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cochrane-simplification-train-2700

cochrane-simplification-train-2700

Twenty-nine trial comparisons involving 11,306 participants contributed to the meta-analysis on the risk ratio (RR) of developing a cold whilst taking vitamin C regularly over the study period. In the general community trials involving 10,708 participants, the pooled RR was 0.97 (95% confidence interval (CI) 0.94 to 1.00). Five trials involving a total of 598 marathon runners, skiers and soldiers on subarctic exercises yielded a pooled RR of 0.48 (95% CI 0.35 to 0.64). Thirty-one comparisons examined the effect of regular vitamin C on common cold duration (9745 episodes). In adults the duration of colds was reduced by 8% (3% to 12%) and in children by 14% (7% to 21%). In children, 1 to 2 g/day vitamin C shortened colds by 18%. The severity of colds was also reduced by regular vitamin C administration. Seven comparisons examined the effect of therapeutic vitamin C (3249 episodes). No consistent effect of vitamin C was seen on the duration or severity of colds in the therapeutic trials. The majority of included trials were randomised, double-blind trials. The exclusion of trials that were either not randomised or not double-blind had no effect on the conclusions. The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C supplementation is not justified, yet vitamin C may be useful for people exposed to brief periods of severe physical exercise. Regular supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them. Further therapeutic RCTs are warranted.

Vitamin C has been proposed for treating respiratory infections since it was isolated in the 1930s. It became particularly popular in the 1970s when Nobel laureate Linus Pauling concluded from earlier placebo-controlled trials that vitamin C would prevent and alleviate the common cold. Over two dozen new trials were undertaken thereafter. Vitamin C has been widely sold and used as a preventive and therapeutic agent. This review is restricted to placebo-controlled trials testing 0.2 g/day or more of vitamin C. Regular ingestion of vitamin C had no effect on common cold incidence in the ordinary population, based on 29 trial comparisons involving 11,306 participants. However, regular supplementation had a modest but consistent effect in reducing the duration of common cold symptoms, which is based on 31 study comparisons with 9745 common cold episodes. In five trials with 598 participants exposed to short periods of extreme physical stress (including marathon runners and skiers) vitamin C halved the common cold risk. The published trials have not reported adverse effects of vitamin C. Trials of high doses of vitamin C administered therapeutically, starting after the onset of symptoms, showed no consistent effect on the duration or severity of common cold symptoms. However, only a few therapeutic trials have been carried out and none have examined children, although the effect of prophylactic vitamin C has been greater in children. One large trial with adults reported benefit from an 8 g therapeutic dose at the onset of symptoms, and two therapeutic trials using five-day supplementation reported benefit. More trials are necessary to settle the possible role of therapeutic vitamin C, meaning administration immediately after the onset of symptoms.

10.1002/14651858.CD000980.pub4

cochrane-simplification-train-2701

cochrane-simplification-train-2701

In this review, we included 22 RCTs that investigated the use of T-cell antibody induction, with a total of 1427 heart-transplant recipients. All trials were judged to be at a high risk of bias. Five trials, with a total of 606 participants, compared any kind of T-cell antibody induction versus no antibody induction; four trials, with a total of 576 participants, compared interleukin-2 receptor antagonist (IL-2 RA) versus no induction; one trial, with 30 participants, compared monoclonal antibody (other than IL-2 RA) versus no antibody induction; two trials, with a total of 159 participants, compared IL-2 RA versus monoclonal antibody (other than IL-2 RA) induction; four trials, with a total of 185 participants, compared IL-2 RA versus polyclonal antibody induction; seven trials, with a total of 315 participants, compared monoclonal antibody (other than IL-2 RA) versus polyclonal antibody induction; and four trials, with a total of 162 participants, compared polyclonal antibody induction versus another kind, or dose of polyclonal antibodies. No significant differences were found for any of the comparisons for the outcomes of mortality, infection, CMV infection, post-transplantation lymphoproliferative disorder, cancer, adverse events, chronic allograft vasculopathy, renal function, hypertension, diabetes mellitus, or hyperlipidaemia. Acute rejection occurred significantly less frequently when IL-2 RA induction was compared with no induction (93/284 (33%) versus 132/292 (45%); RR 0.73; 95% CI 0.59 to 0.90; I2 57%) applying the fixed-effect model. No significant difference was found when the random-effects model was applied (RR 0.73; 95% CI 0.46 to 1.17; I2 57%). In addition, acute rejection occurred more often statistically when IL-2 RA induction was compared with polyclonal antibody induction (24/90 (27%) versus 10/95 (11%); RR 2.43; 95% CI 1.01 to 5.86; I2 28%). For all of these differences in acute rejection, trial sequential alpha-spending boundaries were not crossed and the required information sizes were not reached when trial sequential analysis was performed, indicating that we cannot exclude random errors. We observed some occasional significant differences in adverse events in some of the comparisons, however definitions of adverse events varied between trials, and numbers of participants and events in these outcomes were too small to allow definitive conclusions to be drawn. This review shows that acute rejection might be reduced by IL-2 RA compared with no induction, and by polyclonal antibody induction compared with IL-2 RA, though trial sequential analyses cannot exclude random errors, and the significance of our observations depended on the statistical model used. Furthermore, this review does not show other clear benefits or harms associated with the use of any kind of T-cell antibody induction compared with no induction, or when one type of T-cell antibody is compared with another type of antibody. The number of trials investigating the use of antibodies against T-cells for induction after heart transplantation is small, and the number of participants and outcomes in these RCTs is limited. Furthermore, the included trials are at a high risk of bias. Hence, more RCTs are needed to assess the benefits and harms of T-cell antibody induction for heart-transplant recipients. Such trials ought to be conducted with low risks of systematic and random error.

All these trials had high risk of bias (that is risk of overestimation of benefits and underestimation of harms). We compared any kind of T-cell antibody induction versus no induction. Furthermore, we compared interleukin-2 receptor antagonists versus no induction, monoclonal T-cell antibody versus no induction, interleukin-2 receptor antagonists versus monoclonal antibody (other than IL-2 RA) induction, interleukin-2 receptor antagonists versus polyclonal antibody induction, and monoclonal antibody (other than IL-2 RA) induction versus polyclonal antibody induction. We found no significant differences in incidence of survival, and we found no significant difference in adverse effects (e.g. infection, cytomegalovirus infection, post-transplantation lymphoproliferative disorder, cancer, chronic allograft vasculopathy, renal function, hypertension, diabetes mellitus, or hypertension) for any of the comparisons. The incidence of acute rejection may occur less frequently in patients treated with interleukin-2 receptor antagonist induction compared with no induction , and in patients treated with polyclonal antibody induction compared with interleukin-2 receptor antagonist induction. However, systematic errors and random errors cannot be excluded, and our findings were dependent upon choice of statistical model. Accordingly, our observations are not robust and more trials are needed to confirm or reject these findings.

10.1002/14651858.CD008842.pub2

cochrane-simplification-train-2702

cochrane-simplification-train-2702

We included 71 trials in the review with 26 studies (1398 participants) comparing a bleaching agent to placebo and 51 studies (2382 participants) comparing a bleaching agent to another bleaching agent. Two studies were at low overall risk of bias; two at high overall risk of bias; and the remaining 67 at unclear overall risk of bias. The bleaching agents (carbamide peroxide (CP) gel in tray, hydrogen peroxide (HP) gel in tray, HP strips, CP paint-on gel, HP paint-on gel, sodium hexametaphosphate (SHMP) chewing gum, sodium tripolyphosphate (STPP) chewing gum, and HP mouthwash) at different concentrations with varying application times whitened teeth compared to placebo over a short time period (from 2 weeks to 6 months), however the certainty of the evidence is low to very low. In trials comparing one bleaching agent to another, concentrations, application method and application times, and duration of use varied widely. Most of the comparisons were reported in single trials with small sample sizes and event rates and certainty of the evidence was assessed as low to very low. Therefore the evidence currently available is insufficient to draw reliable conclusions regarding the superiority of home-based bleaching compositions or any particular method of application or concentration or application time or duration of use. Tooth sensitivity and oral irritation were the most common side effects which were more prevalent with higher concentrations of active agents though the effects were mild and transient. Tooth whitening did not have any effect on oral health-related quality of life. We found low to very low-certainty evidence over short time periods to support the effectiveness of home-based chemically-induced bleaching methods compared to placebo for all the outcomes tested. We were unable to draw any conclusions regarding the superiority of home-based bleaching compositions or any particular method of application or concentration or application time or duration of use, as the overall evidence generated was of very low certainty. Well-planned RCTs need to be conducted by standardising methods of application, concentrations, application times, and duration of treatment.

Authors from Cochrane Oral Health carried out this review of existing studies and the evidence is current up to 12 June 2018. We included 71 trials that involved 3780 adults who underwent tooth whitening procedures with various bleaching agents using different methods of application, length of application and duration of treatment. 26 studies compared a bleaching agent to placebo and 51 studies compared one bleaching agent to another bleaching agent. The bleaching agents whitened teeth compared to placebo over a short time period (from 2 weeks to 6 months), however the certainty of the evidence is low to very low. The evidence currently available is insufficient to draw reliable conclusions regarding the superiority of home-based bleaching compositions or any particular method of application or concentration or application time or duration of use. The most common adverse events were tooth sensitivity and oral irritation, which were reported with higher concentrations of active agents, although the effects were mild and transient. Well-planned randomised controlled trials need to be conducted by standardising methods of application, concentrations, application times and duration of treatment. The overall certainty of the evidence was low to very low for all comparisons. This was because most of the comparisons were reported in single trials with small sample sizes and event rates. There was an unclear risk of bias in most of the trials.

10.1002/14651858.CD006202.pub2

cochrane-simplification-train-2703

cochrane-simplification-train-2703

In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed-dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow-up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow-up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed-dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89,  I2 = 0%, 5 studies, N = 5300) and fatal and non-fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low-quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed-dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed-dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate-quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was -6.34 mmHg (95% CI -9.03 to -3.64, 13 trials, 7638 participants, moderate-quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.61 mmol/L (95% CI -0.88 to -0.35, 11 trials, 6565 participants, low-quality evidence) and -0.70 mmol/L (95% CI -0.98 to -0.41, 12 trials, 7153 participants, moderate-quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate-quality evidence). The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes.

