Showing papers in "Cochrane Database of Systematic Reviews in 2014"

Pharmacological interventions for somatoform disorders in adults.

Abstract: BACKGROUND: Somatoform disorders are characterised by chronic, medically unexplained physical symptoms (MUPS). Although different medications are part of treatment routines for people with somatoform disorders in clinics and private practices, there exists no systematic review or meta-analysis on the efficacy and tolerability of these medications. We aimed to synthesise to improve optimal treatment decisions.OBJECTIVES: To assess the effects of pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, and pain disorder) in adults.SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 17 January 2014). This register includes relevant randomised controlled trials (RCTs) from The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). To identify ongoing trials, we searched ClinicalTrials.gov, Current Controlled Trials metaRegister, the World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry. For grey literature, we searched ProQuest Dissertation {\&} Theses Database, OpenGrey, and BIOSIS Previews. We handsearched conference proceedings and reference lists of potentially relevant papers and systematic reviews and contacted experts in the field.SELECTION CRITERIA: We selected RCTs or cluster RCTs of pharmacological interventions versus placebo, treatment as usual, another medication, or a combination of different medications for somatoform disorders in adults. We included people fulfilling standardised diagnostic criteria for somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, or somatoform pain disorder.DATA COLLECTION AND ANALYSIS: One review author and one research assistant independently extracted data and assessed risk of bias. Primary outcomes included the severity of MUPS on a continuous measure, and acceptability of treatment.MAIN RESULTS: We included 26 RCTs (33 reports), with 2159 participants, in the review. They examined the efficacy of different types of antidepressants, the combination of an antidepressant and an antipsychotic, antipsychotics alone, or natural products (NPs). The duration of the studies ranged between two and 12 weeks.One meta-analysis of placebo-controlled studies showed no clear evidence of a significant difference between tricyclic antidepressants (TCAs) and placebo for the outcome severity of MUPS (SMD -0.13; 95{\%} CI -0.39 to 0.13; 2 studies, 239 participants; I(2) = 2{\%}; low-quality evidence). For new-generation antidepressants (NGAs), there was very low-quality evidence showing they were effective in reducing the severity of MUPS (SMD -0.91; 95{\%} CI -1.36 to -0.46; 3 studies, 243 participants; I(2) = 63{\%}). For NPs there was low-quality evidence that they were effective in reducing the severity of MUPS (SMD -0.74; 95{\%} CI -0.97 to -0.51; 2 studies, 322 participants; I(2) = 0{\%}).One meta-analysis showed no clear evidence of a difference between TCAs and NGAs for severity of MUPS (SMD -0.16; 95{\%} CI -0.55 to 0.23; 3 studies, 177 participants; I(2) = 42{\%}; low-quality evidence). There was also no difference between NGAs and other NGAs for severity of MUPS (SMD -0.16; 95{\%} CI -0.45 to 0.14; 4 studies, 182 participants; I(2) = 0{\%}).Finally, one meta-analysis comparing selective serotonin reuptake inhibitors (SSRIs) with a combination of SSRIs and antipsychotics showed low-quality evidence in favour of combined treatment for severity of MUPS (SMD 0.77; 95{\%} CI 0.32 to 1.22; 2 studies, 107 participants; I(2) = 23{\%}).Differences regarding the acceptability of the treatment (rate of all-cause drop-outs) were neither found between NGAs and placebo (RR 1.01, 95{\%} CI 0.64 to 1.61; 2 studies, 163 participants; I(2) = 0{\%}; low-quality evidence) or NPs and placebo (RR 0.85, 95{\%} CI 0.40 to 1.78; 3 studies, 506 participants; I(2) = 0{\%}; low-quality evidence); nor between TCAs and other medication (RR 1.48, 95{\%} CI 0.59 to 3.72; 8 studies, 556 participants; I(2) =14{\%}; low-quality evidence); nor between antidepressants and the combination of an antidepressant and an antipsychotic (RR 0.80, 95{\%} CI 0.25 to 2.52; 2 studies, 118 participants; I(2) = 0{\%}; low-quality evidence). Percental attrition rates due to adverse effects were high in all antidepressant treatments (0{\%} to 32{\%}), but low for NPs (0{\%} to 1.7{\%}).The risk of bias was high in many domains across studies. Seventeen trials (65.4{\%}) gave no information about random sequence generation and only two (7.7{\%}) provided information about allocation concealment. Eighteen studies (69.2{\%}) revealed a high or unclear risk in blinding participants and study personnel; 23 studies had high risk of bias relating to blinding assessors. For the comparison NGA versus placebo, there was relatively high imprecision and heterogeneity due to one outlier study. Although we identified 26 studies, each comparison only contained a few studies and small numbers of participants so the results were imprecise.AUTHORS' CONCLUSIONS: The current review found very low-quality evidence for NGAs and low-quality evidence for NPs being effective in treating somatoform symptoms in adults when compared with placebo. There was some evidence that different classes of antidepressants did not differ in efficacy; however, this was limited and of low to very low quality. These results had serious shortcomings such as the high risk of bias, strong heterogeneity in the data, and small sample sizes. Furthermore, the significant effects of antidepressant treatment have to be balanced against the relatively high rates of adverse effects. Adverse effects produced by medication can have amplifying effects on symptom perceptions, particularly in people focusing on somatic symptoms without medical causes. We can only draw conclusions about short-term efficacy of the pharmacological interventions because no trial included follow-up assessments. For each of the comparisons where there were available data on acceptability rates (NGAs versus placebo, NPs versus placebo, TCAs versus other medication, and antidepressants versus a combination of an antidepressant and an antipsychotic), no clear differences between the intervention and comparator were found.Future high-quality research should be carried out to determine the effectiveness of medications other than antidepressants, to compare antidepressants more thoroughly, and to follow-up participants over longer periods (the longest follow up was just 12 weeks). Another idea for future research would be to include other outcomes such as functional impairment or dysfunctional behaviours and cognitions as well as the classical outcomes such as symptom severity, depression, or anxiety.

Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence

Abstract: Methadone is widely used as a replacement for illicit opioid use such as heroin in medically-supported opioid substitution maintenance programmes. Two other drugs have been used to help reduce illicit opioid use, specifically buprenorphine and LAAM (levo-alpha-acetylmethadol). LAAM is not used in current clinical practice. Buprenorphine is currently used and can reduce illicit opioid use compared with placebo, although it is less effective than methadone. Buprenorphine is an opioid drug that is not as potent as heroin and methadone, although the effects of buprenorphine may last longer. Buprenorphine can be taken once every two days. The trials include different formulations of buprenorphine: sublingual solution, sublingual tablets, combined buprenorphine/naloxone sublingual tablet and an implant. Key results The review of trials found that buprenorphine at high doses (16 mg) can reduce illicit opioid use effectively compared with placebo, and buprenorphine at any dose studied retains people in treatment better than placebo. Buprenorphine appears to be less effective than methadone in retaining people in treatment, if prescribed in a flexible dose regimen or at a fixed and low dose (2 - 6 mg per day). Buprenorphine prescribed at fixed doses (above 7 mg per day) was not different from methadone prescribed at fixed doses (40 mg or more per day) in retaining people in treatment or in suppression of illicit opioid use.

Surgery for weight loss in adults

Abstract: Background: bariatric (weight loss) surgery for obesity is considered when other treatments have failed. The effects of the available bariatric procedures compared with medical management and with each other are uncertain. This is an update of a Cochrane review first published in 2003 and most recently updated in 2009. Objectives: to assess the effects of bariatric surgery for overweight and obesity, including the control of comorbidities. Search methods: studies were obtained from searches of numerous databases, supplemented with searches of reference lists and consultation with experts in obesity research. Date of last search was November 2013. Selection criteria: randomised controlled trials (RCTs) comparing surgical interventions with non-surgical management of obesity or overweight or comparing different surgical procedures. Data collection and analysis: data were extracted by one review author and checked by a second review author. Two review authors independently assessed risk of bias and evaluated overall study quality utilising the GRADE instrument. Main results: twenty-two trials with 1798 participants were included; sample sizes ranged from 15 to 250. Most studies followed participants for 12, 24 or 36 months; the longest follow-up was 10 years. The risk of bias across all domains of most trials was uncertain; just one was judged to have adequate allocation concealment. All seven RCTs comparing surgery with non-surgical interventions found benefits of surgery on measures of weight change at one to two years follow-up. Improvements for some aspects of health-related quality of life (QoL) (two RCTs) and diabetes (five RCTs) were also found. The overall quality of the evidence was moderate. Five studies reported data on mortality, no deaths occurred. Serious adverse events (SAEs) were reported in four studies and ranged from 0% to 37% in the surgery groups and 0% to 25% in the no surgery groups. Between 2% and 13% of participants required reoperations in the five studies that reported these data. Three RCTs found that laparoscopic Roux-en-Y gastric bypass (L)(RYGB) achieved significantly greater weight loss and body mass index (BMI) reduction up to five years after surgery compared with laparoscopic adjustable gastric banding (LAGB). Mean end-of-study BMI was lower following LRYGB compared with LAGB: mean difference (MD) -5.2 kg/m² (95% confidence interval (CI) -6.4 to -4.0; P Open RYGB, LRYGB and laparoscopic sleeve gastrectomy (LSG) led to losses of weight and/or BMI but there was no consistent picture as to which procedure was better or worse in the seven included trials. MD was -0.2 kg/m² (95% CI -1.8 to 1.3); 353 participants; 6 trials; low quality evidence) in favour of LRYGB. No statistically significant differences in QoL were found (one RCT). Six RCTs reported mortality; one death occurred following LRYGB. SAEs were reported by one RCT and were higher in the LRYGB group (4.5%) than the LSG group (0.9%). Reoperations ranged from 6.7% to 24% in the LRYGB group and 3.3% to 34% in the LSG group. Effects on comorbidities, complications and additional surgical procedures were neutral, except gastro-oesophageal reflux disease improved following LRYGB (one RCT). One RCT of people with a BMI 25 to 35 and type 2 diabetes found laparoscopic mini-gastric bypass resulted in greater weight loss and improvement of diabetes compared with LSG, and had similar levels of complications. Two RCTs found that biliopancreatic diversion with duodenal switch (BDDS) resulted in greater weight loss than RYGB in morbidly obese patients. End-of-study mean BMI loss was greater following BDDS: MD -7.3 kg/m² (95% CI -9.3 to -5.4); P One RCT comparing laparoscopic duodenojejunal bypass with sleeve gastrectomy versus LRYGB found BMI, excess weight loss, and rates of remission of diabetes and hypertension were similar at 12 months follow-up (very low quality evidence). QoL, SAEs and reoperation rates were not reported. No deaths occurred in either group. One RCT comparing laparoscopic isolated sleeve gastrectomy (LISG) versus LAGB found greater improvement in weight-loss outcomes following LISG at three years follow-up (very low quality evidence). QoL, mortality and SAEs were not reported. Reoperations occurred in 20% of the LAGB group and in 10% of the LISG group. One RCT (unpublished) comparing laparoscopic gastric imbrication with LSG found no statistically significant difference in weight loss between groups (very low quality evidence). QoL and comorbidities were not reported. No deaths occurred. Two participants in the gastric imbrication group required reoperation. Authors' conclusions: surgery results in greater improvement in weight loss outcomes and weight associated comorbidities compared with non-surgical interventions, regardless of the type of procedures used. When compared with each other, certain procedures resulted in greater weight loss and improvements in comorbidities than others. Outcomes were similar between RYGB and sleeve gastrectomy, and both of these procedures had better outcomes than adjustable gastric banding. For people with very high BMI, biliopancreatic diversion with duodenal switch resulted in greater weight loss than RYGB. Duodenojejunal bypass with sleeve gastrectomy and laparoscopic RYGB had similar outcomes, however this is based on one small trial. Isolated sleeve gastrectomy led to better weight-loss outcomes than adjustable gastric banding after three years follow-up. This was based on one trial only. Weight-related outcomes were similar between laparoscopic gastric imbrication and laparoscopic sleeve gastrectomy in one trial. Across all studies adverse event rates and reoperation rates were generally poorly reported. Most trials followed participants for only one or two years, therefore the long-term effects of surgery remain unclear.

