), laparoscopic surgery is no more effective than conservative management for adults with uncomplicated symptomatic gallstone disease, and as such conservative management should be considered as an alternative to surgery. From an NHS perspective, conservative management may be cost effective for uncomplicated symptomatic gallstone disease. As costs, complications, and benefits will continue to be incurred in both groups beyond 18 months, future research should focus on longer term follow-up to establish effectiveness and lifetime cost effectiveness and to identify the cohort of patients who should be routinely offered surgery. TRIAL REGISTRATION: ISRCTN registry ISRCTN55215960.

A Systematic Review of the Evidence for Non-surgical Weight Management for Adults with Severe Obesity: What is Cost Effective and What are the Implications for the Design of Health Services?

PURPOSE OF REVIEW: Severe obesity (BMI ≥ 35 kg/m2) increases premature mortality and reduces quality-of-life. Obesity-related disease (ORD) places substantial burden on health systems. This review summarises the cost-effectiveness evidence for non-surgical weight management programmes (WMPs) for adults with severe obesity. RECENT FINDINGS: Whilst evidence shows bariatric surgery is often cost-effective, there is no clear consensus on the cost-effectiveness of non-surgical WMPs. Thirty-two studies were included. Most were short-term evaluations that did not capture the long-term costs and consequences of ORD. Decision models often included only a subset of relevant ORDs, and made varying assumptions about the rate of weight regain over time. A lack of sensitivity analyses limited interpretation of results. Heterogeneity in the definition of WMPs and usual care prevents formal evidence synthesis. We were unable to establish the most cost-effective WMPs. Addressing these limitations may help future studies provide more robust cost-effectiveness evidence for decision makers.

Effectiveness and cost-effectiveness of text messages with or without endowment incentives for weight management in men with obesity (Game of Stones): study protocol for a randomised controlled trial.

BACKGROUND: Obesity increases the risk of type 2 diabetes, heart disease, stroke, mobility problems and some cancers, and its prevalence is rising. Men engage less than women in existing weight loss interventions. Game of Stones builds on a successful feasibility study and aims to find out if automated text messages with or without endowment incentives are effective and cost-effective for weight loss at 12 months compared to a waiting list comparator arm in men with obesity. METHODS: A 3-arm, parallel group, assessor-blind superiority randomised controlled trial with process evaluation will recruit 585 adult men with body mass index of 30 kg/m2 or more living in and around three UK centres (Belfast, Bristol, Glasgow), purposively targeting disadvantaged areas. Intervention groups: (i) automated, theory-informed text messages daily for 12 months plus endowment incentives linked to verified weight loss targets at 3, 6 and 12 months; (ii) the same text messages and weight loss assessment protocol; (iii) comparator group: 12 month waiting list, then text messages for 3 months. The primary outcome is percentage weight change at 12 months from baseline. Secondary outcomes at 12 months are as follows: quality of life, wellbeing, mental health, weight stigma, behaviours, satisfaction and confidence. Follow-up includes weight at 24 months. A health economic evaluation will measure cost-effectiveness over the trial and over modelled lifetime: including health service resource-use and quality-adjusted life years. The cost-utility analysis will report incremental cost per quality-adjusted life years gained. Participant and service provider perspectives will be explored via telephone interviews, and exploratory mixed methods process evaluation analyses will focus on mental health, multiple long-term conditions, health inequalities and implementation strategies. DISCUSSION: The trial will report whether text messages (with and without cash incentives) can help men to lose weight over 1 year and maintain this for another year compared to a comparator group; the costs and benefits to the health service; and men's experiences of the interventions. Process analyses with public involvement and service commissioner input will ensure that this open-source digital self-care intervention could be sustainable and scalable by a range of NHS or public services. TRIAL REGISTRATION: ISRCTN 91974895 . Registered on 14/04/2021.

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial.

BACKGROUND: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. METHODS: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between-group difference in the short physical performance battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy. RESULTS: We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect -0.1 points (95%CI -1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.4 kg (95%CI -1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI -1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.3 kg (95%CI -1.0 to 0.4), P = 0.47]. Meta-analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between-group difference -0.1 points (95%CI -0.4 to 0.2)]. CONCLUSIONS: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Vitamin D deficiency, supplementation and testing: have we got it right in New Zealand?