The evidence is current to September 2016. Four studies included individuals with a prior heart attack or stroke or with a high predicted risk for having an initial heart attack and five studies had long-term (12 months or more) follow-up. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Most study participants were middle-aged men with moderate elevations in blood pressure or cholesterol. Two studies specifically included ethnic Aboriginal or Maori minorities in half of the study participants. The fixed-dose combinations ranged from two to five drugs; all studies included at least one blood pressure-lowering and one cholesterol-lowering drug. The effects of fixed-dose combination drug therapy on all-cause mortality and fatal and non-fatal heart attacks and strokes are uncertain, primarily due to the low number of participants experiencing these events in these studies (fewer than 5% for both) and comparisons with usual care (low-quality evidence). Fixed-dose combination drug therapy leads to more adverse events than control (32% versus 27%), including placebo (moderate-quality evidence). This information is not surprising since aspirin, blood pressure-lowering drugs and cholesterol drugs are known to increase the risk for side effects compared with placebo. Fixed-dose combination therapy may modestly lower blood pressure (˜6 mmHg) and cholesterol (-0.6 mmol/L in LDL cholesterol), but these effects were not consistent (moderate-quality evidence for blood pressure and LDL cholesterol but low-quality evidence of total cholesterol). Fixed-dose combination therapy appears to improve adherence to medications to prevent ASCVD (moderate-quality evidence). The quality of evidence from these studies generally ranged from moderate to low. Ongoing trials of fixed-dose combination drug therapy will likely inform clinical endpoints to guide decision-making.

10.1002/14651858.CD009868.pub3

cochrane-simplification-train-2704

cochrane-simplification-train-2704

We included three trials (429 participants) with differences regarding their design (two trials compared bronchial thermoplasty vs medical management and the other compared bronchial thermoplasty vs a sham intervention) and participant characteristics; one of the studies included participants with more symptomatic asthma compared with the others. The pooled analysis showed improvement in quality of life at 12 months in participants who received bronchial thermoplasty that did not reach the threshold for clinical significance (3 trials, 429 participants; mean difference (MD) in Asthma Quality of Life Questionnaire (AQLQ) scores 0.28, 95% confidence interval (CI) 0.07 to 0.50; moderate-quality evidence). Measures of symptom control showed no significant differences (3 trials, 429 participants; MD in Asthma Control Questionnaire (ACQ) scores -0.15, 95% CI -0.40 to 0.10; moderate-quality evidence). The risk of bias for these outcomes was high because two of the studies did not have a sham intervention for the control group. The results from two trials showed a lower rate of exacerbation after 12 months of treatment for participants who underwent bronchial thermoplasty. The trial with sham intervention showed a significant reduction in the proportion of participants visiting the emergency department for respiratory symptoms, from 15.3% on sham treatment to 8.4% over 12 months following thermoplasty. The trials showed no significant improvement in pulmonary function parameters (with the exception of a greater increase in morning peak expiratory flow (PEF) in one trial). Treated participants who underwent bronchial thermoplasty had a greater risk of hospitalisation for respiratory adverse events during the treatment period (3 trials, 429 participants; risk ratio 3.50, 95% CI 1.26 to 9.68; high-quality evidence), which represents an absolute increase from 2% to 8% (95% CI 3% to 23%) over the treatment period. This means that six of 100 participants treated with thermoplasty (95% CI 1 to 21) would require an additional hospitalisation over the treatment period. No significant difference in the risk of hospitalisation was noted at the end of the treatment period. Bronchial thermoplasty was associated with an increase in respiratory adverse events, mainly during the treatment period. Most of these events were mild or moderate, appeared in the 24-hour post-treatment period, and were resolved within a week. Bronchial thermoplasty for patients with moderate to severe asthma provides a modest clinical benefit in quality of life and lower rates of asthma exacerbation, but no significant difference in asthma control scores. The quality of life findings are at risk of bias, as the main benefits were seen in the two studies that did not include a sham treatment arm. This procedure increases the risk of adverse events during treatment but has a reasonable safety profile after completion of the bronchoscopies. The overall quality of evidence regarding this procedure is moderate. For clinical practice, it would be advisable to collect data from patients systematically in independent clinical registries. Further research should provide better understanding of the mechanisms of action of bronchial thermoplasty, as well as its effect in different asthma phenotypes or in patients with worse lung function.

We found three trials comparing groups of adults treated with bronchial thermoplasty versus adults who received standard medical treatment or a "sham" (simulated) bronchial thermoplasty treatment. These studies showed moderate improvement only in quality of life of patients treated with bronchial thermoplasty and in the number of asthma attacks (exacerbations) that they experienced. In addition, patients treated with this procedure had more respiratory problems than patients who received the alternative intervention during the period when they were undergoing treatment, resulting in increased risk of hospitalisation due to a respiratory symptom during this phase, but not afterward. Confidence in the results of this review is moderate because two of the studies had no sham intervention and there were differences regarding the characteristics of patients and the comparisons performed. More studies should be conducted to determine whether the observed effect and safety of bronchial thermoplasty are durable over the long term, and to identify whether particular patients can be identified who could benefit most. This plain language summary is current as of January 2014.

10.1002/14651858.CD009910.pub2

cochrane-simplification-train-2705

cochrane-simplification-train-2705

We identified and included 10 studies (428 total participants, followed for 2-16 weeks) in this review. Our primary outcome was restlessness or uncomfortable leg sensations, which was quantified using the International Restless Legs Scale (IRLS) (range, 0 to 40) in eight trials and a different RLS symptom scale in a ninth trial. Nine studies compared iron to placebo and one study compared iron to a dopamine agonist (pramipexole). The possibility for bias among the trials was variable. Three studies had a single element with high risk of bias, which was lack of blinding in two and incomplete outcome data in one. All studies had at least one feature resulting in unclear risk of bias. Combining data from the seven trials using the IRLS to compare iron and placebo, use of iron resulted in greater improvement in IRLS scores (MD -3.78, 95% CI -6.25 to -1.31; I2= 66%, 7 studies, 345 participants) measured 2 to 12 weeks after treatment. Including an eighth study, which measured restlessness using a different scale, use of iron remained beneficial compared to placebo (SMD -0.74, 95% CI -1.26 to -0.23; I2 = 80%, 8 studies, 370 participants). The GRADE assessment of certainty for this outcome was moderate. The single study comparing iron to a dopamine agonist (pramipexole) found a similar reduction in RLS severity in the two groups (MD -0.40, 95% CI -5.93 to 5.13, 30 participants). Assessment of secondary outcomes was limited by small numbers of trials assessing each outcome. Iron did not improve quality of life as a dichotomous measure (RR 2.01, 95% CI 0.54 to 7.45; I2=54%, 2 studies, 39 participants), but did improve quality of life measured on continuous scales (SMD 0.51, 95% CI 0.15 to 0.87; I2= 0%, 3 studies, 128 participants), compared to placebo. Subjective sleep quality was no different between iron and placebo groups (SMD 0.19, 95% CI -0.18 to 0.56; I2 = 9%, 3 studies, 128 participants), nor was objective sleep quality, as measured by change in sleep efficiency in a single study (-35.5 +/- 92.0 versus -41.4 +/- 98.2, 18 participants). Periodic limb movements of sleep were not significantly reduced with iron compared to placebo ( SMD -0.19, 95% CI -0.70 to 0.32; I2 = 0%, 2 studies, 60 participants). Iron did not improve sleepiness compared to placebo, as measured on the Epworth Sleepiness Scale (data not provided, 1 study, 60 participants) but did improve the daytime tiredness item of the RLS-6 compared to placebo (least squares mean difference -1.5, 95% CI -2.5 to -0.6; 1 study, 110 participants). The GRADE rating for secondary outcomes ranged from low to very low. Prespecified subgroup analyses showed more improvement with iron in those trials studying participants on dialysis. The use of low serum ferritin levels as an inclusion criteria and the use or oral versus intravenous iron did not show significant subgroup differences. Iron did not result in significantly more adverse events than placebo (RR 1.48, 95% CI 0.97 to 2.25; I2=45%, 6 studies, 298 participants). A single study reported that people treated with iron therapy experienced fewer adverse events than the active comparator pramipexole. Iron therapy probably improves restlessness and RLS severity in comparison to placebo. Iron therapy may not increase the risk of side effects in comparison to placebo. We are uncertain whether iron therapy improves quality of life in comparison to placebo. Iron therapy may make little or no difference to pramipexole in restlessness and RLS severity, as well as in the risk of adverse events. The effect on secondary outcomes such as quality of life, daytime functioning, and sleep quality, the optimal timing and formulation of administration, and patient characteristics predicting response require additional study.

We included 10 studies of iron. These 10 studies included 428 people with restless legs syndrome. Not all participants had low blood levels of iron. All participants were adults. Most of the studies used injections of iron, while three studies used iron in pill form. Iron treatment was compared to a non-active treatment (i.e. a placebo) in nine studies. In one study, iron was compared to another restless legs syndrome treatment called a dopamine agonist. The main measure of interest in our review was the severity of restlessness. This was usually measured using a 10-question survey regarding severity and effects of urges to move the legs, called the International Restless Legs Syndrome Severity Rating Scale (IRLS). This was measured 2-4 weeks after injections of iron and 12-14 weeks after iron in pill form. Four trials were funded by the drug manufacturer. Two trials were funded by the USA National Institutes of Health. Two trials were funded by the workplaces of the study investigators. Two studies did not report who funded the study. The four studies funded by drug manufacturers were the largest. The studies funded by drug companies contributed over half of the total number of participants. Overall, the studies showed that iron is better than a placebo for reducing the severity of restless legs syndrome symptoms, although the benefit was low to moderate. This is mostly based on studies using injections of iron, rather than iron pills. Iron was helpful even if blood iron levels were normal at the start of the study. The quality of the evidence was moderate, because not all completed studies have been published, not all important outcomes have been measured, and not enough people have been studied. Side effects were not more common with iron than with placebo. Based on one study, side effects were less common with iron than with another commonly used restless legs syndrome treatment, although the certainty in this result is very low. More studies are needed to allow people with RLS and doctors to make decisions about who should take iron for restless legs syndrome treatment, using what type of iron, and for how long. The evidence is current to September 2017.