Antidepressants for smoking cessation

Abstract: © 2014 The Cochrane Collaboration. Background: There are at least three reasons to believe antidepressants might help in smoking cessation. Firstly, nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode and antidepressants may relieve these. Secondly, nicotine may have antidepressant effects that maintain smoking, and antidepressants may substitute for this effect. Finally, some antidepressants may have a specific effect on neural pathways (e.g. inhibiting monoamine oxidase) or receptors (e.g. blockade of nicotinic-cholinergic receptors) underlying nicotine addiction. Objectives: The aim of this review is to assess the effect and safety of antidepressant medications to aid long-term smoking cessation. The medications include bupropion; doxepin; fluoxetine; imipramine; lazabemide; moclobemide; nortriptyline; paroxetine; S-Adenosyl-L-Methionine (SAMe); selegiline; sertraline; St. John's wort; tryptophan; venlafaxine; and zimeledine. Search methods: We searched the Cochrane Tobacco Addiction Group Specialised Register which includes reports of trials indexed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and PsycINFO, and other reviews and meeting abstracts, in July 2013. Selection criteria: We considered randomized trials comparing antidepressant medications to placebo or an alternative pharmacotherapy for smoking cessation. We also included trials comparing different doses, using pharmacotherapy to prevent relapse or re-initiate smoking cessation or to help smokers reduce cigarette consumption. We excluded trials with less than six months follow-up. Data collection and analysis: We extracted data and assessed risk of bias using standard methodological procedures expected by the Cochrane Collaboration. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline, expressed as a risk ratio (RR). We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed-effect model. Main results: Twenty-four new trials were identified since the 2009 update, bringing the total number of included trials to 90. There were 65 trials of bupropion and ten trials of nortriptyline, with the majority at low or unclear risk of bias. There was high quality evidence that, when used as the sole pharmacotherapy, bupropion significantly increased long-term cessation (44 trials, N = 13,728, risk ratio [RR] 1.62, 95% confidence interval [CI] 1.49 to 1.76). There was moderate quality evidence, limited by a relatively small number of trials and participants, that nortriptyline also significantly increased long-term cessation when used as the sole pharmacotherapy (six trials, N = 975, RR 2.03, 95% CI 1.48 to 2.78). There is insufficient evidence that adding bupropion (12 trials, N = 3487, RR 1.9, 95% CI 0.94 to 1.51) or nortriptyline (4 trials, N = 1644, RR 1.21, 95% CI 0.94 to 1.55) to nicotine replacement therapy (NRT) provides an additional long-term benefit. Based on a limited amount of data from direct comparisons, bupropion and nortriptyline appear to be equally effective and of similar efficacy to NRT (bupropion versus nortriptyline 3 trials, N = 417, RR 1.30, 95% CI 0.93 to 1.82; bupropion versus NRT 8 trials, N = 4096, RR 0.96, 95% CI 0.85 to 1.09; no direct comparisons between nortriptyline and NRT). Pooled results from four trials comparing bupropion to varenicline showed significantly lower quitting with bupropion than with varenicline (N = 1810, RR 0.68, 95% CI 0.56 to 0.83). Meta-analyses did not detect a significant increase in the rate of serious adverse events amongst participants taking bupropion, though the confidence interval only narrowly missed statistical significance (33 trials, N = 9631, RR 1.30, 95% CI 1.00 to 1.69). There is a risk of about 1 in 1000 of seizures associated with bupropion use. Bupropion has been associated with suicide risk, but whether this is causal is unclear. Nortriptyline has the potential for serious side-effects, but none have been seen in the few small trials for smoking cessation. There was no evidence of a significant effect for selective serotonin reuptake inhibitors on their own (RR 0.93, 95% CI 0.71 to 1.22, N = 1594; 2 trials fluoxetine, 1 paroxetine, 1 sertraline) or as an adjunct to NRT (3 trials of fluoxetine, N = 466, RR 0.70, 95% CI 0.64 to 1.82). Significant effects were also not detected for monoamine oxidase inhibitors (RR 1.29, 95% CI 0.93 to 1.79, N = 827; 1 trial moclobemide, 5 selegiline), the atypical antidepressant venlafaxine (1 trial, N = 147, RR 1.22, 95% CI 0.64 to 2.32), the herbal therapy St John's wort (hypericum) (2 trials, N = 261, RR 0.81, 95% CI 0.26 to 2.53), or the dietary supplement SAMe (1 trial, N = 120, RR 0.70, 95% CI 0.24 to 2.07). Authors' conclusions: The antidepressants bupropion and nortriptyline aid long-term smoking cessation. Adverse events with either medication appear to rarely be serious or lead to stopping medication. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressant effect and that they are of similar efficacy to nicotine replacement. Evidence also suggests that bupropion is less effective than varenicline, but further research is needed to confirm this finding. Evidence suggests that neither selective serotonin reuptake inhibitors (e.g. fluoxetine) nor monoamine oxidase inhibitors aid cessation.

Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults.

Abstract: Background Accurate, rapid detection of tuberculosis (TB) and TB drug resistance is critical for improving patient care and decreasing TB transmission. Xpert® MTB/RIF assay is an automated test that can detect both TB and rifampicin resistance, generally within two hours after starting the test, with minimal hands-on technical time. The World Health Organization (WHO) issued initial recommendations on Xpert® MTB/RIF in early 2011. A Cochrane Review on the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB and rifampicin resistance was published January 2013. We performed this updated Cochrane Review as part of a WHO process to develop updated guidelines on the use of the test. Objectives To assess the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB (TB detection), where Xpert® MTB/RIF was used as both an initial test replacing microscopy and an add-on test following a negative smear microscopy result. To assess the diagnostic accuracy of Xpert® MTB/RIF for rifampicin resistance detection, where Xpert® MTB/RIF was used as the initial test replacing culture-based drug susceptibility testing (DST). The populations of interest were adults presumed to have pulmonary, rifampicin-resistant or multidrug-resistant TB (MDR-TB), with or without HIV infection. The settings of interest were intermediate- and peripheral-level laboratories. The latter may be associated with primary health care facilities. Search methods We searched for publications in any language up to 7 February 2013 in the following databases: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; and SCOPUS. We also searched the metaRegister of Controlled Trials (mRCT) and the search portal of the WHO International Clinical Trials Registry Platform to identify ongoing trials. Selection criteria We included randomized controlled trials, cross-sectional studies, and cohort studies using respiratory specimens that allowed for extraction of data evaluating Xpert® MTB/RIF against the reference standard. We excluded gastric fluid specimens. The reference standard for TB was culture and for rifampicin resistance was phenotypic culture-based DST. Data collection and analysis For each study, two review authors independently extracted data using a standardized form. When possible, we extracted data for subgroups by smear and HIV status. We assessed the quality of studies using QUADAS-2 and carried out meta-analyses to estimate pooled sensitivity and specificity of Xpert® MTB/RIF separately for TB detection and rifampicin resistance detection. For TB detection, we performed the majority of analyses using a bivariate random-effects model and compared the sensitivity of Xpert® MTB/RIF and smear microscopy against culture as reference standard. For rifampicin resistance detection, we undertook univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected. Main results We included 27 unique studies (integrating nine new studies) involving 9557 participants. Sixteen studies (59%) were performed in low- or middle-income countries. For all QUADAS-2 domains, most studies were at low risk of bias and low concern regarding applicability. As an initial test replacing smear microscopy, Xpert® MTB/RIF pooled sensitivity was 89% [95% Credible Interval (CrI) 85% to 92%] and pooled specificity 99% (95% CrI 98% to 99%), (22 studies, 8998 participants: 2953 confirmed TB, 6045 non-TB). As an add-on test following a negative smear microscopy result, Xpert®MTB/RIF pooled sensitivity was 67% (95% CrI 60% to 74%) and pooled specificity 99% (95% CrI 98% to 99%; 21 studies, 6950 participants). For smear-positive, culture-positive TB, Xpert® MTB/RIF pooled sensitivity was 98% (95% CrI 97% to 99%; 21 studies, 1936 participants). For people with HIV infection, Xpert® MTB/RIF pooled sensitivity was 79% (95% CrI 70% to 86%; seven studies, 1789 participants), and for people without HIV infection, it was 86% (95% CrI 76% to 92%; seven studies, 1470 participants). Among 180 specimens with nontuberculous mycobacteria (NTM), Xpert® MTB/RIF was positive in only one specimen that grew NTM (14 studies, 2626 participants). Comparison with smear microscopy In comparison with smear microscopy, Xpert® MTB/RIF increased TB detection among culture-confirmed cases by 23% (95% CrI 15% to 32%; 21 studies, 8880 participants). For TB detection, if pooled sensitivity estimates for Xpert® MTB/RIF and smear microscopy are applied to a hypothetical cohort of 1000 patients where 10% of those with symptoms have TB, Xpert® MTB/RIF will diagnose 88 cases and miss 12 cases, whereas sputum microscopy will diagnose 65 cases and miss 35 cases. Rifampicin resistance For rifampicin resistance detection, Xpert® MTB/RIF pooled sensitivity was 95% (95% CrI 90% to 97%; 17 studies, 555 rifampicin resistance positives) and pooled specificity was 98% (95% CrI 97% to 99%; 24 studies, 2411 rifampicin resistance negatives). For rifampicin resistance detection, if the pooled accuracy estimates for Xpert® MTB/RIF are applied to a hypothetical cohort of 1000 individuals where 15% of those with symptoms are rifampicin resistant, Xpert® MTB/RIF would correctly identify 143 individuals as rifampicin resistant and miss eight cases, and correctly identify 833 individuals as rifampicin susceptible and misclassify 17 individuals as resistant. Where 5% of those with symptoms are rifampicin resistant, Xpert® MTB/RIF would correctly identify 48 individuals as rifampicin resistant and miss three cases and correctly identify 931 individuals as rifampicin susceptible and misclassify 19 individuals as resistant. Authors' conclusions In adults thought to have TB, with or without HIV infection, Xpert® MTB/RIF is sensitive and specific. Compared with smear microscopy, Xpert® MTB/RIF substantially increases TB detection among culture-confirmed cases. Xpert® MTB/RIF has higher sensitivity for TB detection in smear-positive than smear-negative patients. Nonetheless, this test may be valuable as an add-on test following smear microscopy in patients previously found to be smear-negative. For rifampicin resistance detection, Xpert® MTB/RIF provides accurate results and can allow rapid initiation of MDR-TB treatment, pending results from conventional culture and DST. The tests are expensive, so current research evaluating the use of Xpert® MTB/RIF in TB programmes in high TB burden settings will help evaluate how this investment may help start treatment promptly and improve outcomes.

