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1.  Effectiveness of physical activity promotion based in primary care: systematic review and meta-analysis of randomised controlled trials 
Objectives To determine whether trials of physical activity promotion based in primary care show sustained effects on physical activity or fitness in sedentary adults, and whether exercise referral interventions are more effective than other interventions.
Design Systematic review and meta-analysis of randomised controlled trials.
Data sources Medline, CINAHL, PsycINFO, EMBASE, SPORTDiscus, Centre for Reviews and Dissemination, the Cochrane Library, and article reference lists.
Review methods Review of randomised controlled trials of physical activity promotion in sedentary adults recruited in primary care, with minimum follow-up of 12 months, reporting physical activity or fitness (or both) as outcomes, and using intention to treat analyses. Two reviewers independently assessed studies for inclusion, appraised risk of bias, and extracted data. Pooled effect sizes were calculated using a random effects model.
Results We included 15 trials (n=8745). Most interventions took place in primary care, included health professionals in delivery, and involved advice or counselling given face to face or by phone (or both) on multiple occasions. Only three trials investigated exercise referral. In 13 trials presenting self reported physical activity, we saw small to medium positive intervention effects at 12 months (odds ratio 1.42, 95% confidence interval 1.17 to 1.73; standardised mean difference 0.25, 0.11 to 0.38). The number needed to treat with an intervention for one additional sedentary adult to meet internationally recommended levels of activity at 12 months was 12 (7 to 33). In four trials reporting cardiorespiratory fitness, a medium positive effect at 12 months was non-significant (standardised mean difference 0.51, −0.18 to 1.20). Three trials of exercise referral found small non-significant effects on self reported physical activity at 12 months (odds ratio 1.38; 0.98 to 1.95; standardised mean difference 0.20, −0.21 to 0.61).
Conclusions Promotion of physical activity to sedentary adults recruited in primary care significantly increases physical activity levels at 12 months, as measured by self report. We found insufficient evidence to recommend exercise referral schemes over advice or counselling interventions. Primary care commissioners should consider these findings while awaiting further trial evaluation of exercise referral schemes and other primary care interventions, with longer follow-up and use of objective measures of outcome.
doi:10.1136/bmj.e1389
PMCID: PMC3312793  PMID: 22451477
2.  Patients’ preferences within randomised trials: systematic review and patient level meta-analysis 
Objective To systematically review fully randomised patient preference trials and to explore the impact of preferences on attrition and outcome by meta-analysis of patient level data.
Data sources Citation search using Science Citation Index and Google Scholar and search of the main electronic databases (Medline, CINAHL, Embase, and AMED) with a combination of key words.
Study selection Fully randomised patient preference trials that compared treatments for any clinical condition were included. Other types of preference trials and crossover trials were excluded. Other inclusion criteria: participants aged 16 years and over; primary, self-reported outcomes measured on a continuous numerical scale. From 167 studies identified and screened, 17 were identified as fully randomised patient preference trials.
Data synthesis Of the 17 trials identified, 11 authors provided raw data for the meta-analysis. Data collected were baseline and follow-up data for the main outcome, randomised allocation data, preference data, and demographic data. Baseline and first post-intervention follow-up data for the main outcome were standardised. To improve homogeneity, data for only the eight musculoskeletal trials (n=1594) were combined. To estimate the effects of preferences on outcomes and attrition, three groups were compared: patients who had a preference and were randomly allocated to their preferred treatment; patients who had a preference and were randomly allocated to the treatment they did not prefer; and patients who had no preference.
Results Patients who were randomised to their preferred treatment had a standardised effect size greater than that of those who were indifferent to the treatment assignment (effect size 0.162, 95% confidence interval 0.011 to 0.314; P=0.04). Participants who received their preferred treatment also did better than participants who did not receive their preferred treatment (effect size 0.152, −0.035 to 0.339), although this was not statistically significant (P=0.11). Participants allocated to their undesired treatment had outcomes that were no different from those who were indifferent. Participants who were allocated to their undesired treatment were less likely to be lost to first follow-up compared with indifferent participants (odds ratio 1.70, 1.076 to 2.693; P=0.02). No difference was found in attrition between patients allocated to their preference and those who were indifferent.
Conclusions Preferences among patients in musculoskeletal trials are associated with treatment effects. In open randomised trials, preferences should be ascertained before randomisation.
doi:10.1136/bmj.a1864
PMCID: PMC2659956  PMID: 18977792
3.  Effectiveness of exercise-referral schemes to promote physical activity in adults: systematic review 
Background
Despite the health benefits of physical activity, most adults do not take the recommended amount of exercise.
Aim
To assess whether exercise-referral schemes are effective in improving exercise participation in sedentary adults.
Design of study
Systematic review.
Method
Studies were identified by searching MEDLINE, CINAHL, EMBASE, AMED, PsycINFO, SPORTDiscus, The Cochrane Library and SIGLE until March 2007. Randomised controlled trials (RCTs), observational studies, process evaluations and qualitative studies of exercise-referral schemes, defined as referral by a primary care clinician to a programme that encouraged physical activity or exercise were included. RCT results were combined in a meta-analysis where there was sufficient homogeneity.
Results
Eighteen studies were included in the review. These comprised six RCTs, one non-randomised controlled study, four observational studies, six process evaluations and one qualitative study. In addition, two of the RCTs and two of the process evaluations incorporated a qualitative component. Results from five RCTs were combined in a meta-analysis. There was a statistically significant increase in the numbers of participants doing moderate exercise with a combined relative risk of 1.20 (95% confidence intervals = 1.06 to 1.35). This means that 17 sedentary adults would need to be referred for one to become moderately active. This small effect may be at least partly due to poor rates of uptake and adherence to the exercise schemes.
Conclusion
Exercise-referral schemes have a small effect on increasing physical activity in sedentary people. The key challenge, if future exercise-referral schemes are to be commissioned by the NHS, is to increase uptake and improve adherence by addressing the barriers described in these studies.
PMCID: PMC2084138  PMID: 18252074
exercise; exercise therapy; meta-analysis; primary health care; referral and consultation; systematic review
4.  Surgical versus nonsurgical treatment of displaced intra-articular calcaneal fracture: a meta-analysis of current evidence base 
International Orthopaedics  2012;36(8):1615-1622.