10.1002/14651858.CD007834.pub3

cochrane-simplification-train-2706

cochrane-simplification-train-2706

Twenty-two RCTs (1744 people) met our inclusion criteria. The RCTs were of variable methodological quality (most at high risk of bias because of lack of blinding). There was no evidence for a sustained BP lowering effect of acupuncture; only one trial investigated a sustained effect and found no BP lowering effect at three and six months after acupuncture. Four sham acupuncture controlled trials provided very low quality evidence that acupuncture had a short-term (one to 24 hours) effect on SBP (change) -3.4 mmHg (-6.0 to -0.9) and DBP -1.9 mmHg (95% CI -3.6 to -0.3). Pooled analysis of eight trials comparing acupuncture with angiotensin-converting enzyme inhibitors and seven trials comparing acupuncture to calcium antagonists suggested that acupuncture lowered short-term BP better than the antihypertensive drugs. However, because of the very high risk of bias in these trials, we think that this is most likely a reflection of bias and not a true effect. As a result, we did not report these results in the 'Summary of findings' table. Safety of acupuncture could not be assessed as only eight trials reported adverse events. At present, there is no evidence for the sustained BP lowering effect of acupuncture that is required for the management of chronically elevated BP. The short-term effects of acupuncture are uncertain due to the very low quality of evidence. The larger effect shown in non-sham acupuncture controlled trials most likely reflects bias and is not a true effect. Future RCTs must use sham acupuncture controls and assess whether there is a BP lowering effect of acupuncture that lasts at least seven days.

We performed a systematic review of medical databases to find clinical trials that compared the effects of acupuncture to controls (sham (pretend) acupuncture, no treatment, or medicines) on blood pressure and safety in adults with hypertension. The results are current to February 2017. We found 22 trials including 1744 people. The trials did not look at death and general health. Four trials compared acupuncture with sham acupuncture and suggested a small short-lasting (one to 24 hours) reduction in blood pressure. The other trials were of very poor quality. There was no evidence for a long-lasting lowering of blood pressure by acupuncture that would be useful in the treatment of hypertension. We could not assess the safety of acupuncture as few trials reported this. At present, there is no evidence that acupuncture is useful in the management of long-lasting hypertension. Future trials must be designed to measure a sustained blood pressure lowering effect of acupuncture.

10.1002/14651858.CD008821.pub2

cochrane-simplification-train-2707

cochrane-simplification-train-2707

In this substantive review update, 30 RCTs (49 papers) (12,461 participants randomised) and seven ongoing trials met our inclusion criteria. The majority of trials contributed to primary prevention: comparisons 1 (nine trials) and 2 (13 trials). Secondary prevention trials were included for comparison 3 (two trials) and comparison 4 (four trials plus an additional two trials that were excluded from the main analyses due to published concerns regarding the reliability of the data). Two trials reported on adverse events where these were absent or minor (low- to moderate-quality evidence). No trials reported on costs or health-related quality of life. Primary prevention The included studies for comparison 1 did not report on clinical endpoints (CVD mortality, total mortality or non-fatal endpoints such as myocardial infarction or stroke). The PREDIMED trial (included in comparison 2) was retracted and re-analysed following concerns regarding randomisation at two of 11 sites. Low-quality evidence shows little or no effect of the PREDIMED (7747 randomised) intervention (advice to follow a Mediterranean diet plus supplemental extra-virgin olive oil or tree nuts) compared to a low-fat diet on CVD mortality (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.50 to 1.32) or total mortality (HR 1.0, 95% CI 0.81 to 1.24) over 4.8 years. There was, however, a reduction in the number of strokes with the PREDIMED intervention (HR 0.60, 95% CI 0.45 to 0.80), a decrease from 24/1000 to 14/1000 (95% CI 11 to 19), moderate-quality evidence). For CVD risk factors for comparison 1 there was low-quality evidence for a possible small reduction in total cholesterol (-0.16 mmol/L, 95% CI -0.32 to 0.00) and moderate-quality evidence for a reduction in systolic (-2.99 mmHg (95% CI -3.45 to -2.53) and diastolic blood pressure (-2.0 mmHg, 95% CI -2.29 to -1.71), with low or very low-quality evidence of little or no effect on LDL or HDL cholesterol or triglycerides. For comparison 2 there was moderate-quality evidence of a possible small reduction in LDL cholesterol (-0.15 mmol/L, 95% CI -0.27 to -0.02) and triglycerides (-0.09 mmol/L, 95% CI -0.16 to -0.01) with moderate or low-quality evidence of little or no effect on total or HDL cholesterol or blood pressure. Secondary prevention For secondary prevention, the Lyon Diet Heart Study (comparison 3) examined the effect of advice to follow a Mediterranean diet and supplemental canola margarine compared to usual care in 605 CHD patients over 46 months and there was low-quality evidence of a reduction in adjusted estimates for CVD mortality (HR 0.35, 95% CI 0.15 to 0.82) and total mortality (HR 0.44, 95% CI 0.21 to 0.92) with the intervention. Only one small trial (101 participants) provided unadjusted estimates for composite clinical endpoints for comparison 4 (very low-quality evidence of uncertain effect). For comparison 3 there was low-quality evidence of little or no effect of a Mediterranean-style diet on lipid levels and very low-quality evidence for blood pressure. Similarly, for comparison 4 where only two trials contributed to the analyses there was low or very low-quality evidence of little or no effect of the intervention on lipid levels or blood pressure. Despite the relatively large number of studies included in this review, there is still some uncertainty regarding the effects of a Mediterranean-style diet on clinical endpoints and CVD risk factors for both primary and secondary prevention. The quality of evidence for the modest benefits on CVD risk factors in primary prevention is low or moderate, with a small number of studies reporting minimal harms. There is a paucity of evidence for secondary prevention. The ongoing studies may provide more certainty in the future.

This review assessed the effects of providing dietary advice to follow a Mediterranean-style diet or provision of foods relevant to the diet (or both) to healthy adults, people at increased risk of cardiovascular disease and those with cardiovascular disease, in order to prevent the occurrence or recurrence of cardiovascular disease and reduce the risk factors associated with it. Definitions of a Mediterranean dietary pattern vary and we included only randomised controlled trials (RCTs) of interventions that reported both of the following key components: a high monounsaturated/saturated fat ratio (use of olive oil as main cooking ingredient and/or consumption of other traditional foods high in monounsaturated fats such as tree nuts) and a high intake of plant-based foods, including fruits, vegetables and legumes. Additional components included: low to moderate red wine consumption; high consumption of whole grains and cereals; low consumption of meat and meat products and increased consumption of fish; moderate consumption of milk and dairy products. The control group was no intervention or minimal intervention, usual care or another dietary intervention. We found 30 RCTs (49 papers) that met these criteria. The trials varied enormously in the participants recruited and the different dietary interventions. We grouped studies to look at the effects of following a Mediterranean-style diet into the following four categories to help us with our interpretation of the results: 1. Mediterranean dietary intervention compared to no intervention or a minimal intervention to prevent the onset of cardiovascular disease; 2. Mediterranean dietary intervention compared to another dietary intervention to prevent the onset of cardiovascular disease; 3. Mediterranean dietary intervention compared to usual care for people with cardiovascular disease to prevent recurrence; 4. Mediterranean dietary intervention compared to another dietary intervention for people with cardiovascular disease to prevent recurrence. Few trials reported on the occurrence of cardiovascular disease either in those with or without disease to begin with. A large trial in people at high risk of cardiovascular disease found a benefit of the Mediterranean dietary intervention compared to a low-fat diet on the risk of having a stroke, but not on heart attacks, death from heart disease or other causes. A further study in people with cardiovascular disease found a benefit of the Mediterranean dietary intervention on death from heart disease or other causes. We rated these two studies as providing low to moderate-quality evidence. We had to exclude two studies from our analyses as concerns had been raised that the data were unreliable. The other trials in the review measured risk factors for cardiovascular disease. There was low to moderate-quality evidence for some beneficial changes in lipid levels and blood pressure with a Mediterranean-style diet in people without disease. In people with cardiovascular disease already there was very low to low-quality evidence that there was no effect of a Mediterranean-style diet on risk factors. Two trials reported side effects of the diet that were either absent or minor. The review concludes that, despite the large number of included trials, there is still uncertainty regarding the effects of a Mediterranean-style diet on cardiovascular disease occurrence and risk factors in people both with and without cardiovascular disease already. We did find seven studies that are still ongoing and when we have the results from these we will incorporate them into the review to help reduce the uncertainty.

10.1002/14651858.CD009825.pub3

cochrane-simplification-train-2708

cochrane-simplification-train-2708

Twelve included studies in 11 publications (1511 participants), all with chronic neuropathic pain: central post-stroke pain (1), chemotherapy-induced neuropathic pain (1), diabetic neuropathy (4), HIV-related neuropathy (2), mixed neuropathic pain (2), spinal cord injury-related pain (1), and trigeminal neuralgia (1). We did not identify any additional studies. Participants were aged between 26 and 77 years. Study duration was two weeks in one study and at least six weeks in the remainder; eight were of eight-week duration or longer. No study provided first-tier evidence for an efficacy outcome. There was no convincing evidence that lamotrigine is effective in treating neuropathic pain and fibromyalgia at doses of 200 mg to 400 mg daily. Almost 10% of participants taking lamotrigine reported a skin rash. Large, high-quality, long-duration studies reporting clinically useful levels of pain relief for individual participants provided no convincing evidence that lamotrigine is effective in treating neuropathic pain and fibromyalgia at doses of about 200 to 400 mg daily. Given the availability of more effective treatments including antiepileptics and antidepressant medicines, lamotrigine does not have a significant place in therapy based on the available evidence. The adverse effect profile of lamotrigine is also of concern.

On 26 November 2013 we performed searches to look for clinical trials where lamotrigine was used to treat neuropathic pain or fibromyalgia. We found 12 studies of reasonable quality that tested lamotrigine against placebo for a number of weeks. Almost half of the 1511 people in the studies had painful limbs because of damaged nerves caused by diabetes, and seven different painful neuropathic conditions were examined. No studies looked at fibromyalgia. Lamotrigine did not help the pain, and was no different from placebo except in causing more side effects. Adverse events were more frequent with lamotrigine than placebo, with rash in 1 person in 27.