Thrombolysis for acute ischaemic stroke

Abstract: Background Most strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred and improve recovery after stroke in some people. Thrombolytic drugs, however, can also cause serious bleeding in the brain, which can be fatal. One drug, recombinant tissue plasminogen activator (rt-PA), is licensed for use in selected patients within 4.5 hours of stroke in Europe and within three hours in the USA. There is an upper age limit of 80 years in some countries, and a limitation to mainly non-severe stroke in others. Forty per cent more data are available since this review was last updated in 2009. Objectives To determine whether, and in what circumstances, thrombolytic therapy might be an effective and safe treatment for acute ischaemic stroke. Search methods We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013) and EMBASE (1980 to November 2013). We also handsearched conference proceedings and journals, searched reference lists and contacted pharmaceutical companies and trialists. Selection criteria Randomised trials of any thrombolytic agent compared with control in people with definite ischaemic stroke. Data collection and analysis Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We verified the extracted data with investigators of all major trials, obtaining additional unpublished data if available. Main results We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes. Thrombolytic therapy, mostly administered up to six hours after ischaemic stroke, significantly reduced the proportion of participants who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.78 to 0.93). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR 3.75, 95% CI 3.11 to 4.51), early death (OR 1.69, 95% CI 1.44 to 1.98; 13 trials, 7458 participants) and death by three to six months after stroke (OR 1.18, 95% CI 1.06 to 1.30). Early death after thrombolysis was mostly attributable to intracranial haemorrhage. Treatment within three hours of stroke was more effective in reducing death or dependency (OR 0.66, 95% CI 0.56 to 0.79) without any increase in death (OR 0.99, 95% CI 0.82 to 1.21; 11 trials, 2187 participants). There was heterogeneity between the trials. Contemporaneous antithrombotic drugs increased the risk of death. Trials testing rt-PA showed a significant reduction in death or dependency with treatment up to six hours (OR 0.84, 95% CI 0.77 to 0.93, P = 0.0006; 8 trials, 6729 participants) with significant heterogeneity; treatment within three hours was more beneficial (OR 0.65, 95% CI 0.54 to 0.80, P < 0.0001; 6 trials, 1779 participants) without heterogeneity. Participants aged over 80 years benefited equally to those aged under 80 years, particularly if treated within three hours of stroke. Authors' conclusions Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice.

Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems

Abstract: Background Pre-eclampsia and eclampsia are common causes of serious morbidity and death. Calcium supplementation may reduce the risk of pre-eclampsia, and may help to prevent preterm birth. Objectives To assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 March 2013) and contacted study authors for more data where possible. We updated the search in May 2014 and added the results to the 'Awaiting Classification' section of the review. Selection criteria Randomised controlled trials (RCTs) comparing high-dose (at least 1 g daily of calcium) or low-dose calcium supplementation during pregnancy with placebo or no calcium. Data collection and analysis We assessed eligibility and trial quality, extracted and double-entered data. Main results High-dose calcium supplementation (≥1 g/day) We included 14 studies in the review, however one study contributed no data. We included 13 high-quality studies in our meta-analyses (15,730 women). The average risk of high blood pressure (BP) was reduced with calcium supplementation compared with placebo (12 trials, 15,470 women: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.53 to 0.81; I² = 74%). There was also a significant reduction in the risk of pre-eclampsia associated with calcium supplementation (13 trials, 15,730 women: RR 0.45, 95% CI 0.31 to 0.65; I² = 70%). The effect was greatest for women with low calcium diets (eight trials, 10,678 women: average RR 0.36, 95% CI 0.20 to 0.65; I² = 76%) and women at high risk of pre-eclampsia (five trials, 587 women: average RR 0.22, 95% CI 0.12 to 0.42; I² = 0%). These data should be interpreted with caution because of the possibility of small-study effect or publication bias. The composite outcome maternal death or serious morbidity was reduced (four trials, 9732 women; RR 0.80, 95% CI 0.65 to 0.97; I² = 0%). Maternal deaths were not significantly different (one trial of 8312 women: calcium group one death versus placebo group six deaths). There was an anomalous increase in the risk of HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome (two trials, 12,901 women: RR 2.67, 95% CI 1.05 to 6.82; I² = 0%) in the calcium group, however, the absolute number of events was low (16 versus six). The average risk of preterm birth was reduced in the calcium group (11 trials, 15,275 women: RR 0.76, 95% CI 0.60 to 0.97; I² = 60%) and amongst women at high risk of developing pre-eclampsia (four trials, 568 women: average RR 0.45, 95% CI 0.24 to 0.83; I² = 60%), but no significant reduction in neonatal high care admission. There was no overall effect on the risk of stillbirth or infant death before discharge from hospital (11 trials 15,665 babies: RR 0.90, 95% CI 0.74 to 1.09; I² = 0%). One study showed a reduction in childhood systolic BP greater than 95th percentile among children exposed to calcium supplementation in utero (514 children: RR 0.59, 95% CI 0.39 to 0.91). In a subset of these children, dental caries at 12 years old was also reduced (195 children, RR 0.73, 95% CI 0.62 to 0.87). Low-dose calcium supplementation (< 1 g/day) We included 10 trials (2234 women) that evaluated low-dose supplementation with calcium alone (4) or in association with vitamin D (3), linoleic acid (2), or antioxidants (1). Most studies recruited women at high risk for pre-eclampsia, and were at high risk of bias, thus the results should be interpreted with caution. Supplementation with low doses of calcium significantly reduced the risk of pre-eclampsia (RR 0.38, 95% CI 0.28 to 0.52; I² = 0%). There was also a reduction in hypertension, low birthweight and neonatal intensive care unit admission. Authors' conclusions Calcium supplementation (≥ 1 g/day) is associated with a significant reduction in the risk of pre-eclampsia, particularly for women with low calcium diets. The treatment effect may be overestimated due to small-study effects or publication bias. It also reduces preterm birth and the occurrence of the composite outcome 'maternal death or serious morbidity'. We considered these benefits to outweigh the increased risk of HELLP syndrome, which was small in absolute numbers. The World Health Organization recommends calcium 1.5 g to 2 g daily for pregnant women with low dietary calcium intake. The limited evidence on low-dose calcium supplementation suggests a reduction in pre-eclampsia, but needs to be confirmed by larger, high-quality trials. Pending such results, in settings of low dietary calcium where high-dose supplementation is not feasible, the option of lower-dose supplements (500 to 600 mg/day) might be considered in preference to no supplementation.

Pelvic floor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women

Abstract: Background Pelvic floor muscle training is the most commonly used physical therapy treatment for women with stress urinary incontinence (SUI). It is sometimes also recommended for mixed and, less commonly, urgency urinary incontinence. Objectives To determine the effects of pelvic floor muscle training for women with urinary incontinence in comparison to no treatment, placebo or sham treatments, or other inactive control treatments. Search methods We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (1999 onwards), MEDLINE (1966 onwards) and MEDLINE In-Process (2001 onwards), and handsearched journals and conference proceedings (searched 15 April 2013) and the reference lists of relevant articles. Selection criteria Randomised or quasi-randomised trials in women with stress, urgency or mixed urinary incontinence (based on symptoms, signs, or urodynamics). One arm of the trial included pelvic floor muscle training (PFMT). Another arm was a no treatment, placebo, sham, or other inactive control treatment arm. Data collection and analysis Trials were independently assessed by two review authors for eligibility and methodological quality. Data were extracted then cross-checked. Disagreements were resolved by discussion. Data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions. Trials were subgrouped by diagnosis of urinary incontinence. Formal meta-analysis was undertaken when appropriate. Main results Twenty-one trials involving 1281 women (665 PFMT, 616 controls) met the inclusion criteria; 18 trials (1051 women) contributed data to the forest plots. The trials were generally small to moderate sized, and many were at moderate risk of bias, based on the trial reports. There was considerable variation in the interventions used, study populations, and outcome measures. There were no studies of women with mixed or urgency urinary incontinence alone. Women with SUI who were in the PFMT groups were 8 times more likely than the controls to report that they were cured (46/82 (56.1%) versus 5/83 (6.0%), RR 8.38, 95% CI 3.68 to 19.07) and 17 times more likely to report cure or improvement (32/58 (55%) versus 2/63 (3.2%), RR 17.33, 95% CI 4.31 to 69.64). In trials in women with any type of urinary incontinence, PFMT groups were also more likely to report cure, or more cure and improvement than the women in the control groups, although the effect size was reduced. Women with either SUI or any type of urinary incontinence were also more satisfied with the active treatment, while women in the control groups were more likely to seek further treatment. Women treated with PFMT leaked urine less often, lost smaller amounts on the short office-based pad test, and emptied their bladders less often during the day. Their sexual outcomes were also better. Two trials (one small and one moderate size) reported some evidence of the benefit persisting for up to a year after treatment. Of the few adverse effects reported, none were serious. The findings of the review were largely supported by the summary of findings tables, but most of the evidence was down-graded to moderate on methodological grounds. The exception was 'Participant perceived cure' in women with SUI, which was rated as high quality. Authors' conclusions The review provides support for the widespread recommendation that PFMT be included in first-line conservative management programmes for women with stress and any type of urinary incontinence. Long-term effectiveness of PFMT needs to be further researched.

Vaccines for preventing influenza in healthy adults

Abstract: Background Different types of influenza vaccines are currently produced worldwide. Healthy adults are presently targeted mainly in North America. Objectives Identify, retrieve and assess all studies evaluating the effects of vaccines against influenza in healthy adults. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, issue 2), MEDLINE (January 1966 to June 2010) and EMBASE (1990 to June 2010). Selection criteria Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally-occurring influenza in healthy individuals aged 16 to 65 years. We also included comparative studies assessing serious and rare harms. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Main results We included 50 reports. Forty (59 sub-studies) were clinical trials of over 70,000 people. Eight were comparative non-RCTs and assessed serious harms. Two were reports of harms which could not be introduced in the data analysis. In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (risk difference (RD) 3%, 95% confidence interval (CI) 2% to 5%). The corresponding figures for poor vaccine matching were 2% and 1% (RD 1, 95% CI 0% to 3%). These differences were not likely to be due to chance. Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms and an estimated 1.6 additional cases of Guillain-Barre Syndrome per million vaccinations. The harms evidence base is limited. Authors' conclusions Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission. WARNING: This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding.

Probiotics for prevention of necrotizing enterocolitis in preterm infants

Abstract: Background Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics (live microbial supplements) may play a role in reducing NEC and the associated morbidity. Objectives To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC or sepsis, or both, in preterm infants. Search methods For this update, searches were made of MEDLINE (1966 to October 2013), EMBASE (1980 to October 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 10), and abstracts of annual meetings of the Society for Pediatric Research (1995 to 2013). Selection criteria Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age or < 2500 g birth weight, or both, were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome. Data collection and analysis Standard methods of The Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials and for data collection and analysis. Main results Twenty-four eligible trials were included. Included trials were highly variable with regard to enrolment criteria (that is birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) (typical relative risk (RR) 0.43, 95% confidence interval (CI) 0.33 to 0.56; 20 studies, 5529 infants) and mortality (typical RR 0.65, 95% CI 0.52 to 0.81; 17 studies, 5112 infants). There was no evidence of significant reduction of nosocomial sepsis (typical RR 0.91, 95% CI 0.80 to 1.03; 19 studies, 5338 infants). The included trials reported no systemic infection with the supplemental probiotics organism. Probiotics preparations containing either lactobacillus alone or in combination with bifidobacterium were found to be effective. Authors' conclusions Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence strongly supports a change in practice. Head to head comparative studies are required to assess the most effective preparations, timing, and length of therapy to be utilized.