Purpose
Controversy still surrounds the optimal treatment for patients with displaced intra-articular calcaneal fractures (DIACF). An up-to-date meta-analysis was performed to evaluate clinical effectiveness of surgical treatment for DIACF compared with nonsurgical treatment.
Methods
We systematically searched four electronic databases (Medline, BIOSIS, Cochrane library and Google Scholar) to identify randomised controlled trials (RCTs) and clinical controlled trials (CCTs) in which surgical treatment was compared with nonsurgical treatment of DIACF from 1980 to 2011. Trial quality was assessed using the modified Jadad scale and effective data were pooled for meta-analysis.
Results
Ten studies (six RCTs and four CCTs) with a total of 891 participants were screened. Results showed that surgical treatment was superior to nonsurgical treatment in better recovery of the Böhler angle (P < 0.0001), more stable calcaneal height (P = 0.0009) and width (P < 0.00001). Moreover, fewer surgically treated patients needed increased shoe size (P = 0.0004) and more were able to resume pre-injury work (P = 0.004) than the nonsurgical patients. No significant difference was identified between the two methods regarding the incidence of residual pain (P = 0.49). However, operative management was associated with a higher risk of complications (P = 0.008).
Conclusions
Although surgical repair may increase the complication probability, it is the price that has to be paid for better reconstruction of the calcaneus and better functional results. Taken as a whole, surgery is probably the optimal choice in DIACF treatment.
doi:10.1007/s00264-012-1563-0
PMCID: PMC3535025  PMID: 22576080
5.  Effect of exercise referral schemes in primary care on physical activity and improving health outcomes: systematic review and meta-analysis  
Objective To assess the impact of exercise referral schemes on physical activity and health outcomes.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, PsycINFO, Cochrane Library, ISI Web of Science, SPORTDiscus, and ongoing trial registries up to October 2009. We also checked study references.
Study selection Design: randomised controlled trials or non-randomised controlled (cluster or individual) studies published in peer review journals. Population: sedentary individuals with or without medical diagnosis. Exercise referral schemes defined as: clear referrals by primary care professionals to third party service providers to increase physical activity or exercise, physical activity or exercise programmes tailored to individuals, and initial assessment and monitoring throughout programmes. Comparators: usual care, no intervention, or alternative exercise referral schemes.
Results Eight randomised controlled trials met the inclusion criteria, comparing exercise referral schemes with usual care (six trials), alternative physical activity intervention (two), and an exercise referral scheme plus a self determination theory intervention (one). Compared with usual care, follow-up data for exercise referral schemes showed an increased number of participants who achieved 90-150 minutes of physical activity of at least moderate intensity per week (pooled relative risk 1.16, 95% confidence intervals 1.03 to 1.30) and a reduced level of depression (pooled standardised mean difference −0.82, −1.28 to −0.35). Evidence of a between group difference in physical activity of moderate or vigorous intensity or in other health outcomes was inconsistent at follow-up. We did not find any difference in outcomes between exercise referral schemes and the other two comparator groups. None of the included trials separately reported outcomes in individuals with specific medical diagnoses.Substantial heterogeneity in the quality and nature of the exercise referral schemes across studies might have contributed to the inconsistency in outcome findings.
Conclusions Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.
doi:10.1136/bmj.d6462
PMCID: PMC3209555  PMID: 22058134
6.  Effect of reducing total fat intake on body weight: systematic review and meta-analysis of randomised controlled trials and cohort studies 
Objective To investigate the relation between total fat intake and body weight in adults and children.
Design Systematic review and meta-analysis of randomised controlled trials and cohort studies.
Data sources Medline, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials to June 2010.
Inclusion criteria Randomised controlled trials and cohort studies of adults or children that compared lower versus usual total fat intake and assessed the effects on measures of body fatness (body weight, body mass index, or waist circumference) after at least six months (randomised controlled trials) or one year (in cohorts). Randomised controlled trials with any intention to reduce weight in participants or confounded by additional medical or lifestyle interventions were excluded.
Data extraction Data were extracted and validity was assessed independently and in duplicate. Random effects meta-analyses, subgroups, sensitivity analyses, and metaregression were done.
Results 33 randomised controlled trials (73 589 participants) and 10 cohort studies were included, all from developed countries. Meta-analysis of data from the trials suggested that diets lower in total fat were associated with lower relative body weight (by 1.6 kg, 95% confidence interval −2.0 to −1.2 kg, I2=75%, 57 735 participants). Lower weight gain in the low fat arm compared with the control arm was consistent across trials, but the size of the effect varied. Metaregression suggested that greater reduction in total fat intake and lower baseline fat intake were associated with greater relative weight loss, explaining most of the heterogeneity. The significant effect of a low fat diet on weight was not lost in sensitivity analyses (including removing trials that expended greater time and attention on low fat groups). Lower total fat intake also led to lower body mass index (−0.51 kg/m2, 95% confidence interval −0.76 to −0.26, nine trials, I2=77%) and waist circumference (by 0.3 cm, 95% confidence interval −0.58 to −0.02, 15 671 women, one trial). There was no suggestion of negative effects on other cardiovascular risk factors (lipid levels or blood pressure). GRADE assessment suggested high quality evidence for the relation between total fat intake and body weight in adults. Only one randomised controlled trial and three cohort studies were found in children and young people, but these confirmed a positive relation between total fat intake and weight gain.
Conclusions There is high quality, consistent evidence that reduction of total fat intake has been achieved in large numbers of both healthy and at risk trial participants over many years. Lower total fat intake leads to small but statistically significant and clinically meaningful, sustained reductions in body weight in adults in studies with baseline fat intakes of 28-43% of energy intake and durations from six months to over eight years. Evidence supports a similar effect in children and young people.
doi:10.1136/bmj.e7666
PMCID: PMC3516671  PMID: 23220130
7.  Effect of low-protein diet on kidney function in diabetic nephropathy: meta-analysis of randomised controlled trials 
BMJ Open  2013;3(5):e002934.
Objective
To evaluate the effect of low-protein diet on kidney function in patients with diabetic nephropathy.
Design
A systematic review and a meta-analysis of randomised controlled trials.