BACKGROUND: Severe prolonged vitamin D deficiency can cause rickets or osteomalacia. Both can be prevented by sunshine exposure or vitamin D supplementation. Although New Zealand guidance does not recommend vitamin D supplementation for the general population, it can be considered for individuals at risk of vitamin D deficiency. Routine measurement of 25-hydroxyvitamin D (25OHD) is also considered unnecessary. METHODS: We investigated the rates of vitamin D supplementation, rickets and osteomalacia in New Zealand, and of 25OHD results in Auckland, over the last two decades. RESULTS: Vitamin D prescriptions increased 14-fold, from 86,295/year to 1,215,507/year, between 2003 and 2019, with medication costs alone in 2019 being >$1 million. Despite these changes, the annual prevalence of hospital admissions for rickets, osteomalacia and unspecified vitamin D deficiency remained low and stable (10-20/year). 25OHD concentrations increased between 2002 and 2003 and between 2009 and 2019, and in the later time-period, 25OHD tests mainly identified individuals without vitamin D deficiency (40-50% >75nmol/L, 65-70% >50nmol/L and only 7-12.5% <25nmol/L). CONCLUSIONS: Osteomalacia and rickets persist at low rates despite widespread, increasingly costly vitamin D supplementation and testing, which largely identifies individuals without vitamin D deficiency. These results suggest that vitamin D guidance and practice in New Zealand should change.

Prevalence of biochemical osteomalacia in adults undergoing vitamin D testing.

OBJECTIVE: Prolonged severe vitamin D deficiency can cause osteomalacia, but the 25-hydroxyvitamin D (25OHD) concentration below which this occurs is unknown. We investigated the prevalence of biochemical osteomalacia in adults with a measurement of 25OHD. DESIGN, MEASUREMENT, AND PATIENTS: 25OHD results between 1/1/2009 and 15/6/2020 were obtained from the regional laboratory database, together with measurements of serum calcium, parathyroid hormone (PTH) and alkaline phosphatase (ALP) within 6 months of the index 25OHD. We defined biochemical osteomalacia as all 3 of: albumin-adjusted serum calcium (aCa)<2.0 mmol/L, PTH>7.3 pmol/L and ALP>150 IU/L. Possible osteomalacia was 2/3 criteria with the other test not done. 25OHD measurements associated with significant renal impairment, elevated hepatic transaminases or hypercalcaemia were excluded. RESULTS: 110,046 25OHD measurements were identified over the 11.5 years period. After removal of ineligible measurements, 42,171 25OHD measurements from 32,386 individuals with at least 2 of aCa, PTH and ALP were included in analyses. Median 25OHD was 63 nmol/L; 8% were <25 nmol/L, and 33% were <50 nmol/L. Five index 25OHD measurements met the definition of biochemical osteomalacia, and another 11 were possible osteomalacia. After reviewing available clinical records for these 16 episodes, we classified 9 cases as osteomalacia and 7 as other diagnoses. Thus, the prevalence of biochemical osteomalacia was 0.02% (9/42,171) for 25OHD measurements and 0.23% (8/3432) for 25OHD<25 nmol/L. All cases of osteomalacia with 25OHD measurements prior to supplementation had 25OHD≤18 nmol/L. CONCLUSION: The prevalence of biochemical osteomalacia is very low, even in individuals with 25OHD<25 nmol/L.

Associations between frailty, physical performance, and renal biomarkers in older people with advanced chronic kidney disease.