10.1002/14651858.CD006044.pub4

cochrane-simplification-train-2709

cochrane-simplification-train-2709

We included three small trials (total 397 women) of average quality in the review. Magnesium sulphate was associated with fewer maternal deaths (risk ratio (RR) 0.14, 95% confidence interval (CI) 0.03 to 0.59; 3 trials, 397 women) and was better at preventing further seizures (RR 0.06, 95% CI 0.03 to 0.12; 3 trials, 397 women) than lytic cocktail. Magnesium sulphate was also associated with less respiratory depression (RR 0.12, 95% CI 0.02 to 0.91; 2 trials, 198 women), less coma (RR 0.04, 95% CI 0.00 to 0.74; 1 trial, 108 women), and less pneumonia (RR 0.20, 95% CI 0.06 to 0.67; 2 trials, 307 women). There was no clear difference in the RR for any death of the baby (RR 0.35, 95% CI 0.05 to 2.38, random effects; 2 trials, 177 babies). Magnesium sulphate, rather than lytic cocktail, for women with eclampsia reduces the RR of maternal death, of further seizures and of serious maternal morbidity (respiratory depression, coma, pneumonia). Magnesium sulphate is the anticonvulsant of choice for women with eclampsia; the use of lytic cocktail should be abandoned.

Pre-eclampsia, also known as toxaemia, is a condition which leads to high blood pressure and protein in the urine. Eclampsia is when a pregnant woman with pre-eclampsia has one or more seizures (fits). Eclampsia is a serious threat to the life of both mother and baby. We identified three randomised trials, involving 397 women with eclampsia who were randomly assigned to treatment with magnesium sulphate or a lytic mixture of chlorpromazine, promethazine and pethidine that lowers blood pressure and is a sedative. Both drugs could be given either by intravenous or intramuscular injection. Although the trials were small and of average quality, the review found that magnesium sulphate was better than lytic cocktail at preventing maternal deaths, further seizures, and breathing problems and coma for the mother. Magnesium sulphate is also relatively cheap and easy to use. The adverse effects of magnesium sulphate come largely from its smooth muscle relaxant activity; respiratory depression is dose dependent and, with monitoring of the woman's clinical condition, uncommon.

10.1002/14651858.CD002960.pub2

cochrane-simplification-train-2710

cochrane-simplification-train-2710

We included six trials with 596 participants in this review. All studies had a randomised controlled parallel group design, with two conducted in the UK, three in the US and one in Israel. Meta-analyses were performed to pool data on response and remission from studies comparing antidepressants with placebo. No meta-analyses could be conducted for other comparisons due to the small number of trials identified. Four studies compared selective serotonin reuptake inhibitors (SSRIs) with placebo (two using sertraline, one using paroxetine and one using fluoxetine; 233 participants in total). In two of these studies both the experimental and placebo groups also received psychological therapy. Pooled risk ratios based on data from three of these studies (146 participants) showed that women randomised to SSRIs had higher rates of response and remission than those randomised to placebo (response: RR 1.43, 95% CI 1.01 to 2.03; remission: RR 1.79, 95% CI 1.08 to 2.98); the fourth study did not report data on response or remission. One study (254 participants) compared antidepressant treatment with treatment as usual (for the first four weeks) followed by listening visits. The study found significantly higher rates of improvement in the antidepressant group than treatment-as-usual group after the first four weeks, but no difference between antidepressants and listening visits at the later follow-up. In addition, one study comparing sertraline with nortriptyline (a tricyclic antidepressant) found no difference in effectiveness (109 participants). Side effects were experienced by a substantial proportion of women, but there was no evidence of a meaningful difference in the number of adverse effects between treatment arms in any study. There were very limited data on adverse effects experienced by breastfed infants, with no long-term follow-up. All but one of the studies were assessed as being at high or uncertain risk of attrition bias and selective outcome reporting. In particular, one of the placebo-controlled studies had over 50% drop-out. The evidence base for this review was very limited, with a small number of studies and little information on a number of important outcomes, particularly regarding potential effects on the child. Risk of bias, for example from high attrition rates, as well as low representativeness of participants (e.g. exclusion of women with severe or chronic depression in several trials) also limit the conclusions that can be drawn. Pooled estimates for response and remission found that SSRIs were significantly more effective than placebo for women with postnatal depression. However the quality of evidence contributing to this comparison was assessed as very low owing to the small sample size for this comparison (146 participants from three studies), the risk of bias in included studes and the inclusion of one study where all participants in both study arms additionally received psychological therapy. There was insufficient evidence to conclude whether, and for whom, antidepressant or psychological/psychosocial treatments are more effective, or whether some antidepressants are more effective or better tolerated than others. There is also inadequate evidence on whether the benefits of antidepressants persist beyond eight weeks or whether they have short- or long-term adverse effects on breastfeeding infants. Professionals treating women with severe depression in the postnatal period will need to draw on other evidence, including trials among general adult populations and observational studies of antidepressant safety when breastfeeding (although the potential for confounding in non-randomised studies must be considered). More RCTs are needed with larger sample sizes and longer follow-up, including assessment of the impact on the child and safety of breastfeeding. Further larger-scale trials comparing antidepressants with alternative treatment modalities are also required.

The quality of evidence from this review was assessed as being very low quality due to the small number of studies, risk of bias in the included studies (in particular, high proportions of participants dropped out) and the fact that many studies excluded women with chronic (i.e. long lasting) or severe depression, or both. We were able to combine data from three studies comparing a type of commonly used antidepressant called selective serotonin reuptake inhibitors (SSRIs) with placebo. The results showed that women with postnatal depression who were given SSRIs were more likely to improve or recover than those given placebo. We were unable to combine the data from studies comparing antidepressants with other treatments or treatment as usual due to the very small number of studies identified for these comparisons. There was insufficient evidence to conclude whether, and for whom, antidepressant or psychosocial/psychological treatments are more effective, or whether some antidepressants are more effective or better tolerated (or both) than others. Conclusions were also limited by the lack of data on long-term follow-up, the safety of breastfeeding or child outcomes. Larger studies need to be done, and treatment decisions for women with postnatal depression will need to use evidence from other sources such as trials in general adult populations and observational studies of antidepressant safety in the postnatal period. The review authors recommend that future studies in this area should include women with severe postnatal depression, long-term follow-up on psychiatric symptoms and quality of life in mothers who have been treated for postnatal depression. In addition, more evidence is needed on outcomes for infants, particularly with regards to the safety of breastfeeding and effect of treatment for postnatal depression on the maternal-infant relationship.

10.1002/14651858.CD002018.pub2

cochrane-simplification-train-2711

cochrane-simplification-train-2711

Twenty-six RCTs met the inclusion criteria, randomly assigning 14,939 people with COPD to receive twice-daily LABA or placebo. Study duration ranged from three months to three years; the median duration was six months. Participants were more often male with moderate to severe symptoms at randomisation; mean forced expiratory volume in 1 second (FEV1) was between 33% and 55% predicted normal in the studies, and mean St George's Respiratory Questionnaire score (SGRQ) ranged from 44 to 55 when reported. Moderate-quality evidence showed that LABA treatment improved quality of life on the SGRQ (mean difference (MD) -2.32, 95% confidence interval (CI) -3.09 to -1.54; I2 = 50%; 17 trials including 11,397 people) and reduced the number of exacerbations requiring hospitalisation (odds ratio (OR) 0.73, 95% CI 0.56 to 0.95; I2 = 10%; seven trials including 3804 people). In absolute terms, 18 fewer people per 1000 were hospitalised as the result of an exacerbation while receiving LABA therapy over a weighted mean of 7 months (95% CI 3 to 31 fewer). Scores were also improved on the Chronic Respiratory Disease Questionnaire (CRQ), and more people receiving LABA treatment showed clinically important improvement of at least four points on the SGRQ. The number of people who had exacerbations requiring a course of oral steroids or antibiotics was also lower among those taking LABA (52 fewer per 1000 treated over 8 months; 95% CI 24 to 78 fewer, moderate quality evidence). Mortality was low, and combined findings of all studies showed that LABA therapy did not significantly affect mortality (OR 0.90, 95% CI 0.75 to 1.08; I2 = 21%; 23 trials including 14,079 people, moderate quality evidence). LABA therapy did not affect the rate of serious adverse events (OR 0.97, 95% CI 0.83 to 1.14; I2 = 34%, moderate quality evidence), although there was significant unexplained heterogeneity, especially between the two formoterol doses. LABA therapy improved predose FEV1 by 73 mL more than placebo (95% CI 48 to 98; I2 = 71%, low quality evidence), and people were more likely to withdraw from placebo than from LABA therapy (OR 0.74, 95% CI 0.69 to 0.80; I2 = 0%). Higher rates of withdrawal in the placebo arm may reduce our confidence in some results, but the disparity is more likely to reduce the magnitude of difference between LABA and placebo than inflate the true effect; removing studies at highest risk of bias on the basis of high and unbalanced attrition did not change conclusions for the primary outcomes. Moderate-quality evidence from 26 studies showed that inhaled long-acting beta2-agonists are effective over the medium and long term for patients with moderate to severe COPD. Their use is associated with improved quality of life and reduced exacerbations, including those requiring hospitalisation. Overall, findings showed that inhaled LABAs did not significantly reduce mortality or serious adverse events.

Twenty-six studies (including 14,939 people with moderate to severe symptoms of COPD) compared twice-daily salmeterol or formoterol with a dummy inhaler. The evidence gathered for this review is current up to June 2013. Results within studies were described most often after six months of treatment, but some were reported at three months and others after as long as three years. More men than women took part, and they had moderate to severe symptoms when they began treatment. People who took LABA inhalers showed greater improvement on quality of life scales than those taking dummy inhalers, and they had fewer serious flare-ups that resulted in a hospital stay (18 fewer per 1000). They also had better lung function than people who had taken placebo. LABA inhalers did not reduce the number of people who died, and no significant difference was noted in the number who had serious adverse events while taking the medication. These studies were most often sponsored by drug companies and were generally well designed. People in the studies did not know which treatment they were getting, and neither did the people doing the research. Several studies did not describe flare-ups, hospital stays or lung volume, so there is a chance that evidence obtained in future studies would change the strength of what has been concluded. Additionally, quite a lot of variation was noted between studies in the effects of LABA inhalers on quality of life, serious side effects and lung function. This may be explained in part by variation in study methods regarding what medications people could continue to take.