Data sources
MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number (ISRCTN) Register and University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) from inception to 10 December 2012. Internet searches were also carried out with general search engines (Google and Google Scholar).
Study selection
Randomised controlled trials that compared low-protein diet versus control diet and assessed the effects on kidney function, proteinuria, glycaemic control or nutritional status.
Primary and secondary outcome measures and data synthesis
The primary outcome was a change in the glomerular filtration rate (GFR). The secondary outcomes were changes in proteinuria, post-treatment value of glycated haemoglobin A1C (HbA1c) and post-treatment value of serum albumin. The results were summarised as the mean difference for continuous outcomes and pooled by the random effects model. Subgroup analyses and sensitivity analyses were conducted regarding patient characteristics, intervention period, methodological quality and assessment of diet compliance. The assessment of diet compliance was performed based on the actual protein intake ratio (APIR) of the low-protein diet group to the control group.
Results
We identified 13 randomised controlled trials enrolling 779 patients. A low-protein diet was associated with a significant improvement in GFR (5.82 ml/min/1.73 m2, 95% CI 2.30 to 9.33, I2=92%; n=624). This effect was consistent across the subgroups of type of diabetes, stages of nephropathy and intervention period. However, GFR was improved only when diet compliance was fair (8.92, 95% CI 2.75 to 15.09, I2=92% for APIR <0.9 and 0.03, 95% CI −1.49 to 1.56, I2=90% for APIR ≥0.9). Proteinuria and serum albumin were not differed between the groups. HbA1c was slightly but significantly decreased in the low-protein diet group (−0.26%, 95% CI −0.35 to −0.18, I2=0%; n=536).
Conclusions
Low-protein diet was significantly associated with improvement of diabetic nephropathy. The adverse effects of low-protein diet were not apparent such as worsening of glycaemic control and malnutrition.
doi:10.1136/bmjopen-2013-002934
PMCID: PMC3664345  PMID: 23793703
8.  Multifactorial assessment and targeted intervention for preventing falls and injuries among older people in community and emergency care settings: systematic review and meta-analysis 
BMJ : British Medical Journal  2007;336(7636):130-133.
Objective To evaluate the effectiveness of multifactorial assessment and intervention programmes to prevent falls and injuries among older adults recruited to trials in primary care, community, or emergency care settings.
Design Systematic review of randomised and quasi-randomised controlled trials, and meta-analysis.
Data sources Six electronic databases (Medline, Embase, CENTRAL, CINAHL, PsycINFO, Social Science Citation Index) to 22 March 2007, reference lists of included studies, and previous reviews.
Review methods Eligible studies were randomised or quasi-randomised trials that evaluated interventions to prevent falls that were based in emergency departments, primary care, or the community that assessed multiple risk factors for falling and provided or arranged for treatments to address these risk factors.
Data extraction Outcomes were number of fallers, fall related injuries, fall rate, death, admission to hospital, contacts with health services, move to institutional care, physical activity, and quality of life. Methodological quality assessment included allocation concealment, blinding, losses and exclusions, intention to treat analysis, and reliability of outcome measurement.
Results 19 studies, of variable methodological quality, were included. The combined risk ratio for the number of fallers during follow-up among 18 trials was 0.91 (95% confidence interval 0.82 to 1.02) and for fall related injuries (eight trials) was 0.90 (0.68 to 1.20). No differences were found in admissions to hospital, emergency department attendance, death, or move to institutional care. Subgroup analyses found no evidence of different effects between interventions in different locations, populations selected for high risk of falls or unselected, and multidisciplinary teams including a doctor, but interventions that actively provide treatments may be more effective than those that provide only knowledge and referral.
Conclusions Evidence that multifactorial fall prevention programmes in primary care, community, or emergency care settings are effective in reducing the number of fallers or fall related injuries is limited. Data were insufficient to assess fall and injury rates.
doi:10.1136/bmj.39412.525243.BE
PMCID: PMC2206297  PMID: 18089892
9.  Chocolate consumption and cardiometabolic disorders: systematic review and meta-analysis 
Objective To evaluate the association of chocolate consumption with the risk of developing cardiometabolic disorders.
Design Systematic review and meta-analysis of randomised controlled trials and observational studies.
Data sources Medline, Embase, Cochrane Library, PubMed, CINAHL, IPA, Web of Science, Scopus, Pascal, reference lists of relevant studies to October 2010, and email contact with authors.
Study selection Randomised trials and cohort, case-control, and cross sectional studies carried out in human adults, in which the association between chocolate consumption and the risk of outcomes related to cardiometabolic disorders were reported.
Data extraction Data were extracted by two independent investigators, and a consensus was reached with the involvement of a third. The primary outcome was cardiometabolic disorders, including cardiovascular disease (coronary heart disease and stroke), diabetes, and metabolic syndrome. A meta-analysis assessed the risk of developing cardiometabolic disorders by comparing the highest and lowest level of chocolate consumption.
Results From 4576 references seven studies met the inclusion criteria (including 114 009 participants). None of the studies was a randomised trial, six were cohort studies, and one a cross sectional study. Large variation was observed between these seven studies for measurement of chocolate consumption, methods, and outcomes evaluated. Five of the seven studies reported a beneficial association between higher levels of chocolate consumption and the risk of cardiometabolic disorders. The highest levels of chocolate consumption were associated with a 37% reduction in cardiovascular disease (relative risk 0.63 (95% confidence interval 0.44 to 0.90)) and a 29% reduction in stroke compared with the lowest levels.
Conclusions Based on observational evidence, levels of chocolate consumption seem to be associated with a substantial reduction in the risk of cardiometabolic disorders. Further experimental studies are required to confirm a potentially beneficial effect of chocolate consumption.
doi:10.1136/bmj.d4488
PMCID: PMC3163382  PMID: 21875885
10.  Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials 
Objective To assess the efficacy of vitamin and antioxidant supplements in the prevention of cardiovascular diseases.
Design Meta-analysis of randomised controlled trials.
Data sources and study selection PubMed, EMBASE, the Cochrane Library, Scopus, CINAHL, and ClinicalTrials.gov searched in June and November 2012. Two authors independently reviewed and selected eligible randomised controlled trials, based on predetermined selection criteria.