Interventions for improving the adoption of shared decision making by healthcare professionals

Abstract: Background Shared decision making (SDM) is a process by which a healthcare choice is made jointly by the practitioner and the patient and is said to be the crux of patient-centred care. Policy makers perceive SDM as desirable because of its potential to a) reduce overuse of options not clearly associated with benefits for all (e.g., prostate cancer screening); b) enhance the use of options clearly associated with benefits for the vast majority (e.g., cardiovascular risk factor management); c) reduce unwarranted healthcare practice variations; d) foster the sustainability of the healthcare system; and e) promote the right of patients to be involved in decisions concerning their health. Despite this potential, SDM has not yet been widely adopted in clinical practice. Objectives To determine the effectiveness of interventions to improve healthcare professionals’ adoption of SDM. Search methods We searched the following electronic databases up to 18 March 2009: Cochrane Library (1970-), MEDLINE (1966-), EMBASE (1976-), CINAHL (1982-) and PsycINFO (1965-). We found additional studies by reviewing a) the bibliographies of studies and reviews found in the electronic databases; b) the clinicaltrials.gov registry; and c) proceedings of the International Shared Decision Making Conference and the conferences of the Society for Medical Decision Making. We included all languages of publication. Selection criteria We included randomised controlled trials (RCTs) or well-designed quasi-experimental studies (controlled clinical trials, controlled before and after studies, and interrupted time series analyses) that evaluated any type of intervention that aimed to improve healthcare professionals' adoption of shared decision making. We defined adoption as the extent to which healthcare professionals intended to or actually engaged in SDM in clinical practice or/and used interventions known to facilitate SDM. We deemed studies eligible if the primary outcomes were evaluated with an objective measure of the adoption of SDM by healthcare professionals (e.g., a third-observer instrument). Data collection and analysis At least two reviewers independently screened each abstract for inclusion and abstracted data independently using a modified version of the EPOC data collection checklist. We resolved disagreements by discussion. Statistical analysis considered categorical and continuous primary outcomes. We computed the standard effect size for each outcome separately with a 95% confidence interval. We evaluated global effects by calculating the median effect size and the range of effect sizes across studies. Main results The reviewers identified 6764 potentially relevant documents, of which we excluded 6582 by reviewing titles and abstracts. Of the remainder, we retrieved 182 full publications for more detailed screening. From these, we excluded 176 publications based on our inclusion criteria. This left in five studies, all RCTs. All five were conducted in ambulatory care: three in primary clinical care and two in specialised care. Four of the studies targeted physicians only and one targeted nurses only. In only two of the five RCTs was a statistically significant effect size associated with the intervention to have healthcare professionals adopt SDM. The first of these two studies compared a single intervention (a patient-mediated intervention: the Statin Choice decision aid) to another single intervention (also patient-mediated: a standard Mayo patient education pamphlet). In this study, the Statin Choice decision aid group performed better than the standard Mayo patient education pamphlet group (standard effect size = 1.06; 95% CI = 0.62 to 1.50). The other study compared a multifaceted intervention (distribution of educational material, educational meeting and audit and feedback) to usual care (control group) (standard effect size = 2.11; 95% CI = 1.30 to 2.90). This study was the only one to report an assessment of barriers prior to the elaboration of its multifaceted intervention. Authors' conclusions The results of this Cochrane review do not allow us to draw firm conclusions about the most effective types of intervention for increasing healthcare professionals' adoption of SDM. Healthcare professional training may be important, as may the implementation of patient-mediated interventions such as decision aids. Given the paucity of evidence, however, those motivated by the ethical impetus to increase SDM in clinical practice will need to weigh the costs and potential benefits of interventions. Subsequent research should involve well-designed studies with adequate power and procedures to minimise bias so that they may improve estimates of the effects of interventions on healthcare professionals' adoption of SDM. From a measurement perspective, consensus on how to assess professionals' adoption of SDM is desirable to facilitate cross-study comparisons.

Exercise based rehabilitation for heart failure

Abstract: Background People with heart failure experience marked reductions in their exercise capacity, which has detrimental effects on their activities of daily living, health-related quality of life and ultimately their hospital admission rate and mortality. Study characteristics We searched the scientific literature for randomised controlled trials (experiments in which two or more interventions, possibly including a control intervention or no intervention, are compared by being randomly allocated to participants) looking at the effectiveness of exercise-based treatments compared with no exercise on heart failure in adults over 18 years of age. The inclusion criteria of this updated review were extended to consider not only HF due to reduced ejection fraction (HFREF or 'systolic HF') (ejection fraction is a measure of how well your heart is pumping), but also HF due to preserved ejection fraction (HFPEF or 'diastolic HF'). The search is current to January 2013. Key results We found 33 RCTs that included 4740 participants. The findings of this update are consistent with the previous (2010) version of this Cochrane review and show important benefits of exercise-based rehabilitation that include a reduction in the risk of hospital admissions due to HF and improvements in health-related quality of life compared with not undertaking exercise. There was a high level of variation across studies in health-related quality of life outcome. While the majority of evidence was for exercise-based rehabilitation in people with HFREF, this update did identify a broader evidence base that included higher risk (New York Heart Association class IV) and older people, people with HFPEF and more programmes conducted in a home-based setting. We found no evidence to suggest that exercise training programmes cause harm in terms of an increase in the risk of death in either the short or longer term. A small body of economic evidence was identified indicating exercise-based rehabilitation to be cost-effective. Further evidence is needed to understand the effect of exercise training in people with HFPEF better and the costs and effects of exclusively home-based exercise rehabilitation programmes.

Interventions to improve the appropriate use of polypharmacy for older people

Abstract: Background Inappropriate polypharmacy is a particular concern in older people and is associated with negative health outcomes. Choosing the best interventions to improve appropriate polypharmacy is a priority, hence interest in appropriate polypharmacy, where many medicines may be used to achieve better clinical outcomes for patients, is growing. Objectives This review sought to determine which interventions, alone or in combination, are effective in improving the appropriate use of polypharmacy and reducing medication-related problems in older people. Search methods In November 2013, for this first update, a range of literature databases including MEDLINE and EMBASE were searched, and handsearching of reference lists was performed. Search terms included 'polypharmacy', 'medication appropriateness' and 'inappropriate prescribing'. Selection criteria A range of study designs were eligible. Eligible studies described interventions affecting prescribing aimed at improving appropriate polypharmacy in people 65 years of age and older in which a validated measure of appropriateness was used (e.g. Beers criteria, Medication Appropriateness Index (MAI)). Data collection and analysis Two review authors independently reviewed abstracts of eligible studies, extracted data and assessed risk of bias of included studies. Study-specific estimates were pooled, and a random-effects model was used to yield summary estimates of effect and 95% confidence intervals (CIs). The GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach was used to assess the overall quality of evidence for each pooled outcome. Main results Two studies were added to this review to bring the total number of included studies to 12. One intervention consisted of computerised decision support; 11 complex, multi-faceted pharmaceutical approaches to interventions were provided in a variety of settings. Interventions were delivered by healthcare professionals, such as prescribers and pharmacists. Appropriateness of prescribing was measured using validated tools, including the MAI score post intervention (eight studies), Beers criteria (four studies), STOPP criteria (two studies) and START criteria (one study). Interventions included in this review resulted in a reduction in inappropriate medication usage. Based on the GRADE approach, the overall quality of evidence for all pooled outcomes ranged from very low to low. A greater reduction in MAI scores between baseline and follow-up was seen in the intervention group when compared with the control group (four studies; mean difference -6.78, 95% CI -12.34 to -1.22). Postintervention pooled data showed a lower summated MAI score (five studies; mean difference -3.88, 95% CI -5.40 to -2.35) and fewer Beers drugs per participant (two studies; mean difference -0.1, 95% CI -0.28 to 0.09) in the intervention group compared with the control group. Evidence of the effects of interventions on hospital admissions (five studies) and of medication-related problems (six studies) was conflicting. Authors' conclusions It is unclear whether interventions to improve appropriate polypharmacy, such as pharmaceutical care, resulted in clinically significant improvement; however, they appear beneficial in terms of reducing inappropriate prescribing.

Formula versus donor breast milk for feeding preterm or low birth weight infants

Abstract: BACKGROUND: When sufficient maternal breast milk is not available, alternative forms of enteral nutrition for preterm or low birth weight (LBW) infants are donor breast milk or artificial formula. Donor breast milk may retain some of the non-nutritive benefits of maternal breast milk for preterm or LBW infants. However, feeding with artificial formula may ensure more consistent delivery of greater amounts of nutrients. Uncertainty exists about the balance of risks and benefits of feeding formula versus donor breast milk for preterm or LBW infants. OBJECTIVES: To determine the effect of feeding with formula compared with donor breast milk on growth and development in preterm or low birth weight (LBW) infants. SEARCH METHODS: We used the Cochrane Neonatal search strategy, including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 5), Ovid MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (3 May 2019), as well as conference proceedings, previous reviews, and clinical trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials (RCTs) comparing feeding with formula versus donor breast milk in preterm or LBW infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios (RRs) and risk differences (RDs) for dichotomous data, and mean differences (MDs) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity in subgroup analyses. We assessed the certainty of evidence for the main comparison at the outcome level using GRADE methods. MAIN RESULTS: Twelve trials with a total of 1879 infants fulfilled the inclusion criteria. Four trials compared standard term formula versus donor breast milk and eight compared nutrient-enriched preterm formula versus donor breast milk. Only the five most recent trials used nutrient-fortified donor breast milk. The trials contain various weaknesses in methodological quality, specifically concerns about allocation concealment in four trials and lack of blinding in most of the trials. Most of the included trials were funded by companies that made the study formula.Formula-fed infants had higher in-hospital rates of weight gain (mean difference (MD) 2.51, 95% confidence interval (CI) 1.93 to 3.08 g/kg/day), linear growth (MD 1.21, 95% CI 0.77 to 1.65 mm/week) and head growth (MD 0.85, 95% CI 0.47 to 1.23 mm/week). These meta-analyses contained high levels of heterogeneity. We did not find evidence of an effect on long-term growth or neurodevelopment. Formula feeding increased the risk of necrotising enterocolitis (typical risk ratio (RR) 1.87, 95% CI 1.23 to 2.85; risk difference (RD) 0.03, 95% CI 0.01 to 0.05; number needed to treat for an additional harmful outcome (NNTH) 33, 95% CI 20 to 100; 9 studies, 1675 infants).The GRADE certainty of evidence was moderate for rates of weight gain, linear growth, and head growth (downgraded for high levels of heterogeneity) and was moderate for neurodevelopmental disability, all-cause mortality, and necrotising enterocolitis (downgraded for imprecision). AUTHORS' CONCLUSIONS: In preterm and LBW infants, moderate-certainty evidence indicates that feeding with formula compared with donor breast milk, either as a supplement to maternal expressed breast milk or as a sole diet, results in higher rates of weight gain, linear growth, and head growth and a higher risk of developing necrotising enterocolitis. The trial data do not show an effect on all-cause mortality, or on long-term growth or neurodevelopment.

Antihypertensive drug therapy for mild to moderate hypertension during pregnancy

Abstract: Background Mild to moderate hypertension during pregnancy is common. Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby improve the outcome. Objectives To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2013) and reference lists of retrieved studies. Selection criteria All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy defined, whenever possible, as systolic blood pressure 140 to 169 mmHg and diastolic blood pressure 90 to 109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days. Data collection and analysis Two review authors independently extracted data. Main results Forty-nine trials (4723 women) were included. Twenty-nine trials compared an antihypertensive drug with placebo/no antihypertensive drug (3350 women). There is a halving in the risk of developing severe hypertension associated with the use of antihypertensive drug(s) (20 trials, 2558 women; risk ratio (RR) 0.49; 95% confidence interval (CI) 0.40 to 0.60; risk difference (RD) -0.10 (-0.13 to -0.07); number needed to treat to harm (NNTH) 10 (8 to 13)) but little evidence of a difference in the risk of pre-eclampsia (23 trials, 2851 women; RR 0.93; 95% CI 0.80 to 1.08). Similarly, there is no clear effect on the risk of the baby dying (27 trials, 3230 women; RR 0.71; 95% CI 0.49 to 1.02), preterm birth (15 trials, 2141 women; RR 0.96; 95% CI 0.85 to 1.10), or small-for-gestational-age babies (20 trials, 2586 women; RR 0.97; 95% CI 0.80 to 1.17). There were no clear differences in any other outcomes. Twenty-two trials (1723 women) compared one antihypertensive drug with another. Alternative drugs seem better than methyldopa for reducing the risk of severe hypertension (11 trials, 638 women; RR (random-effects) 0.54; 95% CI 0.30 to 0.95; RD -0.11 (-0.20 to -0.02); NNTH 7 (5 to 69)). There is also a reduction in the overall risk of developing proteinuria/pre-eclampsia when beta blockers and calcium channel blockers considered together are compared with methyldopa (11 trials, 997 women; RR 0.73; 95% CI 0.54 to 0.99). However, the effect on both severe hypertension and proteinuria is not seen in the individual drugs. Other outcomes were only reported by a small proportion of studies, and there were no clear differences. Authors' conclusions It remains unclear whether antihypertensive drug therapy for mild to moderate hypertension during pregnancy is worthwhile.