PURPOSE: Impaired physical performance and frailty are common in older people with advanced chronic kidney disease but it is unclear which metabolic derangements contribute to these impairments. We, therefore, examined associations between renal biochemical markers and both physical performance and frailty in older people with advanced chronic kidney disease. METHODS: Secondary analysis of data from the BiCARB trial, which enrolled non-dialysing patients aged 60 and over, with chronic kidney disease stage 4/5, with serum bicarbonate < 22 mmol/L. Participants undertook the Short Physical Performance Battery, maximum grip strength and six-minute walk test at baseline, 3, 6, 12 and 24 months. Renal biochemistry (serum creatinine, cystatin C, phosphate, and bicarbonate), haemoglobin, 25-hydroxyvitamin D and NT-pro-B-type natriuretic peptide were measured at baseline. Associations between baseline renal biochemistry and physical performance, and between baseline biochemistry and the monthly rate of change in physical performance were assessed. RESULTS: We analysed data from 300 participants (mean age 74 years; 86 [29%] women). 148 (49%) were pre-frail, 86 (29%) were frail. In multivariable cross-sectional baseline analyses, only age and BMI were significantly associated with baseline short physical performance battery; age, sex, body mass index, NT-pro-BNP and 25-hydroxyvitamin D were significantly associated with baseline six-minute walk distance. No significant associations were found between biochemical markers and change in physical performance over time, except between baseline 25-hydroxyvitamin D concentration and change in six-minute walk distance. CONCLUSIONS: Biochemical markers associated with chronic kidney disease did not consistently associate with baseline physical performance or the rate of change of physical performance measures. TRIAL REGISTRATION: ISRCTN09486651.

Protocol for a randomised controlled trial comparing laparoscopic cholecystectomy with observation/conservative management for preventing recurrent symptoms and complications in adults with uncomplicated symptomatic gallstones (C-Gall trial).

BACKGROUND: Gallstone disease (cholelithiasis) is common. In most people it is asymptomatic and does not require treatment, but in about 20% it can become symptomatic, causing pain and other complications requiring medical attention and/or surgery. A proportion of symptomatic people with uncomplicated gallstone disease do not experience further episodes of pain and, therefore, could be treated conservatively. Moreover, surgery carries risks of perioperative and postoperative complications. METHODS AND ANALYSIS: C-Gall is a pragmatic, multicentre, randomised controlled trial and economic evaluation to assess whether cholecystectomy is cost-effective compared with observation/ conservative management (here after referred to as medical management) at 18 months post-randomisation (with internal pilot). PRIMARY OUTCOME MEASURE: Patient-reported quality of life (QoL) (36-Item Short Form Survey (SF-36) bodily pain domain) up to 18 months after randomisation.The primary economic outcome is incremental cost per quality-adjusted life year gained at 18 months. SECONDARY OUTCOME MEASURES: Secondary outcome measures include condition-specific QoL, SF-36 domains, complications, further treatment, persistent symptoms, healthcare resource use, and costs assessed at 18 and 24 months after randomisation. The bodily pain domain of the SF-36 will also be assessed at 24 months after randomisation.A sample size of 430 participants was calculated. Computer-generated 1:1 randomisation was used.The C-Gall Study is currently in follow-up in 20 UK research centres. The first patient was randomised on 1 August 2016, with follow-up to be completed by 30 November 2021. STATISTICAL ANALYSIS: Statistical analysis of the primary outcome will be intention-to-treat and a per-protocol analysis. The primary outcome, area under the curve (AUC) for the SF-36 bodily pain up to 18 months, will be generated using the Trapezium rule and analysed using linear regression with adjustment for the minimisation variables (recruitment site, sex and age). For the secondary outcome, SF-36 bodily pain, AUC up to 24 months will be analysed in a similar way. Other secondary outcomes will be analysed using generalised linear models with adjustment for minimisation and baseline variables, as appropriate. Statistical significance will be at the two-sided 5% level with corresponding CIs. ETHICS AND DISSEMINATION: The North of Scotland Research Ethics Committee approved this study (16/NS/0053). The dissemination plans include Health Technology Assessment monograph, international scientific meetings and publications in high-impact, open-access journals. TRIAL REGISTRATION NUMBER: ISRCTN55215960; pre-results.

Fractures in Adults After Weight Loss from Bariatric Surgery and Weight Management Programs for Obesity: Systematic Review and Meta-analysis.