Results Out of 2240 articles retrieved from databases and relevant bibliographies, 50 randomised controlled trials with 294 478 participants (156 663 in intervention groups and 137 815 in control groups) were included in the final analyses. In a fixed effect meta-analysis of the 50 trials, supplementation with vitamins and antioxidants was not associated with reductions in the risk of major cardiovascular events (relative risk 1.00, 95% confidence interval 0.98 to 1.02; I2=42%). Overall, there was no beneficial effect of these supplements in the subgroup meta-analyses by type of prevention, type of vitamins and antioxidants, type of cardiovascular outcomes, study design, methodological quality, duration of treatment, funding source, provider of supplements, type of control, number of participants in each trial, and supplements given singly or in combination with other supplements. Among the subgroup meta-analyses by type of cardiovascular outcomes, vitamin and antioxidant supplementation was associated with a marginally increased risk of angina pectoris, while low dose vitamin B6 supplementation was associated with a slightly decreased risk of major cardiovascular events. Those beneficial or harmful effects disappeared in subgroup meta-analysis of high quality randomised controlled trials within each category. Also, even though supplementation with vitamin B6 was associated with a decreased risk of cardiovascular death in high quality trials, and vitamin E supplementation with a decreased risk of myocardial infarction, those beneficial effects were seen only in randomised controlled trials in which the supplements were supplied by the pharmaceutical industry.
Conclusion There is no evidence to support the use of vitamin and antioxidant supplements for prevention of cardiovascular diseases.
doi:10.1136/bmj.f10
PMCID: PMC3548618  PMID: 23335472
11.  Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis 
Background: Obstructive Sleep Apnoea Syndrome (OSAS) is a condition of obstruction, apneas and arousals while sleeping. It has been suggested that OSAS independently influences glucose metabolism. The main treatment for OSAS is continuous positive airways pressure (CPAP).
Objectives: To assess the effects of CPAP on insulin resistance and glucose metabolism.
Search strategy: We searched Medline, Embase and the Cochrane Controlled Trial Register (January 2010).
Selection criteria: We included randomised and non-randomised trials comparing CPAP with inactive control or placebo CPAP in adults with OSAS.
Data collection and analysis: Two authors independently assessed trial quality and extracted data. Parallel and crossover group trials were analysed separately. A meta-analysis was carried out.
Results: Three parallel group and two cross-over randomised trials and one controlled trial were included investigating 296 participants. Sample sizes ranged from n=13 to n=102 participants, age was 18 to 75 years, mean body mass index (BMI) 27.2 kg/m² to 37.1 kg/m², mean apnoe hypopnoe index (AHI) 29.7 to 39.7 events per hour, mean dips >4% in arterial oxygen saturation per hour of sleep 1 to 42.7 events. The studies’ methodological quality varied. Follow-up ranged from 4 to 12 weeks. Various endpoints were investigated. CPAP did neither influence plasma insulin levels nor HOMA-index, adiponectin levels or HbA1c value. One study reported a significant positive effect on the insulin sensitivity index (1.68%/min, 95% CI 0.3 to 3.06).
Conclusion: This systematic review does not support the hypothesis that OSAS independently influences glucose metabolism. Sufficiently powered, long-term randomised controlled trials defining changes of insulin resistance as primary endpoint are needed.
doi:10.3205/000143
PMCID: PMC3158650  PMID: 21863134
Insulin resistance; continuous positive airway pressure; obstructive sleep apnea; diabetes mellitus type 2; meta-analysis
12.  Exercise Effects on Depressive Symptoms in Cancer Survivors: A Systematic Review and Meta-Analysis 
Background
Depression is a distressing side effect of cancer and its treatment. In the general population, exercise is an effective antidepressant.
Objective
We conducted a systematic review and meta-analysis to determine the antidepressant effect of exercise in cancer survivors.
Data Sources
In May, 2011, we searched MEDLINE, PsycInfo, EMBASE, CINAHL, CDSR, CENTRAL, AMED, Biosis Previews, and Sport Discus, and citations from relevant papers and reviews.
Study Eligibility Criteria
We included randomized controlled trials (RCTs) comparing exercise interventions to usual care in cancer survivors, utilizing a self-report inventory or clinician rating to assess depressive symptoms, and reporting symptoms pre- and post-intervention.
Study Appraisal
7,042 study titles were identified and screened, with 15 RCTs included.
Synthesis Methods
Effect sizes (ES) were reported as mean change scores. The Q test was conducted to evaluate heterogeneity of ES. Potential moderator variables were evaluated with examination of scatter plots and Wilcoxon rank-sum or Kruskal-Wallis tests.
Results
The overall ES, under a random effects model, was −0.22 (CI −0.43, −0.09, p = 0.04). Significant moderating variables (ps < .05) were exercise location, exercise supervision, and exercise duration.
Limitations
Only one study identified depression as the primary endpoint.
Conclusions
Exercise has modest positive effects on depressive symptoms with larger effects for programs that were supervised or partially supervised, not performed at home, and at least 30 minutes in duration.
Impact
Our results complement other studies showing that exercise is associated with reduced pain and fatigue and with improvements in quality of life among cancer survivors.
doi:10.1158/1055-9965.EPI-11-0634
PMCID: PMC3253916  PMID: 22068286
physical activity; mental health; cancer survivorship
13.  Physical Activity during Cancer Treatment (PACT) Study: design of a randomised clinical trial 
BMC Cancer  2010;10:272.
Background
Fatigue is a major problem of cancer patients. Thirty percent of cancer survivors report serious fatigue three years after finishing treatment. There is evidence that physical exercise during cancer treatment reduces fatigue. This may also lead to an improvement of quality of life. Such findings may result in a decrease of healthcare related expenditures and societal costs due to sick leave. However, no studies are known that investigated these hypotheses. Therefore, the primary aim of our study is to assess the effect of exercise during cancer treatment on reducing complaints of fatigue and on reducing health service utilisation and sick leave.