10.1002/14651858.CD010177.pub2

cochrane-simplification-train-2712

cochrane-simplification-train-2712

We found 33 trials that met our inclusion criteria. The proportion of men who reportedly achieved azoospermia or had no detectable sperm varied widely. A few important differences emerged. 1) Levonorgestrel implants (160 μg daily) combined with injectable testosterone enanthate (TE) were more effective than levonorgestrel 125 µg daily combined with testosterone patches. 2) Levonorgestrel 500 μg daily improved the effectiveness of TE 100 mg injected weekly. 3) Levonorgestrel 250 μg daily improved the effectiveness of testosterone undecanoate (TU) 1000 mg injection plus TU 500 mg injected at 6 and 12 weeks. 4) Desogestrel 150 μg was less effective than desogestrel 300 μg (with testosterone pellets). 5) TU 500 mg was less likely to produce azoospermia than TU 1000 mg (with levonorgestrel implants). 6) Norethisterone enanthate 200 mg with TU 1000 mg led to more azoospermia when given every 8 weeks versus 12 weeks. 7) Four implants of 7-alpha-methyl-19-nortestosterone (MENT) were more effective than two MENT implants. We did not conduct any meta-analysis due to intervention differences. Several trials showed promising efficacy in percentages with azoospermia. Three examined desogestrel and testosterone preparations or etonogestrel and testosterone, and two examined levonorgestrel and testosterone. No male hormonal contraceptive is ready for clinical use. Most trials were small exploratory studies. Their power to detect important differences was limited and their results imprecise. In addition, assessment of azoospermia can vary by sensitivity of the method used. Future trials need more attention to the methodological requirements for RCTs. More trials with adequate power would also be helpful.

In January and February 2012, we did a computer search for studies of hormones tested for contraception in men. We also looked at reference lists of articles. We considered randomized controlled trials in any language. We wrote to trial authors to find other studies we may have missed. We found 33 studies. The focus of the trials was having no sperm found in semen. The percent of men who achieved no sperm varied widely. We found a few major differences and list them here. 1) Implants plus injected testosterone worked better than a pill plus testosterone patch. 2) Adding a hormone pill improved the effect of testosterone injected weekly. 3) A hormone pill also improved the effect of a testosterone injection with more injections at 6 and 12 weeks. 4) A lower dose pill did not work as well as a higher dose when testosterone was put under the skin (implant). 5) When used with implants, a lower dose of injected testosterone led to no sperm more often than a higher dose. 6) An injected hormone plus injected testosterone led to no sperm more often when given every 8 weeks versus 12 weeks. 7) Four implants of a male hormone worked better than two implants. Several trials showed good results for the percent with no sperm. Five trials studied testosterone and another hormone. The other hormones were desogestrel, etonogestrel, and levonorgestrel. No hormonal birth control for men is ready for general use. Most trials were small pilot studies trying out different hormone treatments. Larger trials with better methods are needed to test good leads in this area.

10.1002/14651858.CD004316.pub4

cochrane-simplification-train-2713

cochrane-simplification-train-2713

We included 80 randomised controlled trials with 205,401 eligible participants. We did not consider that the evidence for the key analyses of morbidity and mortality outcomes were affected by risk of bias. The risk ratio (RR) for all-cause mortality was compatible with a reduction and a small increased risk of death with zinc supplementation (RR 0.95, 95% confidence interval (CI) 0.86 to 1.05, 14 studies, high-quality evidence), and also for cause-specific mortality due to diarrhoea (RR 0.95, 95% CI 0.69 to 1.31, four studies, moderate-quality evidence), lower respiratory tract infection (LRTI) (RR 0.86, 95% CI 0.64 to 1.15, three studies, moderate-quality evidence), or malaria (RR 0.90, 95% CI 0.77 to 1.06, two studies, moderate-quality evidence). Supplementation reduced diarrhoea morbidity, including the incidence of all-cause diarrhoea (RR 0.87, 95% CI 0.85 to 0.89, 26 studies, moderate-quality evidence), but the results for LRTI and malaria were imprecise: LRTI (RR 1, 95% CI 0.94 to 1.07, 12 studies, moderate-quality evidence); malaria (RR 1.05, 95% 0.95 to 1.15, four studies, moderate-quality evidence). There was moderate-quality evidence of a very small improvement in height with supplementation (standardised mean difference (SMD) -0.09, 95% CI -0.13 to -0.06; 50 studies), but the size of this effect might not be clinically important. There was a medium to large positive effect on zinc status. Supplementation was associated with an increase in the number of participants with at least one vomiting episode (RR 1.29, 95% CI 1.14 to 1.46, five studies, high-quality evidence). We found no clear evidence of benefit or harm of supplementation with regard to haemoglobin or iron status. Supplementation had a negative effect on copper status. In our opinion, the benefits of preventive zinc supplementation outweigh the harms in areas where the risk of zinc deficiency is relatively high. Further research should determine optimal intervention characteristics such as supplement dose.

We searched a wide range of electronic databases for studies that randomly assigned children aged six months to 12 years to either zinc supplementation or a control group that did not receive zinc. Eighty randomised studies with 205,401 eligible participants were included in this review. The evidence is current to December 2012. Giving children zinc supplements might reduce their risk of death in general, and their risk of death due to diarrhoea, lower respiratory tract infection (LRTI), or malaria. The quality of evidence for overall mortality was high, though evidence for other critical outcomes was only moderate. Children given zinc experience less diarrhoeal disease than children not given zinc; however, zinc does not seem to reduce children's risk of respiratory infection or malaria. Zinc supplementation may have a very small effect on growth, but eating more calories would probably have a larger effect for many malnourished children. Children who take zinc supplements may experience vomiting as a side effect.

10.1002/14651858.CD009384.pub2

cochrane-simplification-train-2714

cochrane-simplification-train-2714

Twenty-four studies containing information about five index tests (rK39 immunochromatographic test (ICT), KAtex latex agglutination test in urine, FAST agglutination test, rK26 ICT, and rKE16 ICT) recruiting 4271 participants (2605 with VL) were included. We carried out a meta-analysis for the rK39 ICT (including 18 studies; 3622 participants) and the latex agglutination test (six studies; 1374 participants). The results showed considerable heterogeneity. For the rK39 ICT, the overall sensitivity was 91.9% (95% confidence interval (95% CI) 84.8 to 96.5) and the specificity 92.4% (95% CI 85.6 to 96.8). The sensitivity was lower in East Africa (85.3%; 95% CI 74.5 to 93.2) than in the Indian subcontinent (97.0%; 95% CI 90.0 to 99.5). For the latex agglutination test, overall sensitivity was 63.6% (95% CI 40.9 to 85.6) and specificity 92.9% (95% CI 76.7 to 99.2). The rK39 ICT shows high sensitivity and specificity for the diagnosis of visceral leishmaniasis in patients with febrile splenomegaly and no previous history of the disease, but the sensitivity is notably lower in east Africa than in the Indian subcontinent. Other rapid tests lack accuracy, validation, or both.

We found 24 studies, which contained information about five different rapid tests. A total of 4271 people participated in these studies. One of the rapid tests (called the rK39 immunochromatographic test) gave correct, positive results in 92% of the people with visceral leishmaniasis and it gave correct, negative results in 92% of the people who did not have the disease. This test worked better in India and Nepal than in east Africa. In India and Nepal, it gave correct, positive results in 97% of the people with the disease. In east Africa, it gave correct, positive results in only 85% of the people with the disease. A second rapid test (called latex agglutination test) gave correct, positive results in 64% of the people with the disease and it gave correct, negative results in 93% of the people without the disease. For the other rapid tests evaluated, there are too few studies to know how accurate they are.

10.1002/14651858.CD009135.pub2

cochrane-simplification-train-2715

cochrane-simplification-train-2715

We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes. We identified no completed non-RCTs or CBAs. We identified no ongoing RCTs, non-RCTs, or CBAs. We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.

We searched scientific databases for clinical studies (randomised controlled trials and well-designed non-randomised studies) of people of any age with bone marrow disorders and a low platelet count. The evidence is current to 12 October 2017. One study was eligible for inclusion in the review. This study was stopped after recruiting only nine participants because it had taken three years to recruit the nine participants (the study had planned to recruit 60 participants in two years). We found no ongoing studies. The only included study in this review did not report any outcomes. We found no evidence to help us decide whether giving platelet transfusions to treat bleeding is as good as giving platelet transfusions when the platelet count is below a prespecified level. There is an urgent need for good-quality studies to answer the questions of this review. We did not assess the quality of the evidence because no data were available from the one included study.

10.1002/14651858.CD012342.pub2

cochrane-simplification-train-2716

cochrane-simplification-train-2716

Nine trials involving 117,272 individuals of age 35 years or older are included in this review. The trials were conducted in Australia, Finland, India, Italy, the United Kingdom and the United States, with duration of follow-up ranging from 2.1 to 12 years. The doses of antioxidant vitamins were higher than the recommended daily allowance. There was no evidence of effect of antioxidant vitamin supplementation in reducing the risk of cataract, cataract extraction, progression of cataract or in slowing the loss of visual acuity. In the pooled analyses, there was no evidence of effect of beta-carotene supplementation in reducing the risk of cataract (two trials) (relative risk (RR) 0.99, 95% confidence interval (CI) 0.91 to 1.08; n = 57,703) or in reducing the risk of cataract extraction (three trials) (RR 1.00, 95% CI 0.91 to 1.10; n = 86,836) or of vitamin E supplementation in reducing the risk of cataract (three trials) (RR 0.97, 95% CI 0.91 to 1.04; n = 50,059) or of cataract extraction (five trials) (RR 0.98, 95% CI 0.91 to 1.05; n = 83,956). The proportion of participants developing hypercarotenodermia (yellowing of skin) while on beta-carotene ranged from 7.4% to 15.8%. There is no evidence from RCTs that supplementation with antioxidant vitamins (beta-carotene, vitamin C or vitamin E) prevents or slows the progression of age-related cataract. We do not recommend any further studies to examine the role of antioxidant vitamins beta-carotene, vitamin C and vitamin E in preventing or slowing the progression of age-related cataract. Costs and adverse effects should be weighed carefully with unproven benefits before recommending their intake above recommended daily allowances.

The review authors searched for randomized controlled trials in which supplementation with the antioxidant vitamins beta-carotene (provitamin A), vitamin C and vitamin E was compared to inactive placebo or no supplement. Nine trials involving 117,272 adults of age 35 years or older were included in this review. The trials were conducted in Australia, Finland, India, Italy, the United Kingdom and the United States and were of high methodological quality. The doses of antioxidants given in each trial were higher than the recommended daily allowances. The trials provided no evidence of effect of the antioxidant vitamins beta-carotene, vitamin E and vitamin C given alone or in combination on the incidence of cataract, its extraction or progression and on the loss of visual acuity. Some participants (7% to 16%) on beta-carotene developed yellowing of the skin (hypercarotenodermia).