Psychological therapies for the management of chronic and recurrent pain in children and adolescents

Abstract: Background This is an update of the original Cochrane review first published in Issue 1, 2003, and previously updated in 2009 and 2012. Chronic pain affects many children, who report severe pain, disability, and distressed mood. Psychological therapies are emerging as effective interventions to treat children with chronic or recurrent pain. This update focuses specifically on psychological therapies delivered face-to-face, adds new randomised controlled trials (RCTs), and additional data from previously included trials. Objectives There were three objectives to this review. First, to determine the effectiveness on clinical outcomes of pain severity, disability, depression, and anxiety of psychological therapy delivered face-to-face for chronic and recurrent pain in children and adolescents compared with active treatment, waiting-list, or standard medical care. Second, to evaluate the impact of psychological therapies on depression and anxiety, which were previously combined as 'mood'. Third, we assessed the risk of bias of the included studies and the quality of outcomes using the GRADE criteria. Search methods Searches were undertaken of CENTRAL, MEDLINE, EMBASE, and PsycINFO. We searched for further RCTs in the references of all identified studies, meta-analyses, and reviews. Trial registry databases were also searched. The date of most recent search was January 2014. Selection criteria RCTs with at least 10 participants in each arm post-treatment comparing psychological therapies with active treatment, standard medical care, or waiting-list control for children or adolescents with episodic, recurrent or persistent pain were eligible for inclusion. Only trials conducted in person (face-to-face) were considered. Studies that delivered treatment remotely were excluded from this update. Data collection and analysis All included studies were analysed and the quality of outcomes were assessed. All treatments were combined into one class, psychological treatments. Pain conditions were split into headache and non-headache. Both conditions were assessed on four outcomes: pain, disability, depression, and anxiety. Data were extracted at two time points; post-treatment (immediately or the earliest data available following end of treatment) and at follow-up (between three and 12 months post-treatment). Main results Seven papers were identified in the updated search. Of these papers, five presented new trials and two presented follow-up data for previously included trials. Five studies that were previously included in this review were excluded as therapy was delivered remotely. The review thus included a total of 37 studies. The total number of participants completing treatments was 2111. Twenty studies addressed treatments for headache (including migraine); nine for abdominal pain; two for mixed pain conditions including headache pain, two for fibromyalgia, two for recurrent abdominal pain or irritable bowel syndrome, and two for pain associated with sickle cell disease. Analyses revealed psychological therapies to be beneficial for children with chronic pain on seven outcomes. For headache pain, psychological therapies reduced pain post-treatment and at follow-up respectively (risk ratio (RR) 2.47, 95% confidence interval (CI) 1.97 to 3.09, z = 7.87, p 0.05). At follow-up, only one study was eligible, therefore no analysis was possible and no conclusions can be drawn. Analyses revealed a small beneficial effect for anxiety post-treatment (SMD -0.33, 95% CI -0.61 to -0.04, z = 2.25, p 0.05). Analyses revealed two beneficial effects of psychological treatment for children with non-headache pain. Pain was found to improve post-treatment (SMD -0.57, 95% CI -0.86 to -0.27, z = 3.74, p 0.05). Psychological therapies also had a beneficial effect for disability post-treatment (SMD -0.45, 95% CI -0.71 to -0.19, z = 3.40, p 0.05). No effect was found for depression or anxiety post-treatment (SMD -0.07, 95% CI -0.30 to 0.17, z = 0.54, p > 0.05; SMD -0.15, 95% CI -0.36 to 0.07, z = 1.33, p > 0.05) or at follow-up (SMD 0.06, 95% CI -0.16 to 0.28, z = 0.53, p > 0.05; SMD 0.05, 95% CI -0.24 to 0.33, z = 0.32, p > 0.05). Authors' conclusions Psychological treatments delivered face-to-face are effective in reducing pain intensity and disability for children and adolescents (<18 years) with headache, and therapeutic gains appear to be maintained, although this should be treated with caution for the disability outcome as only two studies could be included in the follow-up analysis. Psychological therapies are also beneficial at reducing anxiety post-treatment for headache. For non-headache conditions, psychological treatments were found to be beneficial for pain and disability post-treatment but these effects were not maintained at follow-up. There is limited evidence available to estimate the effects of psychological therapies on depression and anxiety for children and adolescents with headache and non-headache pain. The conclusions of this update replicate and add to those of the previous review which found that psychological therapies were effective in reducing pain intensity for children with headache and non-headache pain conditions, and these effects were maintained at follow-up for children with headache conditions.

Interventions for improving upper limb function after stroke

Abstract: Background Improving upper limb function is a core element of stroke rehabilitation needed to maximise patient outcomes and reduce disability. Evidence about effects of individual treatment techniques and modalities is synthesised within many reviews. For selection of effective rehabilitation treatment, the relative effectiveness of interventions must be known. However, a comprehensive overview of systematic reviews in this area is currently lacking. Objectives To carry out a Cochrane overview by synthesising systematic reviews of interventions provided to improve upper limb function after stroke. Methods Search methods: We comprehensively searched the Cochrane Database of Systematic Reviews; the Database of Reviews of Effects; and PROSPERO (an international prospective register of systematic reviews) (June 2013). We also contacted review authors in an effort to identify further relevant reviews. Selection criteria: We included Cochrane and non-Cochrane reviews of randomised controlled trials (RCTs) of patients with stroke comparing upper limb interventions with no treatment, usual care or alternative treatments. Our primary outcome of interest was upper limb function; secondary outcomes included motor impairment and performance of activities of daily living. When we identified overlapping reviews, we systematically identified the most up-to-date and comprehensive review and excluded reviews that overlapped with this. Data collection and analysis: Two overview authors independently applied the selection criteria, excluding reviews that were superseded by more up-to-date reviews including the same (or similar) studies. Two overview authors independently assessed the methodological quality of reviews (using a modified version of the AMSTAR tool) and extracted data. Quality of evidence within each comparison in each review was determined using objective criteria (based on numbers of participants, risk of bias, heterogeneity and review quality) to apply GRADE (Grades of Recommendation, Assessment, Development and Evaluation) levels of evidence. We resolved disagreements through discussion. We systematically tabulated the effects of interventions and used quality of evidence to determine implications for clinical practice and to make recommendations for future research. Main results Our searches identified 1840 records, from which we included 40 completed reviews (19 Cochrane; 21 non-Cochrane), covering 18 individual interventions and dose and setting of interventions. The 40 reviews contain 503 studies (18,078 participants). We extracted pooled data from 31 reviews related to 127 comparisons. We judged the quality of evidence to be high for 1/127 comparisons (transcranial direct current stimulation (tDCS) demonstrating no benefit for outcomes of activities of daily living (ADLs)); moderate for 49/127 comparisons (covering seven individual interventions) and low or very low for 77/127 comparisons. Moderate-quality evidence showed a beneficial effect of constraint-induced movement therapy (CIMT), mental practice, mirror therapy, interventions for sensory impairment, virtual reality and a relatively high dose of repetitive task practice, suggesting that these may be effective interventions; moderate-quality evidence also indicated that unilateral arm training may be more effective than bilateral arm training. Information was insufficient to reveal the relative effectiveness of different interventions. Moderate-quality evidence from subgroup analyses comparing greater and lesser doses of mental practice, repetitive task training and virtual reality demonstrates a beneficial effect for the group given the greater dose, although not for the group given the smaller dose; however tests for subgroup differences do not suggest a statistically significant difference between these groups. Future research related to dose is essential. Specific recommendations for future research are derived from current evidence. These recommendations include but are not limited to adequately powered, high-quality RCTs to confirm the benefit of CIMT, mental practice, mirror therapy, virtual reality and a relatively high dose of repetitive task practice; high-quality RCTs to explore the effects of repetitive transcranial magnetic stimulation (rTMS), tDCS, hands-on therapy, music therapy, pharmacological interventions and interventions for sensory impairment; and up-to-date reviews related to biofeedback, Bobath therapy, electrical stimulation, reach-to-grasp exercise, repetitive task training, strength training and stretching and positioning. Authors' conclusions Large numbers of overlapping reviews related to interventions to improve upper limb function following stroke have been identified, and this overview serves to signpost clinicians and policy makers toward relevant systematic reviews to support clinical decisions, providing one accessible, comprehensive document, which should support clinicians and policy makers in clinical decision making for stroke rehabilitation. Currently, no high-quality evidence can be found for any interventions that are currently used as part of routine practice, and evidence is insufficient to enable comparison of the relative effectiveness of interventions. Effective collaboration is urgently needed to support large, robust RCTs of interventions currently used routinely within clinical practice. Evidence related to dose of interventions is particularly needed, as this information has widespread clinical and research implications.

Antioxidants for male subfertility

Abstract: Background Between 30% to 80% of male subfertility cases are considered to be due to the damaging effects of oxidative stress on sperm and 1 man in 20 will be affected by subfertility. Antioxidants are widely available and inexpensive when compared to other fertility treatments and many men are already using these to improve their fertility. It is thought that oral supplementation with antioxidants may improve sperm quality by reducing oxidative stress. Pentoxifylline, a drug that acts like an antioxidant, was also included in this review. Objectives This Cochrane review aimed to evaluate the effectiveness and safety of oral supplementation with antioxidants for subfertile male partners in couples seeking fertility assistance. Search methods We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from inception until January 2014); trial registers; sources of unpublished literature and reference lists. An updated search was run in August 2014 when potentially eligible studies were placed in 'Studies awaiting assessment'. Selection criteria We included randomised controlled trials (RCTs) comparing any type or dose of antioxidant supplement (single or combined) taken by the subfertile male partner of a couple seeking fertility assistance with a placebo, no treatment or another antioxidant. Data collection and analysis Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates, adverse events, sperm DNA fragmentation, sperm motility and concentration. Data were combined, where appropriate, to calculate pooled odds ratios (ORs) or mean differences (MD) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I2 statistic. We assessed the overall quality of the evidence for the main outcomes using GRADE methods. Main results This updated review included 48 RCTs that compared single and combined antioxidants with placebo, no treatment or another antioxidant in a population of 4179 subfertile men. The duration of the trials ranged from 3 to 26 weeks with follow up ranging from 3 weeks to 2 years. The men were aged from 20 to 52 years. Most of the men enrolled in these trials had low total sperm motility and sperm concentration. One study enrolled men after varicocelectomy, one enrolled men with a varicocoele, and one recruited men with chronic prostatitis. Three trials enrolled men who, as a couple, were undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) and one trial enrolled men who were part of a couple undergoing intrauterine insemination (IUI). Funding sources were stated by 15 trials. Four of these trials stated that funding was from a commercial source and the remaining 11 obtained funding through non-commercial avenues or university grants. Thirty-three trials did not report any funding sources. A limitation of this review was that in a sense we had included two different groups of trials, those that reported on the use of antioxidants and the effect on live birth and clinical pregnancy, and a second group that reported on sperm parameters as their primary outcome and had no intention of reporting the primary outcomes of this review. We included 25 trials reporting on sperm parameters and only three of these reported on live birth or clinical pregnancy. Other limitations included poor reporting of study methods, imprecision, the small number of trials providing usable data, the small sample size of many of the included studies and the lack of adverse events reporting. The evidence was graded as 'very low' to 'low'. The data were current to 31 January 2014. Live birth: antioxidants may have increased live birth rates (OR 4.21, 95% CI 2.08 to 8.51, P< 0.0001, 4 RCTs, 277 men, I2 = 0%, low quality evidence). This suggests that if the chance of a live birth following placebo or no treatment is assumed to be 5%, the chance following the use of antioxidants is estimated to be between 10% and 31%. However, this result was based on only 44 live births from a total of 277 couples in four small studies. Clinical pregnancy rate: antioxidants may have increased clinical pregnancy rates (OR 3.43, 95% CI 1.92 to 6.11, P < 0.0001, 7 RCTs, 522 men, I2 = 0%, low quality evidence). This suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 6%, the chance following the use of antioxidants is estimated at between 11% and 28%. However, there were only seven small studies in this analysis and the quality of the evidence was rated as low. Miscarriage: only three trials reported on this outcome and the event rate was very low. There was insufficient evidence to show whether there was a difference in miscarriage rates between the antioxidant and placebo or no treatment groups (OR 1.74, 95% CI 0.40 to 7.60, P = 0.46, 3 RCTs, 247 men, I2 = 0%, very low quality evidence). The findings suggest that in a population of subfertile men with an expected miscarriage rate of 2%, use of an antioxidant would result in the risk of a miscarriage lying between 1% and 13%. Gastrointestinal upsets: there was insufficient evidence to show whether there was a difference in gastrointestinal upsets when antioxidants were compared to placebo or no treatment as the event rate was very low (OR 1.60, 95% CI 0.47 to 5.50, P = 0.46, 6 RCTs, 429 men, I2 = 0%). We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as not enough trials compared the same interventions. Authors' conclusions There is low quality evidence from only four small randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low quality evidence suggests that clinical pregnancy rates may increase. There is no evidence of increased risk of miscarriage but this is uncertain as the evidence is of very low quality. Data were lacking on other adverse effects. Further large well-designed randomised placebo-controlled trials are needed to clarify these results.