Methods/Design
The Physical Activity during Cancer Treatment study is a multicentre randomised controlled trial in 150 breast and 150 colon cancer patients undergoing cancer treatment. Participants will be randomised to an exercise or a control group. In addition to the usual care, the exercise group will participate in an 18-week supervised group exercise programme. The control group will be asked to maintain their habitual physical activity pattern. Study endpoints will be assessed after 18 weeks (short term) and after 9 months (long term). Validated questionnaires will be used. Primary outcome: fatigue (Multidimensional Fatigue Inventory and Fatigue Quality List) and cost-effectiveness, health service utilisation and sick leave. Secondary outcome: health related quality of life (European Organisation Research and Treatment of Cancer-Quality of Life questionnaire-C30, Short Form 36 healthy survey), impact on functioning and autonomy (Impact on functioning and autonomy questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), physical fitness (aerobic peak capacity, muscle strength), body composition and cognitive-behavioural aspects. To register health service utilisation and sick leave, participants will keep diaries including the EuroQuol-5D. Physical activity level will be measured using the Short Questionnaire to Assess Health-Enhancing Physical Activity and will be monitored with an exercise log and a pedometer.
Discussion
This study investigates the (cost)-effectiveness of exercise during adjuvant treatment of patients with breast or colon cancer. If early physical exercise proves to be (cost) effective, establishing standardised physical exercise programmes during cancer treatment will be planned.
Trial registration
Current Controlled trials ISRCTN43801571, Dutch Trial Register NTR2138
doi:10.1186/1471-2407-10-272
PMCID: PMC2927992  PMID: 20534147
14.  Physical interventions to interrupt or reduce the spread of respiratory viruses: systematic review 
BMJ : British Medical Journal  2007;336(7635):77-80.
Objective To systematically review evidence for the effectiveness of physical interventions to interrupt or reduce the spread of respiratory viruses.
Data extraction Search strategy of the Cochrane Library, Medline, OldMedline, Embase, and CINAHL, without language restriction, for any intervention to prevent transmission of respiratory viruses (isolation, quarantine, social distancing, barriers, personal protection, and hygiene). Study designs were randomised trials, cohort studies, case-control studies, and controlled before and after studies.
Data synthesis Of 2300 titles scanned 138 full papers were retrieved, including 49 papers of 51 studies. Study quality was poor for the three randomised controlled trials and most of the cluster randomised controlled trials; the observational studies were of mixed quality. Heterogeneity precluded meta-analysis of most data except that from six case-control studies. The highest quality cluster randomised trials suggest that the spread of respiratory viruses into the community can be prevented by intervening with hygienic measures aimed at younger children. Meta-analysis of six case-control studies suggests that physical measures are highly effective in preventing the spread of SARS: handwashing more than 10 times daily (odds ratio 0.45, 95% confidence interval 0.36 to 0.57; number needed to treat=4, 95% confidence interval 3.65 to 5.52); wearing masks (0.32, 0.25 to 0.40; NNT=6, 4.54 to 8.03); wearing N95 masks (0.09, 0.03 to 0.30; NNT=3, 2.37 to 4.06); wearing gloves (0.43, 0.29 to 0.65; NNT=5, 4.15 to 15.41); wearing gowns (0.23, 0.14 to 0.37; NNT=5, 3.37 to 7.12); and handwashing, masks, gloves, and gowns combined (0.09, 0.02 to 0.35; NNT=3, 2.66 to 4.97). The incremental effect of adding virucidals or antiseptics to normal handwashing to decrease the spread of respiratory disease remains uncertain. The lack of proper evaluation of global measures such as screening at entry ports and social distancing prevent firm conclusions being drawn.
Conclusion Routine long term implementation of some physical measures to interrupt or reduce the spread of respiratory viruses might be difficult but many simple and low cost interventions could be useful in reducing the spread.
doi:10.1136/bmj.39393.510347.BE
PMCID: PMC2190272  PMID: 18042961
15.  Randomised controlled trial of a supervised exercise rehabilitation program for colorectal cancer survivors immediately after chemotherapy: study protocol 
BMC Cancer  2007;7:154.
Background
Colorectal cancer (CRC) diagnosis and the ensuing treatments can have a substantial impact on the physical and psychological health of survivors. As the number of CRC survivors increases, so too does the need to develop viable rehabilitation programs to help these survivors return to good health as quickly as possible. Exercise has the potential to address many of the adverse effects of CRC treatment; however, to date, the role of exercise in the rehabilitation of cancer patients immediately after the completion of treatment has received limited research attention. This paper presents the design of a randomised controlled trial which will evaluate the feasibility and efficacy of a 12-week supervised aerobic exercise program (ImPACT Program) on the physiological and psychological markers of rehabilitation, in addition to biomarkers of standard haematological outcomes and the IGF axis.
Methods/Design
Forty CRC patients will be recruited through oncology clinics and randomised to an exercise group or a usual care control group. Baseline assessment will take place within 4 weeks of the patient completing adjuvant chemotherapy treatment. The exercise program for patients in the intervention group will commence a week after the baseline assessment. The program consists of three supervised moderate-intensity aerobic exercise sessions per week for 12 weeks. All participants will have assessments at baseline (0 wks), mid-intervention (6 wks), post-intervention (12 wks) and at a 6-week follow-up (18 wks). Outcome measures include cardio-respiratory fitness, biomarkers associated with health and survival, and indices of fatigue and quality of life. Process measures are participants' acceptability of, adherence to, and compliance with the exercise program, in addition to the safety of the program.
Discussion
The results of this study will provide valuable insight into the role of supervised exercise in improving life after CRC. Additionally, process analyses will inform the feasibility of implementing the program in a population of CRC patients immediately after completing chemotherapy.
Trial registration
ACTRN012606000395538
doi:10.1186/1471-2407-7-154
PMCID: PMC1973083  PMID: 17686184
16.  Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data 
Objective To determine the clinical effectiveness of real time continuous glucose monitoring compared with self monitoring of blood glucose in type 1 diabetes.
Design Meta-analysis of randomised controlled trials.
Data sources Cochrane database for randomised controlled trials, Ovid Medline, Embase, Google Scholar, lists of papers supplied by manufacturers of continuous glucose monitors, and cited literature in retrieved articles.
Studies reviewed Randomised controlled trials of two or more months’ duration in men and non-pregnant women with type 1 diabetes that compared real time continuous glucose monitoring with self monitoring of blood glucose and where insulin delivery was the same in both arms.