10.1002/14651858.CD004567.pub2

cochrane-simplification-train-2717

cochrane-simplification-train-2717

Sixty trials involving 66,689 patients were included. During PCI (48 trials with 33,513 participants) glycoprotein IIb/IIIa blockers decreased all-cause mortality at 30 days (OR 0.79, 95% CI 0.64 to 0.97) but not at six months (OR 0.90, 95% CI 0.77 to 1.05). All-cause death or myocardial infarction was decreased both at 30 days (OR 0.66, 95% CI 0.60 to 0.72) and at six months (OR 0.75, 95% CI 0.64 to 0.86), although severe bleeding was increased (OR 1.39, 95% CI 1.21 to 1.61; absolute risk increase (ARI) 8.0 per 1000). The efficacy results were homogeneous for every endpoint according to the clinical condition of the patients, but were less marked for patients pre-treated with clopidogrel, especially in patients without acute coronary syndromes. As initial medical treatment of NSTEACS (12 trials with 33,176 participants), IIb/IIIa blockers did not decrease mortality at 30 days (OR 0.90, 95% CI 0.79 to 1.02) or at six months (OR 1.00, 95% CI 0.87 to 1.15), but slightly decreased death or myocardial infarction at 30 days (OR 0.91, 95% CI 0.85 to 0.98) and at six months (OR 0.88, 95% CI 0.81 to 0.96), although severe bleeding was increased (OR 1.29, 95% CI 1.14 to 1.45; ARI 1.4 per 1000). When administered during PCI, intravenous glycoprotein IIb/IIIa blockers reduce the risk of all-cause death at 30 days but not at six months, and reduce the risk of death or myocardial infarction at 30 days and at six months, at a price of an increase in the risk of severe bleeding. The efficacy effects are homogeneous but are less marked in patients pre-treated with clopidogrel where they seem to be effective only in patients with acute coronary syndromes. When administered as initial medical treatment in patients with NSTEACS, these agents do not reduce mortality although they slightly reduce the risk of death or myocardial infarction.

During the last two decades, doctors have been looking for the best treatment to prevent clots in the coronary arteries of patients with coronary heart disease. This review summarises the results of 60 studies which used a potent class of intravenous antiplatelet drugs - glycoprotein IIb-IIIa blockers - in 66,689 participants. This treatment was tested in two different conditions: in patients undergoing coronary angioplasty (inserting a deflated small balloon in the artery and expand it to open the vessel) with or without inserting a stent (a thin metal expandable tube or sleeve to scaffold the artery open); and as the initial treatment of patients hospitalised for unstable angina and non-ST segment elevation acute myocardial infarction (prolonged coronary chest pain with or without small myocardial infarction). The evidence is up to date as January 2013 and the overall quality of the body of evidence was good. Overall, the use of these drugs during coronary angioplasty with or without inserting a stent reduced the risk of death at 30 days, and the risk of death or myocardial infarction at 30 days and at six months. The results were similar for stable and for unstable patients with coronary artery disease, but there was comparatively less benefit for patients previously treated with clopidogrel, an oral antiplatelet drug. On the other side, these drugs only slightly reduced the risk of death or myocardial infarction when administered as initial medical treatment in patients with unstable angina or non-ST-elevation myocardial infarction. The benefits of glycoprotein IIb/IIIa blockers need to be balanced against the increased risk of bleeding.

10.1002/14651858.CD002130.pub4

cochrane-simplification-train-2718

cochrane-simplification-train-2718

Three trials involving a total of 161 preterm infants were included in this review, but only two trials (131 infants) contributed data for meta-analysis. There was no evidence of a clear effect of exposure to the smell and taste of milk with tube feedings on time taken to reach full sucking feeds (MD -2.57 days, 95% CI -5.15 to 0.02; I2 = 17%; 2 trials, 131 infants; very low-quality evidence). One trial reported no adverse effects. There was no evidence of a clear effect of exposure to the smell and taste of milk on the following outcomes: time taken to reach full enteral feeds (MD -1.57 days, 95% CI -6.25 to 3.11; 1 trial, 51 infants; very low-quality evidence), duration of parenteral nutrition (MD -2.20 days, 95% CI -9.49 to 5.09; 1 trial, 51 infants; very low-quality evidence), incidence of necrotising enterocolitis (RR 0.62, 95% CI 0.15 to 2.48; 1 trial, 51 infants; low-quality evidence), and late infection (RR 2.46, 95% CI 0.27 to 22.13; 1 trial, 51 infants; low-quality evidence). There was very low-quality evidence demonstrating that exposure to the smell and taste of milk decreased duration of hospitalisation by almost four days (MD -3.89 days, 95% CI -7.03 to -0.75; I2 = 51%; 2 trials, 131 infants). In two trials, an increased growth velocity was noted in infants exposed to the intervention, but we were unable to combine data to perform meta-analysis. No data were available to assess feed intolerance and rates of exclusive breastfeeding at discharge. Included trials were small and had methodological limitations including lack of randomisation (one trial), lack of blinding, and different inclusion criteria and administration of the interventions. Evidence from two trials suggests that exposure to the smell and taste of milk with tube feedings has no clear effect on time taken to reach full sucking feeds, but it may decrease length of hospitalisation. However, these results are uncertain due to the very low quality of the evidence. There is also limited evidence about the impact on other important clinical outcomes and on safety. Future research should examine the effect of exposure to the smell and taste of milk with tube feedings on clinical outcomes during hospitalisation, such as attainment of full enteral and sucking feeds, safety, feed tolerance, incidence of infection, and infant growth. Additionally, future research should be sufficiently powered to evaluate the effect of the intervention in infants of different gestational ages, on each sex separately, and on the optimal frequency and duration of exposure.

In a search up to 1 June 2018, we identified three completed studies involving 161 preterm infants admitted to a neonatal intensive care unit (NICU) at a tertiary hospital. One study involved 51 preterm infants, and each infant had an equal chance of being chosen to receive either treatment (a randomised controlled trial). One study involved 80 preterm infants who were sequentially assigned to control and treatment groups (a quasi-randomised trial). One study was a prospective randomised trial involving 30 infants, but the way it was reported meant there was not enough information for us to include in our analyses. We found that exposure to the smell and taste of milk with orogastric or nasogastric tube feedings had no clear effect on the time to reach full sucking feeds. One study reported no adverse effects. Exposure to the smell and taste of milk also had no clear effect on time to reach full tube feeding, feed tolerance, incidence of late infection and severe intestinal infection, duration of intravenous nutrition, and growth. Very low-quality evidence from two studies suggested that exposure to the smell and taste of milk decreased the length of hospital stay by almost four days compared to no exposure to the smell and taste of milk. However, the included studies were small and had several limitations in terms of how they were done. Exposure to the smell and taste of milk with orogastric or nasogastric tube feedings may decrease length of hospitalisation for preterm infants. However, the effect of this treatment to accelerate feeding in preterm infants is uncertain due to limited and very low-quality evidence. Future research needs to explore the effect of exposure to the smell and taste of milk with tube feedings on important clinical outcomes, such as time to full sucking feeds, adverse effects, time to reach full tube feedings, feed tolerance, incidence of infection, and growth.

10.1002/14651858.CD013038.pub2

cochrane-simplification-train-2719

cochrane-simplification-train-2719

We included two trials with 26,340 participants aged 40 to 82 years of whom 11,610 were aged 70 or older. All participants had a history of, or risk factors for, vascular disease. The studies used different statins (simvastatin and pravastatin). Mean follow-up was 3.2 years in one study and five years in one study. The risk of bias was low. Only one study reported on the incidence of dementia (20,536 participants, 31 cases in each group; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.61 to 1.65, moderate quality evidence, downgraded due to imprecision). Both studies assessed cognitive function, but at different times using different scales, so we judged the results unsuitable for a meta-analysis. There were no differences between statin and placebo groups on five different cognitive tests (high quality evidence). Rates of treatment discontinuation due to non-fatal adverse events were less than 5% in both studies and there was no difference between statin and placebo groups in the risk of withdrawal due to adverse events (26,340 participants, 2 studies, OR 0.94, 95% CI 0.83 to 1.05). There is good evidence that statins given in late life to people at risk of vascular disease do not prevent cognitive decline or dementia. Biologically, it seems feasible that statins could prevent dementia due to their role in cholesterol reduction and initial evidence from observational studies was very promising. However, indication bias may have been a factor in these studies and the evidence from subsequent RCTs has been negative. There were limitations in the included studies involving the cognitive assessments used and the inclusion of participants at moderate to high vascular risk only.

We searched medical databases for clinical trials comparing giving a statin to giving a placebo (pretend medicine) to people with normal cognitive function (which is brain activities that allow us to gain and use knowledge) and of sufficient age to be at risk of Alzheimer's disease. We found two suitable randomised trials for inclusion in this review with 26,340 participants; neither showed any reduction in occurrence of Alzheimer's disease or dementia in people treated with statins compared to people given placebo. Side effects were low in both statin and placebo groups with no difference between groups in the risk of dropping out of the trial due to side effects. There were limitations in the included studies involving the methods of assessment of cognition and the inclusion only of participants deemed to be of moderate to high risk of a problem with their blood (vascular) system. Nevertheless, there was good evidence that statins given in late life to people at risk of vascular disease do not prevent cognitive decline or dementia.

10.1002/14651858.CD003160.pub3

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cochrane-simplification-train-2720

This review includes eight studies with a total of 250 participants comparing nebuliser versus pMDI plus spacer treatment. We identified no studies comparing DPI with nebulisers. We found two studies assessing the primary outcome of 'change in forced expiratory volume in one second (FEV1) one hour after dosing'. We could not pool these studies, but both showed a non-significant difference in favour of the nebuliser group, with similar frequencies of serious adverse events. For the secondary outcome, 'change in FEV1 closest to one hour after dosing': we found a significant difference of 83 ml (95% CI 10 to 156, P = 0.03) in favour of nebuliser treatment. For the secondary outcome of adverse events, we found a non-significant odds ratio of 1.65 (95% CI 0.42 to 6.48) in favour of the pMDI plus spacer group. There is a lack of evidence in favour of one mode of delivery over another for bronchodilators during exacerbations of COPD. We found no difference between nebulisers versus pMDI plus spacer regarding the primary outcomes of FEV1 at one hour and safety. For the secondary outcome 'change in FEV1 closest to one hour after dosing' during an exacerbation of COPD, we found a greater improvement in FEV1 when treating with nebulisers than with pMDI plus spacers. A limited amount of data are available (eight studies involving 250 participants). These studies were difficult to pool, of low quality and did not provide enough evidence to favour one mode of delivery over another. No data of sufficient quality have been published comparing nebulisers versus DPIs in this setting. More studies are required to assess the optimal mode of delivery during exacerbations of COPD.