BACKGROUND: Weight loss interventions for obesity, such as bariatric surgery, are associated with reductions in bone mineral density and may increase the risk of fractures. We undertook a systematic review and meta-analysis of bariatric surgery and lifestyle weight management programs (WMPs) with fracture outcomes. METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials from 1966 to 2018, and our trial registry of WMP randomized controlled trials (RCTs). We included RCTs, non-randomized trials, and observational studies of bariatric surgery, and RCTs of WMPs. Studies had follow-up ≥ 12 months, mean group body mass index ≥ 30 kg/m2. The primary outcome measure was incidence of any type of fracture in participants, and the secondary outcome was weight change. We used random effects meta-analysis for trial data. RESULTS: Fifteen studies were included. Three small trials provided short-term evidence of the association between bariatric surgery and participants with any fracture (365 participants; RR 0.82; 95% CI 0.29 to 2.35). Four out of six observational studies of bariatric surgery demonstrated significantly increased fracture risk. Six RCTs of WMPs with 6214 participants, the longest follow-up 11.3 years, showed no clear effect on any type of fracture (RR 1.04; 95% CI 0.91 to 1.18), although authors of the largest RCT reported an increased risk of frailty fracture by their definition (RR 1.40; 95% CI 1.04 to 1.90). CONCLUSION: Bariatric surgery appears to increase the risk of any fracture; however, longer-term trial data are needed. The effect of lifestyle WMPs on the risk of any fracture is currently unclear.

Bariatric surgery, lifestyle interventions and orlistat for severe obesity: the REBALANCE mixed-methods systematic review and economic evaluation.

BACKGROUND: Adults with severe obesity [body mass index (BMI) of ≥ 35 kg/m2] have an increased risk of comorbidities and psychological, social and economic consequences. OBJECTIVES: Systematically review bariatric surgery, weight-management programmes (WMPs) and orlistat pharmacotherapy for adults with severe obesity, and evaluate the feasibility, acceptability, clinical effectiveness and cost-effectiveness of treatment. DATA SOURCES: Electronic databases including MEDLINE, EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials and the NHS Economic Evaluation Database were searched (last searched in May 2017). REVIEW METHODS: Four systematic reviews evaluated clinical effectiveness, cost-effectiveness and qualitative evidence for adults with a BMI of ≥ 35 kg/m2. Data from meta-analyses populated a microsimulation model predicting costs, outcomes and cost-effectiveness of Roux-en-Y gastric bypass (RYGB) surgery and the most effective lifestyle WMPs over a 30-year time horizon from a NHS perspective, compared with current UK population obesity trends. Interventions were cost-effective if the additional cost of achieving a quality-adjusted life-year is < £20,000-30,000. RESULTS: A total of 131 randomised controlled trials (RCTs), 26 UK studies, 33 qualitative studies and 46 cost-effectiveness studies were included. From RCTs, RYGB produced the greatest long-term weight change [-20.23 kg, 95% confidence interval (CI) -23.75 to -16.71 kg, at 60 months]. WMPs with very low-calorie diets (VLCDs) produced the greatest weight loss at 12 months compared with no WMPs. Adding a VLCD to a WMP gave an additional mean weight change of -4.41 kg (95% CI -5.93 to -2.88 kg) at 12 months. The intensive Look AHEAD WMP produced mean long-term weight loss of 6% in people with type 2 diabetes mellitus (at a median of 9.6 years). The microsimulation model found that WMPs were generally cost-effective compared with population obesity trends. Long-term WMP weight regain was very uncertain, apart from Look AHEAD. The addition of a VLCD to a WMP was not cost-effective compared with a WMP alone. RYGB was cost-effective compared with no surgery and WMPs, but the model did not replicate long-term cost savings found in previous studies. Qualitative data suggested that participants could be attracted to take part in WMPs through endorsement by their health-care provider or through perceiving innovative activities, with WMPs being delivered to groups. Features improving long-term weight loss included having group support, additional behavioural support, a physical activity programme to attend, a prescribed calorie diet or a calorie deficit. LIMITATIONS: Reviewed studies often lacked generalisability to UK settings in terms of participants and resources for implementation, and usually lacked long-term follow-up (particularly for complications for surgery), leading to unrealistic weight regain assumptions. The views of potential and actual users of services were rarely reported to contribute to service design. This study may have failed to identify unpublished UK evaluations. Dual, blinded numerical data extraction was not undertaken. CONCLUSIONS: Roux-en-Y gastric bypass was costly to deliver, but it was the most cost-effective intervention. Adding a VLCD to a WMP was not cost-effective compared with a WMP alone. Most WMPs were cost-effective compared with current population obesity trends. FUTURE WORK: Improved reporting of WMPs is needed to allow replication, translation and further research. Qualitative research is needed with adults who are potential users of, or who fail to engage with or drop out from, WMPs. RCTs and economic evaluations in UK settings (e.g. Tier 3, commercial programmes or primary care) should evaluate VLCDs with long-term follow-up (≥ 5 years). Decision models should incorporate relevant costs, disease states and evidence-based weight regain assumptions. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016040190. FUNDING: The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit and Health Economics Research Unit are core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate.

Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation.

BACKGROUND: Research waste can occur when trials are conducted in the wrong populations. Vitamin D deficient populations are most likely to benefit from vitamin D supplementation. We investigated waste attributable to randomised controlled trials (RCTs) of supplementation in populations that were not vitamin D deficient. METHODS: In December 2015, we searched Pubmed, recent systematic reviews, and three trial registries for RCTs of vitamin D with clinical endpoints in adults, and 25-hydroxvitamin D (25OHD) survey data relevant to large (N ≥ 1000) RCTs. We investigated the proportion of RCTs that studied vitamin D deficient populations, temporal trends in baseline 25OHD, and whether investigators in large RCTs considered relevant 25OHD survey data or systematic reviews in their trial justifications. RESULTS: Of 137 RCTs of vitamin D with clinical endpoints, 118 (86%) reported baseline mean/median 25OHD, which was < 25, 25-49, 50-74, and ≥ 75 nmol/L in 12 (10%), 62 (53%), 36 (31%), and 8 (7%) RCTs, respectively. In 70% of RCTs, baseline 25OHD was > 40 nmol/L. Baseline 25OHD increased over time. Before 2006, 38%, 62%, 0% and 0% of RCTs had baseline 25OHD < 25, 25-49, 50-74, and ≥ 75 nmol/L respectively; in 2011-15, the respective proportions were 9%, 49%, 37%, and 6%. Of 12 RCTs with baseline 25OHD < 25 nmol/L, 8 had neutral findings. Of 25 large RCTs (18 completed, 7 ongoing), 1 was undertaken in a vitamin D deficient population, 3 in vitamin D insufficient populations, and 17 had, or probably will have, baseline 25OHD > 40 nmol/L. 44% (8/18) of large completed RCTs cited relevant prior population 25OHD data, and only 3/10 (30%) relevant prior systematic reviews. CONCLUSIONS: Up to 70% of RCTs of vitamin D with clinical endpoints, 71% of large completed RCTs, and 100% of ongoing large RCTs could be considered research waste because they studied cohorts that were not vitamin D deficient.

Cancer and vitamin D supplementation: a systematic review and meta-analysis.

Background: Low 25-hydroxyvitamin D status has been associated with a higher risk of cancer in epidemiologic studies. Objective: The aim of this study was to undertake a systematic review and meta-analysis of randomized clinical trials (RCTs) investigating the effect of vitamin D supplementation alone on cancer incidence and mortality. Design: A systematic review was undertaken. MEDLINE, Embase, CENTRAL, conference abstracts, and clinical trial registries were searched (last search March 2017) for RCTs investigating vitamin D supplementation alone. RCTs with ≥12 mo of follow-up and in participants with a mean or median age ≥60 y were eligible. During-study events were used as the main analysis, but after-study events were included in a secondary analysis. Subgroup analyses concerning different forms of vitamin D supplementation, 25-hydroxyvitamin D status at baseline, vitamin D dose, and exclusion of open-label trials were undertaken. Results: Thirty studies in 18,808 participants were included in the systematic review, with a median follow-up ranging from 1 to 6.2 y. The results of the meta-analysis for during-study events showed no evidence of an effect of vitamin D supplementation for cancer incidence (RR: 1.03; 95% CI: 0.91, 1.15) and cancer-related deaths (RR: 0.88; 95% CI: 0.70, 1.09). Including after-study events, the RRs were 1.02 (95% CI: 0.92, 1.13) and 0.86 (95% CI: 0.72, 1.03), respectively. These results did not appear to be affected by baseline 25-hydroxyvitamin D status, vitamin D dose, or the exclusion of open-label trials. Conclusion: We did not find evidence to suggest that vitamin D supplementation alone reduces the incidence of cancer or cancer mortality, even after including long-term follow-up results.

Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis.