Analysis Two step meta-analysis of individual patient data with the primary outcome of final glycated haemoglobin (HbA1c) percentage and area under the curve of hypoglycaemia (glucose concentration <3.9 mmol/L) during either treatment, followed by one step metaregression exploring patient level determinants of HbA1c and hypoglycaemia.
Results Six trials were identified, consisting of 449 patients randomised to continuous glucose monitoring and 443 to self monitoring of blood glucose. The overall mean difference in HbA1c for continuous glucose monitoring versus self monitoring of blood glucose was −0.30% (95% confidence interval −0.43% to −0.17%) (−3.0, −4.3 to −1.7 mmol/mol). A best fit regression model of determinants of final HbA1c showed that for every one day increase of sensor usage per week the effect of continuous glucose monitoring versus self monitoring of blood glucose increased by 0.150% (95% credibility interval −0.194% to −0.106%) (1.5, −1.9 to −1.1 mmol/mol) and every 1% (10 mmol/mol) increase in baseline HbA1c increased the effect by 0.126% (−0.257% to 0.0007%) (1.3, −2.6 to 0.0 mmol/mol). The model estimates that, for example, a patient using the sensor continuously would experience a reduction in HbA1c of about 0.9% (9 mmol/mol) when the baseline HbA1c is 10% (86 mmol/mol). The overall reduction in area under the curve of hypoglycaemia was −0.28 (−0.46 to −0.09), corresponding to a reduction in median exposure to hypoglycaemia of 23% for continuous glucose monitoring compared with self monitoring of blood glucose. In a best fit regression model, baseline area under the curve of hypoglycaemia was only weakly related to the effect of continuous glucose monitoring compared with self monitoring of blood glucose on hypoglycaemia outcome, and sensor usage was unrelated to hypoglycaemia at outcome.
Conclusions Continuous glucose monitoring was associated with a significant reduction in HbA1c percentage, which was greatest in those with the highest HbA1c at baseline and who most frequently used the sensors. Exposure to hypoglycaemia was also reduced during continuous glucose monitoring. The most cost effective or appropriate use of continuous glucose monitoring is likely to be when targeted at people with type 1 diabetes who have continued poor control during intensified insulin therapy and who frequently use continuous glucose monitoring.
doi:10.1136/bmj.d3805
PMCID: PMC3131116  PMID: 21737469
17.  Satisfaction of the uncertainty principle in cancer clinical trials: retrospective cohort analysis 
BMJ : British Medical Journal  2004;328(7454):1463.
Objective To assess whether publicly funded adult cancer trials satisfy the uncertainty principle, which states that physicians should enrol a patient in a trial only if they are substantially uncertain which of the treatments in the trial is most appropriate for the patient. This principle is violated if trials systematically favour either the experimental or the standard treatment.
Design Retrospective cohort study of completed cancer trials, with randomisation as the unit of analysis.
Setting Two cooperative research groups in the United States.
Studies included 93 phase III randomised trials (103 randomisations) that completed recruitment of patients between 1981 and 1995.
Main outcome measures Whether the randomisation favoured the experimental treatment, the standard treatment, or neither treatment; effect size (outcome of the experimental treatment compared with outcome of the standard treatment) for each randomisation.
Results Three randomisations (3%) favoured the standard treatment, 70 (68%) found no significant difference between treatments, and 30 (29%) favoured the experimental treatment. The average effect size was 1.20 (95% confidence interval 1.13 to 1.28), reflecting a slight advantage for the experimental treatment.
Conclusions In cooperative group trials in adults with cancer, there is a measurable average improvement in disease control associated with assignment to the experimental rather than the standard arm. However, the heterogeneity of outcomes and the small magnitude of the advantage suggest that, as a group, these trials satisfy the uncertainty principle.
doi:10.1136/bmj.38118.685289.55
PMCID: PMC428513  PMID: 15163611
18.  Obtaining data from randomised controlled trials: how much do we need for reliable and informative meta-analyses? 
BMJ : British Medical Journal  1994;309(6960):1007-1010.
Many randomised controlled trials compare treatments that will produce only moderate differences in outcome, but these differences can be clinically important. However, they are difficult to assess reliably and require a large amount of randomised evidence. This can be achieved through large prospective randomised trials which will accrue future patients, the meta-analysis of results from randomised trials involving patients from the past, or--ideally--both. The techniques require that all possible biases are minimised, and in meta-analyses this can best be achieved by ensuring that all of the randomised evidence--both trials and participants in those trials--is included. The meta-analysis of individual patient data has been described as the gold standard for this approach. It will remove many of the problems associated with relying solely on published data and some of the problems arising from a reliance on aggregate data, and will also add to the analyses that can be performed. Such projects, however, require considerable time and effort.
PMCID: PMC2541306  PMID: 7950694
19.  Should Finasteride Be Routinely Given Preoperatively for TURP? 
ISRN Urology  2013;2013:458353.
Objective. The aim of the review was to compare the use of finasteride to placebo in patients undergoing TURP procedures. Material & Methods. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966–November 2011), EMBASE (1980–November 2011), CINAHL, Clinicaltrials.gov, Google Scholar, reference lists of articles, and abstracts from conference proceedings without language restriction for studies comparing finasteride to placebo patients needing TURPs. Results. Four randomised controlled trials were included comparing finasteride to a placebo. A meta-analysis was not conducted due to the disparity present in the results between the studies. Three of the studies found that finasteride could reduce either intra- or postoperative bleeding after TURP. One study found finasteride to significantly lower the microvessel density (MVD) and vascular endothelial growth factor (VEGF). None of the studies reported any long-term complications related to either the medication or the procedure. Conclusion. finasteride reduces bleeding either during or after TURP.
doi:10.1155/2013/458353
PMCID: PMC3747465  PMID: 23984104
20.  Effect of running therapy on depression (EFFORT-D). Design of a randomised controlled trial in adult patients [ISRCTN 1894] 
BMC Public Health  2012;12:50.