Electronic cigarettes for smoking cessation and reduction

Abstract: © 2014 The Cochrane Collaboration. Background: Electronic cigarettes (ECs) are electronic devices that heat a liquid - usually comprising propylene glycol and glycerol, with or without nicotine and flavours, stored in disposable or refillable cartridges or a reservoir - into an aerosol for inhalation. Since ECs appeared on the market in 2006 there has been a steady growth in sales. Smokers report using ECs to reduce risks of smoking, but some healthcare organisations have been reluctant to encourage smokers to switch to ECs, citing lack of evidence of efficacy and safety. Smokers, healthcare providers and regulators are interested to know if these devices can reduce the harms associated with smoking. In particular, healthcare providers have an urgent need to know what advice they should give to smokers enquiring about ECs. Objectives: To examine the efficacy of ECs in helping people who smoke to achieve long-term abstinence; to examine the efficacy of ECs in helping people reduce cigarette consumption by at least 50% of baseline levels; and to assess the occurrence of adverse events associated with EC use. Search methods: We searched the Cochrane Tobacco Addiction Groups Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and two other databases for relevant records from 2004 to July 2014, together with reference checking and contact with study authors. Selection criteria: We included randomized controlled trials (RCTs) in which current smokers (motivated or unmotivated to quit) were randomized to EC or a control condition, and which measured abstinence rates or changes in cigarette consumption at six months or longer. As the field of EC research is new, we also included cohort follow-up studies with at least six months follow-up. We included randomized cross-over trials and cohort follow-up studies that included at least one week of EC use for assessment of adverse events. Data collection and analysis: One review author extracted data from the included studies and another checked them. Our main outcome measure was abstinence from smoking after at least six months follow-up, and we used the most rigorous definition available (continuous, biochemically validated, longest follow-up). For reduction we used a dichotomous approach (no change/reduction < 50% versus reduction by 50% or more of baseline cigarette consumption). We used a fixed-effect Mantel-Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for each study, and where appropriate we pooled data from these studies in meta-analyses. Main results: Our search identified almost 600 records, from which we include 29 representing 13 completed studies (two RCTs, 11 cohort). We identified nine ongoing trials. Two RCTs compared EC with placebo (non-nicotine) EC, with a combined sample size of 662 participants. One trial included minimal telephone support and one recruited smokers not intending to quit, and both used early EC models with low nicotine content. We judged the RCTs to be at low risk of bias, but under the GRADE system the overall quality of the evidence for our outcomes was rated 'low' or 'very low' because of imprecision due to the small number of trials. A 'low' grade means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. A 'very low' grade means we are very uncertain about the estimate. Participants using an EC were more likely to have abstained from smoking for at least six months compared with participants using placebo EC (RR 2.29, 95% CI 1.05 to 4.96; placebo 4% versus EC 9%; 2 studies; GRADE: low). The one study that compared EC to nicotine patch found no significant difference in six-month abstinence rates, but the confidence intervals do not rule out a clinically important difference (RR 1.26, 95% CI: 0.68 to 2.34; GRADE: very low). A higher number of people were able to reduce cigarette consumption by at least half with ECs compared with placebo ECs (RR 1.31, 95% CI 1.02 to 1.68, 2 studies; placebo: 27% versus EC: 36%; GRADE: low) and compared with patch (RR 1.41, 95% CI 1.20 to 1.67, 1 study; patch: 44% versus EC: 61%; GRADE: very low). Unlike smoking cessation outcomes, reduction results were not biochemically verified. None of the RCTs or cohort studies reported any serious adverse events (SAEs) that were considered to be plausibly related to EC use. One RCT provided data on the proportion of participants experiencing any adverse events. Although the proportion of participants in the study arms experiencing adverse events was similar, the confidence intervals are wide (ECs vs placebo EC RR 0.97, 95% CI 0.71 to 1.34; ECs vs patch RR 0.99, 95% CI 0.81 to 1.22). The other RCT reported no statistically significant difference in the frequency of AEs at three- or 12-month follow-up between the EC and placebo EC groups, and showed that in all groups the frequency of AEs (with the exception of throat irritation) decreased significantly over time. Authors' conclusions: There is evidence from two trials that ECs help smokers to stop smoking long-term compared with placebo ECs. However, the small number of trials, low event rates and wide confidence intervals around the estimates mean that our confidence in the result is rated 'low' by GRADE standards. The lack of difference between the effect of ECs compared with nicotine patches found in one trial is uncertain for similar reasons. ECs appear to help smokers unable to stop smoking altogether to reduce their cigarette consumption when compared with placebo ECs and nicotine patches, but the above limitations also affect certainty in this finding. In addition, lack of biochemical assessment of the actual reduction in smoke intake further limits this evidence. No evidence emerged that short-term EC use is associated with health risk.

Interventions for preoperative smoking cessation.

Abstract: Smokers have a substantially increased risk of postoperative complications. Preoperative smoking intervention may be effective in decreasing this incidence, and surgery may constitute a unique opportunity for smoking cessation interventions. The objective of this review was to assess the effect of preoperative smoking intervention on smoking cessation at the time of surgery and 12 months postoperatively and on the incidence of postoperative complications.

Intravenous immunoglobulin for Guillain-Barré syndrome

Abstract: Background Guillain-Barre syndrome (GBS) is an acute, paralysing, inflammatory peripheral nerve disease. Intravenous immunoglobulin (IVIg) is beneficial in other autoimmune diseases. This is an update of a review first published in 2001 and previously updated in 2003, 2005, 2007, 2010 and 2012. Other Cochrane systematic reviews have shown that plasma exchange (PE) significantly hastens recovery in GBS compared with supportive treatment alone, and that corticosteroids alone are ineffective. Objectives We had the following four objectives. 1. To examine the efficacy of intravenous immunoglobulin (IVIg) in hastening recovery and reducing the long-term morbidity from Guillain-Barre syndrome (GBS). 2. To determine the most efficacious dose of IVIg in hastening recovery and reducing the long-term morbidity from GBS. 3. To compare the efficacy of IVIg and plasma exchange (PE) or immunoabsorption in hastening recovery and reducing the long-term morbidity from GBS. 4. To compare the efficacy of IVIg added to PE with PE alone in hastening recovery and reducing the long-term morbidity from GBS. Search methods We searched the Cochrane Neuromuscular Disease Group Specialized Register (2 December 2013), CENTRAL (2013, Issue 12 in The Cochrane Library), MEDLINE (January 1966 to November 2013) and EMBASE (January 1980 to November 2013). We checked the bibliographies in reports of the randomised trials and contacted the authors and other experts in the field to identify additional published or unpublished data. Selection criteria Randomised and quasi-randomised trials of IVIg compared with no treatment, placebo treatment, PE, or other immunomodulatory treatments in children and adults with GBS of all degrees of severity. We also included trials in which IVIg was added to another treatment. Data collection and analysis Two authors independently selected papers, extracted data and assessed quality. We collected data about adverse events from the included trials. Main results Twelve trials were found to be eligible for inclusion in this review. Seven trials with a variable risk of bias compared IVIg with PE in 623 severely affected participants. In five trials with 536 participants for whom the outcome was available, the mean difference (MD) of change in a seven-grade disability scale after four weeks was not significantly different between the two treatments: MD of 0.02 of a grade more improvement in the intravenous immunoglobulin than the plasma exchange group; 95% confidence interval (CI) 0.25 to -0.20. There were also no statistically significant differences in the other measures considered. Three studies including a total of 75 children suggested that IVIg significantly hastens recovery compared with supportive care. The primary outcome for this review, available for only one trial with 21 mildly affected children, showed significantly more improvement in disability grade after four weeks with IVIg than supportive treatment alone, MD 1.42, 95% CI 2.57 to 0.27. In one trial involving 249 participants comparing PE followed by IVIg with PE alone, the mean grade improvement was 0.2 (95% CI -0.14 to 0.54) more in the combined treatment group than in the PE alone group; not clinically significantly different, but not excluding the possibility of significant extra benefit. Another trial with 34 participants comparing immunoabsorption followed by IVIg with immunoabsorption alone did not reveal significant extra benefit from the combined treatment. Adverse events were not significantly more frequent with either treatment, but IVIg is significantly much more likely to be completed than PE. One trial in altogether 51 children showed no significant difference when the standard dose was given over two days rather than five days. Authors' conclusions A previous Cochrane review has shown that PE hastens recovery compared with supportive treatment alone. There are no adequate comparisons of IVIg with placebo in adults, but this review provides moderate quality evidence that, in severe disease, IVIg started within two weeks from onset hastens recovery as much as PE. Adverse events were not significantly more frequent with either treatment but IVIg is significantly much more likely to be completed than PE. Also, according to moderate quality evidence, giving IVIg after PE did not confer significant extra benefit. In children, according to low quality evidence, IVIg probably hastens recovery compared with supportive care alone. More research is needed in mild disease and in patients whose treatment starts more than two weeks after onset. Dose-ranging studies are also needed and one is in progress.