We found eight studies including 250 participants in a search of the available studies up to 1 July 2016. All of the studies took place in a hospital. The primary outcomes of the review showed no difference between the inhaler with a spacer and the nebuliser. However, in our secondary outcomes, we found some evidence that nebuliser treatment improves lung function more than inhalers with a spacer, but the quality and quantity of the data is limited. We found no difference between the therapies in terms of side effects or for reducing breathlessness. There are no studies available testing dry powder inhalation against a nebuliser. Due to the low quality and quantity of the data, it is not clear whether nebulisers or inhalers with spacers are better for lung attacks. We found no difference between an inhaler with a spacer and the nebuliser in lung function after one hour or in unwanted side effects during lung attacks of COPD. The secondary outcome for lung function did favour nebulisers over inhalers with a spacer.

10.1002/14651858.CD011826.pub2

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cochrane-simplification-train-2721

Five studies met the inclusion criteria. The pooled estimates of MMSE cognitive and ADAS-cognitive change scores from three of these studies revealed non-significant cognitive effects for melatonin treatment. In two of these studies, significant improvements in psychopathological behaviours (e.g., decreased mood symptoms of depression, anxiety and apathy and decreased behavior symptoms of hallucinations, delusions, agitation, irritability, and appetite disturbances), were found from meta-analysis of the change scores from the NPI (7 weeks, 2.5 mg melatonin), and ADAS non-cognitive (4 weeks, 3 mg melatonin) scales. Sensitivity analyses found similar results to those of the original meta-analyses, and thus, supported the effect estimates for non-significant cognitive outcomes. Individual study estimates for treatment effect of 2.5 mg melatonin at one year demonstrated a significant worsening of mood (e.g. decrease in positive affect) as measured by the Philadelphia Geriatric Centre Affect Rating Scale (positive). The remainder of the treatment effects for mood, behavior, and function of daily living were non-significant. There were no reported adverse effects associated with melatonin use. The analyses did not support the use of melatonin for treatment of cognitive impairment associated with dementia. Meta-analysis of psychopathologic behavior scale scores suggested that melatonin may be effective in treating these dementia-related disturbances.

There are a number of studies that suggest a relationship between decline of melatonin function and the symptoms of dementia. Meta-analysis was conducted on data from three randomised, placebo controlled trials that were designed to evaluate melatonin for managing dementia-related cognitive changes; data also were pooled from two of these trials that evaluated melatonin for managing mood and behavioral disturbances. Significantly improved outcomes were found from the meta-analysis of psychopathologic behavior and mood scale scores. Melatonin treatment may be effective for the treatment of dementia-related psychopathologic behavior disturbances. No evidence was found to support the effectiveness of melatonin for the treatment of cognitive impairment.

10.1002/14651858.CD003802.pub3

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cochrane-simplification-train-2722

Nine studies (162 participants) are included in this review. No significant difference was noted between NCS and SCG with respect to the maximum percent decrease in FEV1 (WMD = -0.88; 95% CI: -4.50, 2.74), complete protection (i.e. maximum % fall FEV1 still =>10%); OR = 0.95; 95% CI: 0.50 to 1.8, clinical protection (i.e. < 50% improvement over placebo); OR = 0.71; 95% CI: 0.36 to 1.39; unpleasant taste (OR = 6.85; 95% CI: 0.77, 60.73), or sore throat (OR = 3.46; 95% CI: 0.32, 37.48). For these pooled comparisons, no statistically significant heterogeneity was identified. Subgroup analyses based on age, dosage of medications and timing of exercise post-inhalation were consistent with the overall pooled analyses. No significant differences were evident between the effect of NCS and SCG during the immediate post-exercise period in adults and children with EIB with regards to pulmonary function - specifically maximum percent decrease in FEV1, complete protection, clinical protection, or side effects.

The review of trials found that both were similarly effective in relieving exercise-induced asthma for both children and adults. More people have sore throats and an unpleasant after-taste after using nedocromil sodium.

10.1002/14651858.CD002731

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cochrane-simplification-train-2723

We included in this review a total of 12 RCTs. Ten studies assessed fibrinolytic agents versus placebo (993 participants); one study compared streptokinase with urokinase (50 participants); and one compared alteplase versus urokinase (99 participants). The primary outcomes were death, requirement for surgical intervention, overall treatment failure and serious adverse effects. All studies were in the inpatient setting. Outcomes were measured at varying time points from hospital discharge to three months. Seven trials were at low or unclear risk of bias and two at high risk of bias due to inadequate randomisation and inappropriate study design respectively. We found no evidence of difference in overall mortality with fibrinolytic versus placebo (OR 1.16, 95% CI 0.71 to 1.91; 8 studies, 867 participants; I² = 0%; moderate certainty of evidence). We found evidence of a reduction in surgical intervention with fibrinolysis in the same studies (OR 0.37, 95% CI 0.21 to 0.68; 8 studies, 897 participants; I² = 51%; low certainty of evidence); and overall treatment failure (OR 0.16, 95% CI 0.05 to 0.58; 7 studies, 769 participants; I² = 88%; very low certainty of evidence, with evidence of significant heterogeneity). We found no clear evidence of an increase in adverse effects with intrapleural fibrinolysis, although this cannot be excluded (OR 1.28, 95% CI 0.36 to 4.57; low certainty of evidence). In a sensitivity analysis, the reduction in referrals for surgery and overall treatment failure with fibrinolysis disappeared when the analysis was confined to studies at low or unclear risk of bias. In a moderate-risk population (baseline 14% risk of death, 20% risk of surgery, 27% risk of treatment failure), intra-pleural fibrinolysis leads to 19 more deaths (36 fewer to 59 more), 115 fewer surgical interventions (150 fewer to 55 fewer) and 214 fewer overall treatment failures (252 fewer to 93 fewer) per 1000 people. A single study of streptokinase versus urokinase found no clear difference between the treatments for requirement for surgery (OR 1.00, 95% CI 0.13 to 7.72; 50 participants; low-certainty evidence). A single study of alteplase versus urokinase showed no clear difference in requirement for surgery (OR alteplase versus urokinase 0.46, 95% CI 0.04 to 5.24) but an increased rate of adverse effects, primarily bleeding, with alteplase (OR 5.61, 95% CI 1.16 to 27.11; 99 participants; low-certainty evidence). This translated into 154 (6 to 499 more) serious adverse events with alteplase compared with urokinase per 1000 people treated. In patients with complicated infective pleural effusion or empyema, intrapleural fibrinolytic therapy was associated with a reduction in the requirement for surgical intervention and overall treatment failure but with no evidence of change in mortality. Discordance between the negative largest trial of this therapy and other studies is of concern, however, as is an absence of significant effect when analysing low risk of bias trials only. The reasons for this difference are uncertain but may include publication bias. Intrapleural fibrinolytics may increase the rate of serious adverse events, but the evidence is insufficient to confirm or exclude this possibility.

We searched for studies up to August 2019. We included 10 studies with a total of 993 patients comparing fibrinolytics with a placebo and compared these to look for differences. We also included two studies comparing different fibrinolytics with a total of 149 patients and compared these separately. We found some low-certainty evidence that fibrinolytics moderately reduced the need for surgery. There was no clear evidence that fibrinolytics changed the risk of death. There was some low-certainty evidence which showed that there may be a risk of more side effects (mostly bleeding) with fibrinolytics but this is uncertain. We found no clear evidence that any single fibrinolytic was better than another. We considered the certainty of the evidence identified comparing fibrinolytic with placebo to vary from moderate (risk of death) to very low (overall treatment failure). This was mostly due to some studies having one or more domains at high risk of bias as well as concerns that not all studies of this treatment appear to have been published. We considered the evidence comparing individual fibrinolytics to be of low certainty due to not enough patients in the studies as well as one study being at a high risk of bias.

10.1002/14651858.CD002312.pub4

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cochrane-simplification-train-2724

We included a total of 39 studies (36 randomised controlled trials (RCTs) and 3 quasi-RCTs) that involved a total of 2492 adults. Most studies were small (median = 59 participants). Participants' mean ages ranged from 34 years to 59 years. When reported, most participants had heel pain for several months. The trials were usually conducted in outpatient specialty clinics of tertiary care hospitals in 17 countries. Steroid injection was given with a local anaesthetic agent in 34 trials. Follow-up was from one month to over two years. With one exception, trials were assessed at high risk of bias in one or more domains, mostly relating to lack of blinding, including lack of confirmation of allocation concealment. With two exceptions, we rated the available evidence as very low quality, implying in each case that we are 'very uncertain about the estimate'. The 39 trials covered 18 comparisons, with six of the seven trials with three or four groups providing evidence towards two comparisons. Eight trials (724 participants) compared steroid injection versus placebo or no treatment. Steroid injection may lead to lower heel pain visual analogue scores (VAS) (0 to 100; higher scores = worse pain) in the short-term (< 1 month) (MD -6.38, 95% CI -11.13 to -1.64; 350 participants; 5 studies; I² = 65%; low quality evidence). Based on a minimal clinically significant difference (MCID) of 8 for average heel pain, the 95% CI includes a marginal clinical benefit. This potential benefit was diminished when data were restricted to three placebo-controlled trials. Steroid injection made no difference to average heel pain in the medium-term (1 to 6 months follow-up) (MD -3.47, 95% CI -8.43 to 1.48; 382 participants; 6 studies; I² = 40%; low quality evidence). There was very low quality evidence for no effect on function in the medium-term and for an absence of serious adverse events (219 participants, 4 studies). No studies reported on other adverse events, such as post-injection pain, and on return to previous activity. There was very low quality evidence for fewer treatment failures (defined variously as persistent heel pain at 8 weeks, steroid injection at 12 weeks, and unrelieved pain at 6 months) after steroid injection. The available evidence for other comparisons was rated as very low quality. We are therefore very uncertain of the estimates for the relative effects on people with heel pain of steroids compared with other interventions in: 1. Tibial nerve block with anaesthetic (2 trials); orthoses (4 trials); oral NSAIDs (2 trials); and intensive physiotherapy (1 trial). 2. Physical modalities: ESWT (5 trials); laser (2 trials); and radiation therapy (1 trial). 3. Other invasive procedures: locally injectable NSAID (1 trial); platelet-rich plasma injections (5 trials); autologous blood injections (2 trials); botulinum toxin injections (2 trials); cryopreserved human amniotic membrane injection (1 trial); localised peppering with a needle (1 trial); dry needling (1 trial); and mini scalpel needle release (1 trial). We are also uncertain about the estimates from trials testing different techniques of local steroid injection: ultrasonography-guided versus palpation-guided (5 trials); and scintigraphy-guided versus palpation-guided (1 trial). An exploratory analysis involving pooling data from 21 trials reporting on adverse events revealed two ruptures of plantar fascia (reported in 1 trial) and three injection site infections (reported in 2 trials) in 699 participants allocated to steroid injection study arms. Five trials reported a total of 27 participants with less serious short-term adverse events in the 699 participants allocated steroid injection study arms. Reported treatments were analgesia, ice or both. Given the high risk of selective reporting for these outcomes and imprecision, this evidence was rated at very low quality. We found low quality evidence that local steroid injections compared with placebo or no treatment may slightly reduce heel pain up to one month but not subsequently. The available evidence for other outcomes of this comparison was very low quality. Where available, the evidence from comparisons of steroid injections with other interventions used to treat heel pain and of different methods of guiding the injection was also very low quality. Although serious adverse events relating to steroid injection were rare, these were under-reported and a higher risk cannot be ruled out. Further research should focus on establishing the effects (benefits and harms) of injected steroids compared with placebo in typical clinical settings, subsequent to a course of unsuccessful conservative therapy. Ideally, this should be preceded by research, including patient involvement, aimed to obtain consensus on the priority questions for treating plantar heel pain.