Background
The societal and personal burden of depressive illness is considerable. Despite the developments in treatment strategies, the effectiveness of both medication and psychotherapy is not ideal. Physical activity, including exercise, is a relatively cheap and non-harmful lifestyle intervention which lacks the side-effects of medication and does not require the introspective ability necessary for most psychotherapies. Several cohort studies and randomised controlled trials (RCTs) have been performed to establish the effect of physical activity on prevention and remission of depressive illness. However, recent meta-analysis's of all RCTs in this area showed conflicting results. The objective of the present article is to describe the design of a RCT examining the effect of exercise on depressive patients.
Methods/Design
The EFFect Of Running Therapy on Depression in adults (EFFORT-D) is a RCT, studying the effectiveness of exercise therapy (running therapy (RT) or Nordic walking (NW)) on depression in adults, in addition to usual care. The study population consists of patients with depressive disorder, Hamilton Rating Scale for Depression (HRSD) ≥ 14, recruited from specialised mental health care. The experimental group receives the exercise intervention besides treatment as usual, the control group receives treatment as usual. The intervention program is a group-based, 1 h session, two times a week for 6 months and of increasing intensity. The control group only performs low intensive non-aerobic exercises. Measurements are performed at inclusion and at 3,6 and 12 months.
Primary outcome measure is reduction in depressive symptoms measured by the HRSD. Cardio-respiratory fitness is measured using a sub maximal cycling test, biometric information is gathered and blood samples are collected for metabolic parameters. Also, co-morbidity with pain, anxiety and personality traits is studied, as well as quality of life and cost-effectiveness.
Discussion
Exercise in depression can be used as a standalone or as an add-on intervention. In specialised mental health care, chronic forms of depression, co-morbid anxiety or physical complaints and treatment resistance are common. An add-on strategy therefore seems the best choice. This is the first high quality large trial into the effectiveness of exercise as an add-on treatment for depression in adult patients in specialised mental health care.
Trial registration
Netherlands Trial Register (NTR): NTR1894
doi:10.1186/1471-2458-12-50
PMCID: PMC3299590  PMID: 22260713
21.  Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: comprehensive network meta-analysis 
Objectives To investigate the safety and efficacy of durable polymer drug eluting stents (DES) and biodegradable polymer biolimus eluting stents (biolimus-ES).
Design Network meta-analysis of randomised controlled trials.
Data sources and study selection Medline, Google Scholar, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) database search for randomised controlled trials comparing at least two of durable polymer sirolimus eluting stents (sirolimus-ES) and paclitaxel eluting stents (paclitaxel-ES), newer durable polymer everolimus eluting stents (everolimus-ES), Endeavor and Resolute zotarolimus eluting stents (zotarolimus-ES), and biodegradable polymer biolimus-ES.
Primary outcomes Safety (death, myocardial infarction, definite or probable stent thrombosis) and efficacy (target lesion and target vessel revascularisation) assessed at up to one year and beyond.
Results 60 randomised controlled trials were compared involving 63 242 patients with stable coronary artery disease or acute coronary syndrome treated with a DES. At one year, there were no differences in mortality among devices. Resolute and Endeavor zotarolimus-ES, everolimus-ES, and sirolimus-ES, but not biodegradable polymer biolimus-ES, were associated with significantly reduced odds of myocardial infarction (by 29-34%) compared with paclitaxel-ES. Compared with everolimus-ES, biodegradable polymer biolimus-ES were associated with significantly increased odds of myocardial infarction (by 29%), while Endeavor zotarolimus-ES and paclitaxel-ES were associated with significantly increased odds of stent thrombosis. All investigated DES were similar with regards to efficacy endpoints, except for Endeavor zotarolimus-ES and paclitaxel-ES, which were associated with significantly increased the odds of target lesion and target vessel revascularisations compared with other devices. Direction of results beyond one year did not diverge from the findings for up to one year follow-up. Bayesian probability curves showed a gradient in the magnitude of effect, with everolimus-ES and Resolute zotarolimus-ES offering the highest safety profiles.
Conclusions The newer durable polymer everolimus-ES and Resolute zotarolimus-ES and the biodegradable polymer biolimus-ES maintain the efficacy of sirolimus-ES; however, for safety endpoints, differences become apparent, with everolimus-ES and Resolute zotarolimus-ES emerging as the safest stents to date.
doi:10.1136/bmj.f6530
PMCID: PMC3819044  PMID: 24196498
22.  Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis 
Objective To determine whether there is sufficient evidence to conclude that exercise interventions are more effective than no exercise control and to compare the effectiveness of different exercise interventions in relieving pain and improving function in patients with lower limb osteoarthritis.
Data sources Nine electronic databases searched from inception to March 2012.
Study selection Randomised controlled trials comparing exercise interventions with each other or with no exercise control for adults with knee or hip osteoarthritis.
Data extraction Two reviewers evaluated eligibility and methodological quality. Main outcomes extracted were pain intensity and limitation of function. Trial sequential analysis was used to investigate reliability and conclusiveness of available evidence for exercise interventions. Bayesian network meta-analysis was used to combine both direct (within trial) and indirect (between trial) evidence on treatment effectiveness.
Results 60 trials (44 knee, two hip, 14 mixed) covering 12 exercise interventions and with 8218 patients met inclusion criteria. Sequential analysis showed that as of 2002 sufficient evidence had been accrued to show significant benefit of exercise interventions over no exercise control. For pain relief, strengthening, flexibility plus strengthening, flexibility plus strengthening plus aerobic, aquatic strengthening, and aquatic strengthening plus flexibility, exercises were significantly more effective than no exercise control. A combined intervention of strengthening, flexibility, and aerobic exercise was also significantly more effective than no exercise control for improving limitation in function (standardised mean difference −0.63, 95% credible interval −1.16 to −0.10).
Conclusions As of 2002 sufficient evidence had accumulated to show significant benefit of exercise over no exercise in patients with osteoarthritis, and further trials are unlikely to overturn this result. An approach combining exercises to increase strength, flexibility, and aerobic capacity is likely to be most effective in the management of lower limb osteoarthritis. The evidence is largely from trials in patients with knee osteoarthritis.
Protocol registration PROSPERO (www.crd.york.ac.uk/prospero/) No CRD42012002267.
doi:10.1136/bmj.f5555
PMCID: PMC3779121  PMID: 24055922
23.  The effects of excluding patients from the analysis in randomised controlled trials: meta-epidemiological study 
Objective To examine whether excluding patients from the analysis of randomised trials are associated with biased estimates of treatment effects and higher heterogeneity between trials.