Self management for patients with chronic obstructive pulmonary disease

Abstract: Background Self management interventions help patients with chronic obstructive pulmonary disease (COPD) acquire and practise the skills they need to carry out disease-specific medical regimens, guide changes in health behaviour and provide emotional support to enable patients to control their disease. Since the first update of this review in 2007, several studies have been published. The results of the second update are reported here. Objectives 1. To evaluate whether self management interventions in COPD lead to improved health outcomes. 2. To evaluate whether self management interventions in COPD lead to reduced healthcare utilisation. Search methods We searched the Cochrane Airways Group Specialised Register of trials (current to August 2011). Selection criteria Controlled trials (randomised and non-randomised) published after 1994, assessing the efficacy of self management interventions for individuals with COPD, were included. Interventions with fewer than two contact moments between study participants and healthcare providers were excluded. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Investigators were contacted to ask for additional information. When appropriate, study results were pooled using a random-effects model. The primary outcomes of the review were health-related quality of life (HRQoL) and number of hospital admissions. Main results Twenty-nine studies were included. Twenty-three studies on 3189 participants compared self management versus usual care; six studies on 499 participants compared different components of self management on a head-to-head basis. Although we included non-randomised controlled clinical trials as well as RCTs in this review, we restricted the primary analysis to RCTs only and reported these trials in the abstract. In the 23 studies with a usual care control group, follow-up time ranged from two to 24 months. The content of the interventions was diverse. A statistically relevant effect of self management on HRQoL was found (St George's Respiratory Questionnaire (SGRQ) total score, mean difference (MD) -3.51, 95% confidence interval (CI) -5.37 to -1.65, 10 studies, 1413 participants, moderate-quality evidence). Self management also led to a lower probability of respiratory-related hospitalisations (odds ratio (OR) 0.57, 95% CI 0.43 to 0.75, nine studies, 1749 participants, moderate-quality evidence) and all cause hospitalisations (OR 0.60; 95% CI 0.40 to 0.89, 6 studies, 1365 participants, moderate-quality evidence). Over one year of follow-up, eight (95% CI 5 to 14) participants with a high baseline risk of respiratory-related hospital admission needed to be treated to prevent one participant with at least one hospital admission, and 20 (95% CI 15 to 35) participants with a low baseline risk of hospitalisation needed to be treated to prevent one participant with at least one respiratory-related hospital admission. No statistically significant effect of self management on mortality (OR 0.79, 95% CI 0.58 to 1.07, 8 studies, 2134 participants, very low-quality evidence) was detected. Also, dyspnoea measured by the (modified) Medical Research Council Scale ((m)MRC) was reduced in individuals who participated in self management (MD -0.83, 95% CI -1.36 to -0.30, 3 studies, 119 participants, low-quality evidence). The difference in exercise capacity as measured by the six-minute walking test was not statistically significant (MD 33.69 m, 95% CI -9.12 to 76.50, 6 studies, 570 participants, very low-quality evidence). Subgroup analyses depending on the use of an exercise programme as part of the intervention revealed no statistically significant differences between studies with and without exercise programmes in our primary outcomes of HRQoL and respiratory-related hospital admissions. We were unable to pool head-to-head trials because of heterogeneity among interventions and controls; thus results are presented narratively within the review. Authors' conclusions Self management interventions in patients with COPD are associated with improved health-related quality of life as measured by the SGRQ, a reduction in respiratory-related and all cause hospital admissions, and improvement in dyspnoea as measured by the (m)MRC. No statistically significant differences were found in other outcome parameters. However, heterogeneity among interventions, study populations, follow-up time and outcome measures makes it difficult to formulate clear recommendations regarding the most effective form and content of self management in COPD.

Vitamin D supplementation for prevention of mortality in adults

Abstract: Background Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality. Objectives To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease. Search methods We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index–Expanded and Conference Proceedings Citation Index–Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials. Selection criteria Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). Data collection and analysis Six review authors extracted data independently. Random-effects and fixed-effect meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RRs). To account for trials with zero events, we performed meta-analyses of dichotomous data using risk differences (RDs) and empirical continuity corrections. We used published data and data obtained by contacting trial authors. To minimise the risk of systematic error, we assessed the risk of bias of the included trials. Trial sequential analyses controlled the risk of random errors possibly caused by cumulative meta-analyses. Main results We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL). Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I2 = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I2 = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I2 = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I2 = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I2 = 17%; 710 participants; 3 trials). Authors' conclusions Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.

Omalizumab for asthma in adults and children.

Abstract: Background Asthma is a respiratory (airway) condition that affects an estimated 300 million people worldwide and is associated with significant morbidity and mortality. Omalizumab is a monoclonal antibody that binds and inhibits free serum immunoglobulin E (IgE). It is called an 'anti-IgE' drug. IgE is an immune mediator involved in clinical manifestations of asthma. A recent update of National Institute for Health and Care Excellence (NICE) guidance in 2013 recommends omalizumab for use as add-on therapy in adults and children over six years of age with inadequately controlled severe persistent allergic IgE-mediated asthma who require continuous or frequent treatment with oral corticosteroids. Objectives To assess the effects of omalizumab versus placebo or conventional therapy for asthma in adults and children. Search methods We searched the Cochrane Airways Group Specialised Register of trials for potentially relevant studies. The most recent search was performed in June 2013. We also checked the reference lists of included trials and searched online trial registries and drug company websites. Selection criteria Randomised controlled trials examining anti-IgE administered in any manner for any duration. Trials with co-interventions were included, as long as they were the same in each arm. Data collection and analysis Two review authors independently assessed study quality and extracted and entered data. Three modes of administration were identified from the published literature: inhaled, intravenous and subcutaneous injection. The main focus of the updated review is subcutaneous administration, as this route is currently used in clinical practice. Subgroup analysis was performed by asthma severity. Data were extracted from published and unpublished sources. Main results In all, 25 trials were included in the review, including 11 new studies since the last update, for a total of 19 that considered the efficacy of subcutaneous anti-IgE treatment as an adjunct to treatment with corticosteroids. For participants with moderate or severe asthma who were receiving background inhaled corticosteroid steroid (ICS) therapy, a significant advantage favoured subcutaneous omalizumab with regard to experiencing an asthma exacerbation (odds ratio (OR) 0.55, 95% confidence interval (CI) 0.42 to 0.60; ten studies, 3261 participants). This represents an absolute reduction from 26% for participants suffering an exacerbation on placebo to 16% on omalizumab, over 16 to 60 weeks. A significant benefit was noted for subcutaneous omalizumab versus placebo with regard to reducing hospitalisations (OR 0.16, 95% CI 0.06 to 0.42; four studies, 1824 participants), representing an absolute reduction in risk from 3% with placebo to 0.5% with omalizumab over 28 to 60 weeks. No separate data on hospitalisations were available for the severe asthma subgroup, and all of these data were reported for participants with the diagnosis of moderate to severe asthma. Participants treated with subcutaneous omalizumab were also significantly more likely to be able to withdraw their ICS completely than those treated with placebo (OR 2.50, 95% CI 2.00 to 3.13), and a small but statistically significant reduction in daily inhaled steroid dose was reported for omalizumab-treated participants compared with those given placebo (weighted mean difference (WMD) -118 mcg beclomethasone dipropionate (BDP) equivalent per day, 95% CI -154 to -84). However, no significant difference between omalizumab and placebo treatment groups was seen in the number of participants who were able to withdraw from oral corticosteroid (OCS) therapy (OR 1.18, 95% CI 0.53 to 2.63). Participants treated with subcutaneous omalizumab as an adjunct to treatment with corticosteroids required a small but significant reduction in rescue beta2-agonist medication compared with placebo (mean difference (MD) -0.39 puffs per day, 95% CI -0.55 to -0.24; nine studies, 3524 participants). This benefit was observed in both the moderate to severe (MD -0.58, 95% CI -0.84 to -0.31) and severe (MD -0.30, 95% CI -0.49 to -0.10) asthma subgroups on a background therapy of inhaled corticosteroids; however, no significant difference between subcutaneous omalizumab and placebo was noted for this outcome in participants with severe asthma who were receiving a background therapy of inhaled plus oral corticosteroids. Significantly fewer serious adverse events were reported in participants assigned to subcutaneous omalizumab than in those receiving placebo (OR 0.72, 95% CI 0.57 to 0.91; 15 studies, 5713 participants), but more injection site reactions were observed (from 5.6% with placebo to 9.1% with omalizumab). To reflect current clinical practice, discussion of the results is limited to subcutaneous use, and trials involving intravenous and inhaled routes have been archived. Authors' conclusions Omalizumab was effective in reducing asthma exacerbations and hospitalisations as an adjunctive therapy to inhaled steroids and during steroid tapering phases of clinical trials. Omalizumab was significantly more effective than placebo in increasing the numbers of participants who were able to reduce or withdraw their inhaled steroids. Omalizumab was generally well tolerated, although more injection site reactions were seen with omalizumab. Further assessment in paediatric populations is necessary, as is direct double-dummy comparison with ICS. Although subgroup analyses suggest that participants receiving prednisolone had better asthma control when they received omalizumab, it remains to be tested prospectively whether the addition of omalizumab has a prednisolone-sparing effect. It is also not clear whether there is a threshold level of baseline serum IgE for optimum efficacy of omalizumab. Given the high cost of the drug, identification of biomarkers predictive of response is of major importance for future research.

Psychological interventions for overweight or obesity

Abstract: Several psychological methods are used to try and help people who are overweight or obese to lose weight. This review found that cognitive behaviour therapy and behaviour therapy significantly improved the success of weight loss for these people. Cognitive therapy was not effective as a weight loss treatment. There was not enough evidence to reach a conclusion about other psychological forms of therapy, such as relaxation therapy and hypnotherapy, however the evidence that is available suggests that these therapies may also be successful in improving weight loss. No data on mortality, morbidity or quality of life were found.

Over-the-counter medications for acute cough in children and adults in ambulatory settings.

Abstract: Background Acute cough due to upper respiratory tract infection (URTI) is a common symptom. Non-prescription, over-the-counter (OTC) medicines are frequently recommended as a first-line treatment, but there is little evidence as to whether these drugs are effective. Objectives To assess the effects of oral OTC cough preparations for acute cough in children and adults in community settings. Search methods We searched CENTRAL (2014, Issue 1), MEDLINE (January 1966 to March week 3 2014), EMBASE (January 1974 to March 2014), CINAHL (January 2010 to March 2014), LILACS (January 2010 to March 2014), Web of Science (January 2010 to March 2014) and the UK Department of Health National Research Register (March 2010). Selection criteria Randomised controlled trials (RCTs) comparing oral OTC cough preparations with placebo in children and adults suffering from acute cough in community settings. We considered all cough outcomes; secondary outcomes of interest were adverse effects. Data collection and analysis Two review authors independently screened potentially relevant citations, extracted data and assessed study quality. We performed quantitative analysis where appropriate. Main results Due to the small numbers of trials in each category, the limited quantitative data available and the marked differences between trials in terms of participants, interventions and outcome measurement, we felt that pooling of the results was inappropriate. We included 29 trials (19 in adults, 10 in children) involving 4835 people (3799 adults and 1036 children). All studies were placebo-controlled RCTs. However, assessment of the risk of bias of the included studies was limited by poor reporting, particularly for the earlier studies. In the adult studies, six trials compared antitussives with placebo and had variable results. Three trials compared the expectorant guaifenesin with placebo; one indicated significant benefit, whereas the other two did not. One trial found that a mucolytic reduced cough frequency and symptom scores. Two studies examined antihistamine-decongestant combinations and found conflicting results. Four studies compared other combinations of drugs with placebo and indicated some benefit in reducing cough symptoms. Three trials found that antihistamines were no more effective than placebo in relieving cough symptoms. In the child studies, antitussives (data from three studies), antihistamines (data from three studies), antihistamine-decongestants (two studies) and antitussive/bronchodilator combinations (one study) were no more effective than placebo. No studies using expectorants met our inclusion criteria. The results of one trial favoured active treatment with mucolytics over placebo. One trial tested two paediatric cough syrups and both preparations showed a 'satisfactory response' in 46% and 56% of children compared to 21% of children in the placebo group. One new trial indicated that three types of honey were more effective than placebo over a three-day period. Twenty-one studies reported adverse effects. There was a wide range across studies, with higher numbers of adverse effects in participants taking preparations containing antihistamines and dextromethorphan. Authors' conclusions The results of this review have to be interpreted with caution because the number of studies in each category of cough preparations was small. Availability, dosing and duration of use of over-the-counter cough medicines vary significantly in different countries. Many studies were poorly reported making assessment of risk of bias difficult and studies were also very different from each other, making evaluation of overall efficacy difficult. There is no good evidence for or against the effectiveness of OTC medicines in acute cough. This should be taken into account when considering prescribing antihistamines and centrally active antitussive agents in children; drugs that are known to have the potential to cause serious harm.