Objective To assess whether weight loss interventions for adults with obesity affect all cause, cardiovascular, and cancer mortality, cardiovascular disease, cancer, and body weight.Design Systematic review and meta-analysis of randomised controlled trials (RCTs) using random effects, estimating risk ratios, and mean differences. Heterogeneity investigated using Cochran's Q and I2 statistics. Quality of evidence assessed by GRADE criteria.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, and full texts in our trials' registry for data not evident in databases. Authors were contacted for unpublished data.Eligibility criteria for selecting studies RCTs of dietary interventions targeting weight loss, with or without exercise advice or programmes, for adults with obesity and follow-up ≥1 year.Results 54 RCTs with 30 206 participants were identified. All but one trial evaluated low fat, weight reducing diets. For the primary outcome, high quality evidence showed that weight loss interventions decrease all cause mortality (34 trials, 685 events; risk ratio 0.82, 95% confidence interval 0.71 to 0.95), with six fewer deaths per 1000 participants (95% confidence interval two to 10). For other primary outcomes moderate quality evidence showed an effect on cardiovascular mortality (eight trials, 134 events; risk ratio 0.93, 95% confidence interval 0.67 to 1.31), and very low quality evidence showed an effect on cancer mortality (eight trials, 34 events; risk ratio 0.58, 95% confidence interval 0.30 to 1.11). Twenty four trials (15 176 participants) reported high quality evidence on participants developing new cardiovascular events (1043 events; risk ratio 0.93, 95% confidence interval 0.83 to 1.04). Nineteen trials (6330 participants) provided very low quality evidence on participants developing new cancers (103 events; risk ratio 0.92, 95% confidence interval 0.63 to 1.36).Conclusions Weight reducing diets, usually low in fat and saturated fat, with or without exercise advice or programmes, may reduce premature all cause mortality in adults with obesity.Systematic review registration PROSPERO CRD42016033217.

How effective are weight-loss interventions for improving fertility in women and men who are overweight or obese? A systematic review and meta-analysis of the evidence.

BACKGROUND: The prevalence of obesity is increasing worldwide, with a corresponding increase in overweight and obese patients referred with infertility. This systematic review aimed to determine whether non-surgical weight reduction strategies result in an improvement in reproductive parameters affected by obesity, e.g. delayed time to pregnancy, oligozoospermia and azoospermia. No prior reviews have examined this within the general fertility population, or in both sexes. OBJECTIVE AND RATIONALE: Our objective was to answer the question: 'In overweight and obese women, men and couples seeking fertility treatment, what non-surgical weight-loss interventions have been used, and how effective are they at weight loss and improving reproductive outcomes?' SEARCH METHODS: An electronic search of MEDLINE, EMBASE and the Cochrane Library was performed for studies between January 1966 and March 2016. Text word and MESH search terms used related to infertility, weight and barriers to weight loss. Inclusion criteria were an intervention to change lifestyle evaluated in any study design in participants of either gender with an unfulfilled desire to conceive. Studies were excluded if they included participants not attempting pregnancy, with illnesses that might cause weight fluctuations, or studies evaluating bariatric surgery. Two reviewers performed data extraction and quality assessment using the Cochrane Risk of Bias Tool for randomized trials, and a ratified checklist (ReBIP) for non-randomized studies. OUTCOMES: A total of 40 studies were included, of which 14 were randomised control trials. Primary outcomes were pregnancy, live birth rate and weight change. In women, reduced calorie diets and exercise interventions were more likely than control interventions to result in pregnancy [risk ratio 1.59, 95% CI (1.01, 2.50)], and interventions resulted in weight loss and ovulation improvement, where reported. Miscarriage rates were not reduced by any intervention. WIDER IMPLICATIONS: Overweight and obese persons seeking fertility should be educated on the detrimental effects of fatness and the benefits of weight reduction, including improvement in pregnancy rates. A combination of a reduced calorie diet, by reducing fat and refined carbohydrate intake, and increased aerobic exercise should form the basis of programmes designed for such individuals. A lack of randomized studies in men and couples, and studies evaluating barriers to undertaking weight loss in infertile populations is evident, and future research should examine these issues further.

Nutritional supplementation for hip fracture aftercare in older people.