Design Meta-epidemiological study based on a collection of meta-analyses of randomised trials.
Data sources 14 meta-analyses including 167 trials that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patient reported pain as an outcome.
Methods Effect sizes were calculated from differences in means of pain intensity between groups at the end of follow-up, divided by the pooled standard deviation. Trials were combined by using random effects meta-analysis. Estimates of treatment effects were compared between trials with and trials without exclusions from the analysis, and the impact of restricting meta-analyses to trials without exclusions was assessed.
Results 39 trials (23%) had included all patients in the analysis. In 128 trials (77%) some patients were excluded from the analysis. Effect sizes from trials with exclusions tended to be more beneficial than those from trials without exclusions (difference −0.13, 95% confidence interval −0.29 to 0.04). However, estimates of bias between individual meta-analyses varied considerably (τ2=0.07). Tests of interaction between exclusions from the analysis and estimates of treatment effects were positive in five meta-analyses. Stratified analyses indicated that differences in effect sizes between trials with and trials without exclusions were more pronounced in meta-analyses with high between trial heterogeneity, in meta-analyses with large estimated treatment benefits, and in meta-analyses of complementary medicine. Restriction of meta-analyses to trials without exclusions resulted in smaller estimated treatment benefits, larger P values, and considerable decreases in between trial heterogeneity.
Conclusion Excluding patients from the analysis in randomised trials often results in biased estimates of treatment effects, but the extent and direction of bias is unpredictable. Results from intention to treat analyses should always be described in reports of randomised trials. In systematic reviews, the influence of exclusions from the analysis on estimated treatment effects should routinely be assessed.
doi:10.1136/bmj.b3244
PMCID: PMC2739282  PMID: 19736281
24.  Acupuncture and other physical treatments for the relief of pain due to osteoarthritis of the knee: network meta-analysis☆ 
Osteoarthritis and Cartilage  2013;21(9):1290-1298.
Summary
Objective
To compare the effectiveness of acupuncture with other relevant physical treatments for alleviating pain due to knee osteoarthritis.
Design
Systematic review with network meta-analysis, to allow comparison of treatments within a coherent framework. Comprehensive searches were undertaken up to January 2013 to identify randomised controlled trials in patients with osteoarthritis of the knee, which reported pain.
Results
Of 156 eligible studies, 114 trials (covering 22 treatments and 9,709 patients) provided data suitable for analysis. Most trials studied short-term effects and many were classed as being of poor quality with high risk of bias, commonly associated with lack of blinding (which was sometimes impossible to achieve). End of treatment results showed that eight interventions: interferential therapy, acupuncture, TENS, pulsed electrical stimulation, balneotherapy, aerobic exercise, sham acupuncture, and muscle-strengthening exercise produced a statistically significant reduction in pain when compared with standard care. In a sensitivity analysis of satisfactory and good quality studies, most studies were of acupuncture (11 trials) or muscle-strengthening exercise (9 trials); both interventions were statistically significantly better than standard care, with acupuncture being statistically significantly better than muscle-strengthening exercise (standardised mean difference: 0.49, 95% credible interval 0.00–0.98).
Conclusions
As a summary of the current available research, the network meta-analysis results indicate that acupuncture can be considered as one of the more effective physical treatments for alleviating osteoarthritis knee pain in the short-term. However, much of the evidence in this area of research is of poor quality, meaning there is uncertainty about the efficacy of many physical treatments.
doi:10.1016/j.joca.2013.05.007
PMCID: PMC3769860  PMID: 23973143
Osteoarthritis; Knee; Pain; Physical treatments; Network meta-analysis
25.  Effectiveness of antibiotic prophylaxis in critically ill adult patients: systematic review of randomised controlled trials 
BMJ : British Medical Journal  1998;316(7140):1275-1285.
Objective: To determine whether antibiotic prophylaxis reduces respiratory tract infections and overall mortality in unselected critically ill adult patients.
Design: Meta-analysis of randomised controlled trials from 1984 and 1996 that compared different forms of antibiotic prophylaxis used to reduce respiratory tract infections and mortality with aggregate data and, in a subset of trials, data from individual patients.
Subjects: Unselected critically ill adult patients; 5727 patients for aggregate data meta-analysis, 4343 for confirmatory meta-analysis with data from individual patients.
Main outcome measures: Respiratory tract infections and total mortality.
Results: Two categories of eligible trials were defined: topical plus systemic antibiotics versus no treatment and topical preparation with or without a systemic antibiotic versus a systemic agent or placebo. Estimates from aggregate data meta-analysis of 16 trials (3361 patients) that tested combined treatment indicated a strong significant reduction in infection (odds ratio 0.35; 95% confidence interval 0.29 to 0.41) and total mortality (0.80; 0.69 to 0.93). With this treatment five and 23 patients would need to be treated to prevent one infection and one death, respectively. Similar analysis of 17 trials (2366 patients) that tested only topical antibiotics indicated a clear reduction in infection (0.56; 0.46 to 0.68) without a significant effect on total mortality (1.01; 0.84 to 1.22). Analysis of data from individual patients yielded similar results. No significant differences in treatment effect by major subgroups of patients emerged from the analyses.
Conclusions: This meta-analysis of 15 years of clinical research suggests that antibiotic prophylaxis with a combination of topical and systemic drugs can reduce respiratory tract infections and overall mortality in critically ill patients. This effect is significant and worth while, and it should be considered when practice guidelines are defined.
Key messages Over 40% of patients who need ventilation in intensive care develop respiratory tract infections and about 30% may die in the units If the most effective antibiotic prophylaxis (that is, a protocol combining topical and systemic antibiotics) is used the incidence of respiratory tract infections can be reduced by 65% and total mortality by 20% A regimen of topical antibiotics alone reduces respiratory tract infections but does not influence survival The concern that widespread antibiotic use may lead to resistance cannot be confirmed or ruled out by this review. Trials with different design are probably warranted to handle this question This important effect of antibiotic prophylaxis with a combination of topical and systemic antibiotics on survival should be considered by intensivists when treatment policies are designed
PMCID: PMC28528  PMID: 9554897

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