The WHO Health Promoting School framework for improving the health and well‐being of students and their academic achievement

Abstract: BACKGROUND: The World Health Organization's (WHO's) Health Promoting Schools (HPS) framework is an holistic, settings-based approach to promoting health and educational attainment in school. The effectiveness of this approach has not been previously rigorously reviewed. OBJECTIVES: To assess the effectiveness of the Health Promoting Schools (HPS) framework in improving the health and well-being of students and their academic achievement. SEARCH METHODS: We searched the following electronic databases in January 2011 and again in March and April 2013: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, Campbell Library, ASSIA, BiblioMap, CAB Abstracts, IBSS, Social Science Citation Index, Sociological Abstracts, TRoPHI, Global Health Database, SIGLE, Australian Education Index, British Education Index, Education Resources Information Centre, Database of Education Research, Dissertation Express, Index to Theses in Great Britain and Ireland, ClinicalTrials.gov, Current controlled trials, and WHO International Clinical Trials Registry Platform. We also searched relevant websites, handsearched reference lists, and used citation tracking to identify other relevant articles. SELECTION CRITERIA: We included cluster-randomised controlled trials where randomisation took place at the level of school, district or other geographical area. Participants were children and young people aged four to 18 years, attending schools or colleges. In this review, we define HPS interventions as comprising the following three elements: input to the curriculum; changes to the school's ethos or environment or both; and engagement with families or communities, or both. We compared this intervention against schools that implemented either no intervention or continued with their usual practice, or any programme that included just one or two of the above mentioned HPS elements. DATA COLLECTION AND ANALYSIS: At least two review authors identified relevant trials, extracted data, and assessed risk of bias in the trials. We grouped different types of interventions according to the health topic targeted or the approach used, or both. Where data permitted, we performed random-effects meta-analyses to provide a summary of results across studies. MAIN RESULTS: We included 67 eligible cluster trials, randomising 1443 schools or districts. This is made up of 1345 schools and 98 districts. The studies tackled a range of health issues: physical activity (4), nutrition (12), physical activity and nutrition combined (18), bullying (7), tobacco (5), alcohol (2), sexual health (2), violence (2), mental health (2), hand-washing (2), multiple risk behaviours (7), cycle-helmet use (1), eating disorders (1), sun protection (1), and oral health (1). The quality of evidence overall was low to moderate as determined by the GRADE approach. 'Risk of bias' assessments identified methodological limitations, including heavy reliance on self-reported data and high attrition rates for some studies. In addition, there was a lack of long-term follow-up data for most studies.We found positive effects for some interventions for: body mass index (BMI), physical activity, physical fitness, fruit and vegetable intake, tobacco use, and being bullied. Intervention effects were generally small but have the potential to produce public health benefits at the population level. We found little evidence of effectiveness for standardised body mass index (zBMI) and no evidence of effectiveness for fat intake, alcohol use, drug use, mental health, violence and bullying others; however, only a small number of studies focused on these latter outcomes. It was not possible to meta-analyse data on other health outcomes due to lack of data. Few studies provided details on adverse events or outcomes related to the interventions. In addition, few studies included any academic, attendance or school-related outcomes. We therefore cannot draw any clear conclusions as to the effectiveness of this approach for improving academic achievement. AUTHORS' CONCLUSIONS: The results of this review provide evidence for the effectiveness of some interventions based on the HPS framework for improving certain health outcomes but not others. More well-designed research is required to establish the effectiveness of this approach for other health topics and academic achievement.

Multidisciplinary biopsychosocial rehabilitation for chronic low back pain

Abstract: Background Low back pain (LBP) is responsible for considerable personal suffering worldwide. Those with persistent disabling symptoms also contribute to substantial costs to society via healthcare expenditure and reduced work productivity. While there are many treatment options, none are universally endorsed. The idea that chronic LBP is a condition best understood with reference to an interaction of physical, psychological and social influences, the 'biopsychosocial model', has received increasing acceptance. This has led to the development of multidisciplinary biopsychosocial rehabilitation (MBR) programs that target factors from the different domains, administered by healthcare professionals from different backgrounds. Objectives To review the evidence on the effectiveness of MBR for patients with chronic LBP. The focus was on comparisons with usual care and with physical treatments measuring outcomes of pain, disability and work status, particularly in the long term. Search methods We searched the CENTRAL, MEDLINE, EMBASE, PsycINFO and CINAHL databases in January and March 2014 together with carrying out handsearches of the reference lists of included and related studies, forward citation tracking of included studies and screening of studies excluded in the previous version of this review. Selection criteria All studies identified in the searches were screened independently by two review authors; disagreements regarding inclusion were resolved by consensus. The inclusion criteria were published randomised controlled trials (RCTs) that included adults with non-specific LBP of longer than 12 weeks duration; the index intervention targeted at least two of physical, psychological and social or work-related factors; and the index intervention was delivered by clinicians from at least two different professional backgrounds. Data collection and analysis Two review authors extracted and checked information to describe the included studies, assessed risk of bias and performed the analyses. We used the Cochrane risk of bias tool to describe the methodological quality. The primary outcomes were pain, disability and work status, divided into the short, medium and long term. Secondary outcomes were psychological functioning (for example depression, anxiety, catastrophising), healthcare service utilisation, quality of life and adverse events. We categorised the control interventions as usual care, physical treatment, surgery, or wait list for surgery in separate meta-analyses. The first two comparisons formed our primary focus. We performed meta-analyses using random-effects models and assessed the quality of evidence using the GRADE method. We performed sensitivity analyses to assess the influence of the methodological quality, and subgroup analyses to investigate the influence of baseline symptom severity and intervention intensity. Main results From 6168 studies identified in the searches, 41 RCTs with a total of 6858 participants were included. Methodological quality ratings ranged from 1 to 9 out 12, and 13 of the 41 included studies were assessed as low risk of bias. Pooled estimates from 16 RCTs provided moderate to low quality evidence that MBR is more effective than usual care in reducing pain and disability, with standardised mean differences (SMDs) in the long term of 0.21 (95% CI 0.04 to 0.37) and 0.23 (95% CI 0.06 to 0.4) respectively. The range across all time points equated to approximately 0.5 to 1.4 units on a 0 to 10 numerical rating scale for pain and 1.4 to 2.5 points on the Roland Morris disability scale (0 to 24). There was moderate to low quality evidence of no difference on work outcomes (odds ratio (OR) at long term 1.04, 95% CI 0.73 to 1.47). Pooled estimates from 19 RCTs provided moderate to low quality evidence that MBR was more effective than physical treatment for pain and disability with SMDs in the long term of 0.51 (95% CI -0.01 to 1.04) and 0.68 (95% CI 0.16 to 1.19) respectively. Across all time points this translated to approximately 0.6 to 1.2 units on the pain scale and 1.2 to 4.0 points on the Roland Morris scale. There was moderate to low quality evidence of an effect on work outcomes (OR at long term 1.87, 95% CI 1.39 to 2.53). There was insufficient evidence to assess whether MBR interventions were associated with more adverse events than usual care or physical interventions. Sensitivity analyses did not suggest that the pooled estimates were unduly influenced by the results from low quality studies. Subgroup analyses were inconclusive regarding the influence of baseline symptom severity and intervention intensity. Authors' conclusions Patients with chronic LBP receiving MBR are likely to experience less pain and disability than those receiving usual care or a physical treatment. MBR also has a positive influence on work status compared to physical treatment. Effects are of a modest magnitude and should be balanced against the time and resource requirements of MBR programs. More intensive interventions were not responsible for effects that were substantially different to those of less intensive interventions. While we were not able to determine if symptom intensity at presentation influenced the likelihood of success, it seems appropriate that only those people with indicators of significant psychosocial impact are referred to MBR.

Selenium for preventing cancer

Abstract: Background This review is an update of the first Cochrane publication on selenium for preventing cancer (Dennert 2011). Selenium is a metalloid with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancers.

Bronchodilators for bronchiolitis

Abstract: Background Bronchiolitis is an acute, viral lower respiratory tract infection affecting infants and is sometimes treated with bronchodilators. Objectives To assess the effects of bronchodilators on clinical outcomes in infants (0 to 12 months) with acute bronchiolitis. Search methods We searched CENTRAL 2013, Issue 12, MEDLINE (1966 to January Week 2, 2014) and EMBASE (1998 to January 2014). Selection criteria Randomized controlled trials (RCTs) comparing bronchodilators (other than epinephrine) with placebo for bronchiolitis. Data collection and analysis Two authors assessed trial quality and extracted data. We obtained unpublished data from trial authors. Main results We included 30 trials (35 data sets) representing 1992 infants with bronchiolitis. In 11 inpatient and 10 outpatient studies, oxygen saturation did not improve with bronchodilators (mean difference (MD) -0.43, 95% confidence interval (CI) -0.92 to 0.06, n = 1242). Outpatient bronchodilator treatment did not reduce the rate of hospitalization (11.9% in bronchodilator group versus 15.9% in placebo group, odds ratio (OR) 0.75, 95% CI 0.46 to 1.21, n = 710). Inpatient bronchodilator treatment did not reduce the duration of hospitalization (MD 0.06, 95% CI -0.27 to 0.39, n = 349). Effect estimates for inpatients (MD -0.62, 95% CI -1.40 to 0.16) were slightly larger than for outpatients (MD -0.25, 95% CI -0.61 to 0.11) for oximetry. Oximetry outcomes showed significant heterogeneity (I2 statistic = 81%). Including only studies with low risk of bias had little impact on the overall effect size of oximetry (MD -0.38, 95% CI -0.75 to 0.00) but results were close to statistical significance. In eight inpatient studies, there was no change in average clinical score (standardized MD (SMD) -0.14, 95% CI -0.41 to 0.12) with bronchodilators. In nine outpatient studies, the average clinical score decreased slightly with bronchodilators (SMD -0.42, 95% CI -0.79 to -0.06), a statistically significant finding of questionable clinical importance. The clinical score outcome showed significant heterogeneity (I2 statistic = 73%). Including only studies with low risk of bias reduced the heterogeneity but had little impact on the overall effect size of average clinical score (SMD -0.22, 95% CI -0.41 to -0.03). Sub-analyses limited to nebulized albuterol or salbutamol among outpatients (nine studies) showed no effect on oxygen saturation (MD -0.19, 95% CI -0.59 to 0.21, n = 572), average clinical score (SMD -0.36, 95% CI -0.83 to 0.11, n = 532) or hospital admission after treatment (OR 0.77, 95% CI 0.44 to 1.33, n = 404). Adverse effects included tachycardia, oxygen desaturation and tremors. Authors' conclusions Bronchodilators such as albuterol or salbutamol do not improve oxygen saturation, do not reduce hospital admission after outpatient treatment, do not shorten the duration of hospitalization and do not reduce the time to resolution of illness at home. Given the adverse side effects and the expense associated with these treatments, bronchodilators are not effective in the routine management of bronchiolitis. This meta-analysis continues to be limited by the small sample sizes and the lack of standardized study design and validated outcomes across the studies. Future trials with large sample sizes, standardized methodology across clinical sites and consistent assessment methods are needed to answer completely the question of efficacy.