BACKGROUND: Older people with hip fractures are often malnourished at the time of fracture, and subsequently have poor food intake. This is an update of a Cochrane review first published in 2000, and previously updated in 2010. OBJECTIVES: To review the effects (benefits and harms) of nutritional interventions in older people recovering from hip fracture. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, CENTRAL, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Embase, CAB Abstracts, CINAHL, trial registers and reference lists. The search was last run in November 2015. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of nutritional interventions for people aged over 65 years with hip fracture where the interventions were started within the first month after hip fracture. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data and assessed risk of bias. Where possible, we pooled data for primary outcomes which were: all cause mortality; morbidity; postoperative complications (e.g. wound infections, pressure sores, deep venous thromboses, respiratory and urinary infections, cardiovascular events); and 'unfavourable outcome' defined as the number of trial participants who died plus the number of survivors with complications. We also pooled data for adverse events such as diarrhoea. MAIN RESULTS: We included 41 trials involving 3881 participants. Outcome data were limited and risk of bias assessment showed that trials were often methodologically flawed, with less than half of trials at low risk of bias for allocation concealment, incomplete outcome data, or selective reporting of outcomes. The available evidence was judged of either low or very low quality indicating that we were uncertain or very uncertain about the estimates.Eighteen trials evaluated oral multinutrient feeds that provided non-protein energy, protein, vitamins and minerals. There was low-quality evidence that oral feeds had little effect on mortality (24/486 versus 31/481; risk ratio (RR) 0.81 favouring supplementation, 95% confidence interval (CI) 0.49 to 1.32; 15 trials). Thirteen trials evaluated the effect of oral multinutrient feeds on complications (e.g. pressure sore, infection, venous thrombosis, pulmonary embolism, confusion). There was low-quality evidence that the number of participants with complications may be reduced with oral multinutrient feeds (123/370 versus 157/367; RR 0.71, 95% CI 0.59 to 0.86; 11 trials). Based on very low-quality evidence from six studies (334 participants), oral supplements may result in lower numbers with 'unfavourable outcome' (death or complications): RR 0.67, 95% CI 0.51 to 0.89. There was very low-quality evidence for six studies (442 participants) that oral supplementation did not result in an increased incidence of vomiting and diarrhoea (RR 0.99, 95% CI 0.47 to 2.05).Only very low-quality evidence was available from the four trials examining nasogastric multinutrient feeding. Pooled data from three heterogeneous trials showed no evidence of an effect of supplementation on mortality (14/142 versus 14/138; RR 0.99, 95% CI 0.50 to 1.97). One trial (18 participants) found no difference in complications. None reported on unfavourable outcome. Nasogastric feeding was poorly tolerated. One study reported no cases of aspiration pneumonia.There is very low-quality evidence from one trial (57 participants, mainly men) of no evidence for an effect of tube feeding followed by oral supplementation on mortality or complications. Tube feeding, however, was poorly tolerated.There is very low-quality evidence from one trial (80 participants) that a combination of intravenous feeding and oral supplements may not affect mortality but could reduce complications. However, this expensive intervention is usually reserved for people with non-functioning gastrointestinal tracts, which is unlikely in this trial.Four trials tested increasing protein intake in an oral feed. These provided low-quality evidence for no clear effect of increased protein intake on mortality (30/181 versus 21/180; RR 1.42, 95% CI 0.85 to 2.37; 4 trials) or number of participants with complications but very low-quality and contradictory evidence of a reduction in unfavourable outcomes (66/113 versus 82/110; RR 0.78, 95% CI 0.65 to 0.95; 2 trials). There was no evidence of an effect on adverse events such as diarrhoea.Trials testing intravenous vitamin B1 and other water soluble vitamins, oral 1-alpha-hydroxycholecalciferol (vitamin D), high dose bolus vitamin D, different oral doses or sources of vitamin D, intravenous or oral iron, ornithine alpha-ketoglutarate versus an isonitrogenous peptide supplement, taurine versus placebo, and a supplement with vitamins, minerals and amino acids, provided low- or very low-quality evidence of no clear effect on mortality or complications, where reported.Based on low-quality evidence, one trial evaluating the use of dietetic assistants to help with feeding indicated that this intervention may reduce mortality (19/145 versus 36/157; RR 0.57, 95% CI 0.34 to 0.95) but not the number of participants with complications (79/130 versus 84/125). AUTHORS' CONCLUSIONS: There is low-quality evidence that oral multinutrient supplements started before or soon after surgery may prevent complications within the first 12 months after hip fracture, but that they have no clear effect on mortality. There is very low-quality evidence that oral supplements may reduce 'unfavourable outcome' (death or complications) and that they do not result in an increased incidence of vomiting and diarrhoea. Adequately sized randomised trials with robust methodology are required. In particular, the role of dietetic assistants, and peripheral venous feeding or nasogastric feeding in very malnourished people require further evaluation.

Long-term non-pharmacological weight loss interventions for adults with type 2 diabetes mellitus

ABSTRACT: BACKGROUND: Most persons with type 2 diabetes are overweight and obesity worsens the metabolic and physiologic abnormalities associated with diabetes. OBJECTIVE: The objective of this review is to assess the effectiveness of lifestyle and behavioral weight loss and weight control interventions for adults with type 2 diabetes. METHODS: Search methods: Studies were obtained from computerized searches of multiple electronic bibliographic databases, supplemented with hand searches of selected journals and consultation with experts in obesity research. Selection criteria: Studies were included if they were published or unpublished randomized controlled trials in any language, and examined weight loss or weight control strategies using one or more dietary, physical activity, or behavioral interventions, with a follow-up interval of at least 12 months. Data collection and analysis: Effects were combined using a random effects model. MAIN RESULTS: The 22 studies of weight loss interventions identified had a 4,659 participants and follow-up of 1 to 5 years. The pooled weight loss for any intervention in comparison to usual care among 585 subjects was 1.7 kg (95 % confidence interval [CI] 0.3 to 3.2), or 3.1% of baseline body weight among 517 subjects. Other main comparisons demonstrated non significant results: among 126 persons receiving a physical activity and behavioral intervention, those who also received a very low calorie diet lost 3.0 kg (95% CI -0.5 to 6.4), or 1.6% of baseline body weight, more than persons receiving a low-calorie diet. Among 53 persons receiving identical dietary and behavioral interventions, those receiving more intense physical activity interventions lost 3.9 kg (95% CI -1.9 to 9.7), or 3.6% of baseline body weight, more than those receiving a less intense or no physical activity intervention. Comparison groups often achieved significant weight loss (up to 10.0 kg), minimizing between-group differences. Changes in glycated hemoglobin generally corresponded to changes in weight and were not significant when between-group differences were examined. No data were identified on quality of life and mortality. AUTHORS CONCLUSIONS: Weight loss strategies using dietary, physical activity, or behavioral interventions produced small between-group improvements in weight. These results were minimized by weight loss in the comparison group, however, and examination of individual study arms revealed that multicomponent interventions including very low calorie diets or low calorie diets may hold promise for achieving weight loss in adults with type 2 diabetes.

Behavioural Interventions for Severe Obesity Before and/or After Bariatric Surgery: a Systematic Review and Meta-analysis.

BACKGROUND: Significant, sustained weight loss through conventional, non-surgical interventions is often unattainable for people with severe obesity (e.g. BMI ≥40 or ≥35 kg/m(2) with co-morbidities). Bariatric surgery is effective in treating severe obesity, but surgery alone without additional behaviour change management may not result in optimum long-term weight loss and maintenance. This systematic review and meta-analysis of randomised controlled trials evaluated the effectiveness of lifestyle interventions before and/or after bariatric surgery. METHODS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials and clinical trials registers were searched for eligible studies. Key journals were handsearched. Last search date was on December 2014. Eligible interventions had the explicit aim of changing behaviour related to diet and/or physical activity, starting within 12 months of surgery, either pre- or post-operatively, and with at least 6 months' follow-up. The primary outcome was weight change; secondary outcomes included surgical complications, quality of life and changes in co-morbidities. Random effect meta-analyses were undertaken. Study quality was assessed with the Cochrane Collaboration's risk of bias tool. RESULTS: Eleven trials met the inclusion criteria. Behavioural interventions appear to improve weight loss at 12 months after bariatric surgery. Secondary outcome data were lacking and weight outcomes were reported inconsistently. Overall, the methodological quality of the identified trials was low. CONCLUSIONS: The strength of evidence is limited by the relatively small number of trials identified and by their low methodological quality and short follow-up duration. Well-designed randomised controlled trials (RCTs) with long-term follow-up are required.