We included 39 studies that involved a total of 2492 adults. The average ages of the participants in the studies ranged from 34 years to 59 years. When reported, most participants had heel pain for several months. Studies were usually conducted in outpatient specialty clinics of hospitals in 17 countries. Steroid injections were usually given with a local anaesthetic agent. Study follow-up was from one month to over two years. The studies compared steroid injection with placebo or no treatment (8 studies); tibial nerve block with anaesthetic (2 studies); heel pads (4 studies); oral anti-inflammatory drugs (NSAIDs) (2 studies); an intensive exercise programme (1 study); shock wave therapy (5 studies); laser (2 studies); radiation therapy (1 study); local NSAID injection (1 study); platelet-rich plasma injections (5 studies); injection of the person's own (autologous) blood (2 studies); botulinum toxin (Botox) injections (2 studies); frozen (cryopreserved) human amniotic membrane injection (1 study); localised peppering involving multiple pricking of the tissues using an inserted needle (1 study); dry needling (1 study); and mini scalpel-needle release (1 study). We also compared different techniques of local steroid injection (5 studies). The eight studies comparing steroid injection with placebo or no steroid injection control provided evidence on heel pain, function, serious adverse events and treatment failure. No studies reported on time to return to work or other activities or short-term adverse events, such as injection-site pain. Steroid injection may slightly reduce heel pain for up to one month after treatment, but not in the longer term including up to six months. We are very unsure whether steroid injection affects longer-term function or reduces treatment failure. There were no serious adverse events, such as infection, reported by these studies. However, these are known to be rare events and we looked at the evidence from all of the studies in the review. Of the 21 studies that reported on adverse events, two studies reported three infections and two ruptures of heel tissues in relation to steroid injection. The evidence for all reported outcomes, including heel pain, for the other comparisons was always very low quality. This means we are very unsure of the results of these trials. There is low quality evidence that local steroid injections may slightly reduce heel pain up to one month but not subsequently. Although serious complications relating to steroid injection were rare, these were under-reported in the included studies and more cannot be ruled out.

10.1002/14651858.CD009348.pub2

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cochrane-simplification-train-2725

Three studies, involving a total of 354 participants, met our inclusion criteria for the primary outcome. Compared with intermittent monitoring, continuous monitoring significantly reduced death and disability at three months or discharge (odds ratio (OR) 0.27, 95% confidence interval (CI) 0.13 to 0.56) and was associated with a non-significant reduction in deaths from any cause at discharge (OR 0.72, 95% CI 0.28 to 1.85). These significant results depend on one study that has a high risk of bias. Continuous monitoring was associated with a non-significant reduction of dependency (OR 0.79, 95% CI 0.30 to 2.06), death from vascular causes (OR 0.48, 95% CI 0.10 to 2.39), neurological complications (OR 0.81, 95% CI 0.46 to 1.43), length of stay (mean difference (MD) -5.24, 95% CI -10.51 to 0.03) and institutionalisation (OR 0.83, 95% CI 0.04 to 15.72) (secondary outcomes). For the last two outcomes we detected consistent heterogeneity across trials. Cardiac complications (OR 8.65, 95% CI 2.52 to 29.66), fever (OR 2.17, 95% CI 1.22 to 3.84) and hypotension (OR 4.32, 95% CI 1.68 to 14.38) were detected significantly more often in participants who received continuous monitoring (surrogate outcomes). We detected no significant increase in adverse events due to immobility (pneumonia, other infections or deep vein thrombosis) in participants who were continuously monitored compared with those allocated to intermittent monitoring. Continuous monitoring of physiological variables for the first two to three days may improve outcomes and prevent complications. Attention to the changes in physiological variables is a key feature of a stroke unit, and can most likely be aided by continuous monitoring without complications related to immobility or to treatments triggered by the relief of abnormal physiological variables. Well-designed, high-quality studies are needed because many questions remain open and deserve further research. These include when to start continuous monitoring, when to interrupt it, which people should be given priority, and which treatments are most appropriate after the identification of abnormalities in physiological variables.

We searched for all trials that compared continuous monitoring with intermittent monitoring in people with acute stroke. We identified three studies including a total of 354 participants. Stroke unit care with continuous monitoring was associated with a significant reduction in the chance of being dead or disabled after the stroke. Unfortunately this evidence is not entirely reliable because of the small number of participants, differences in the definitions of abnormal results, and the less reliable methods used in the largest trial. Further research is required to answer many remaining questions, such as when to start continuous monitoring, when to interrupt it, which people should be given priority, and which treatments are most appropriate after the identification of abnormalities in physiological variables.

10.1002/14651858.CD008444.pub2

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cochrane-simplification-train-2726

Four high-quality RCTs (585 patients) met the selection criteria. Clinical heterogeneity prevented the use of meta-analysis. Therefore, a qualitative synthesis was completed. There was conflicting evidence about whether TENS was beneficial in reducing back pain intensity and consistent evidence in two trials (410 patients) that it did not improve back-specific functional status. There was moderate evidence that work status and the use of medical services did not change with treatment. Conflicting results were obtained from two studies regarding generic health status, with one study showing no improvement on the modified Sickness Impact Profile and another study showing significant improvements on several, but not all subsections of the SF-36 questionnaire. Multiple physical outcome measures lacked statistically significant improvement relative to placebo. In general, patients treated with acupuncture-like TENS responded similarly to those treated with conventional TENS. However, in two of the trials, an inadequate stimulation intensity was used for acupuncture-like TENS, given that muscle twitching was not induced. Optimal treatment schedules could not be reliably determined based on the available data. Adverse effects included minor skin irritation at the site of electrode placement. At this time, the evidence from the small number of placebo-controlled trials does not support the use of TENS in the routine management of chronic LBP. Further research is encouraged.

Four high-quality randomized controlled trials (RCTs; 585 patients) comparing TENS with placebo for chronic low-back pain were included in this study.  Due to conflicting evidence, it is unclear if TENS is beneficial in reducing back pain intensity.  However, there was consistent evidence in two trials (410 patients) that TENS did not improve the level of disability due to back pain. There was moderate evidence that use of medical services and work status (e.g. loss of work, sick days) did not change during treatment. Finally, there did not seem to be a difference between conventional and acupuncture-like TENS. Some adverse effects were reported, typically minor skin irritations observed equally in the treatment and placebo groups. However, there was one participant who developed a severe rash four days after the start of treatment. In summary, the review authors found conflicting evidence regarding the benefits of TENS for chronic LBP, which does not support the use of TENS in the routine management of chronic LBP.

10.1002/14651858.CD003008.pub3

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cochrane-simplification-train-2727

We included five placebo-controlled pharmacotherapy RCTs (with 290 participants) in the review. Most of the trials provided little information on how randomization was performed or on whether both participants and study personnel were blinded to the intervention. Two of the three trials reporting superiority of medication compared with placebo on anxiety symptom outcomes were industry funded. We regarded one trial as being at high risk of bias due to selective reporting. Study participants had Diagnostic and Statistical Manual (DSM) III- and DSM IV-diagnosed alcohol use disorders and post-traumatic stress disorder (two studies), social anxiety disorder (SAD; two studies) or generalized anxiety disorder (GAD; one study). Four trials assessed the efficacy of the selective serotonin re-uptake inhibitors (SSRIs: sertraline, paroxetine); one RCT investigated the efficacy of buspirone, a 5-hydroxytryptamine (5-HT) partial agonist. Treatment duration lasted between eight and 24 weeks. Overall, 70% of participants included in the review were male. There was very low quality evidence for an effect of paroxetine on global clinical response to treatment, as assessed by the Clinical Global Impressions - Improvement scale (CGI-I). Global clinical response was observed in more than twice as many participants with paroxetine than with placebo (57.7% with paroxetine versus 25.8% with placebo; risk ratio (RR) 2.23, 95% CI 1.13 to 4.41; 2 trials, 57 participants). However, there was substantial uncertainty regarding the size of the effect of paroxetine due to the small number of studies providing data on clinically diverse patient samples. The second primary outcome measure was reduction of anxiety symptom severity. Although study investigators reported that buspirone (one trial) was superior to placebo in reducing the severity of anxiety symptoms over 12 weeks, no evidence of efficacy was observed for paroxetine (mean difference (MD) -14.70, 95% CI -33.00 to 3.60, 2 trials, 44 participants) and sertraline (one trial). Paroxetine appeared to be equally effective in reducing the severity of post-traumatic stress disorder (PTSD) symptoms as the tricyclic antidepressant desipramine in one RCT. The maximal reduction in anxiety disorder symptom severity was achieved after six weeks with paroxetine (two RCTs) and 12 weeks with buspirone (one RCT), with maintenance of medication efficacy extending to 16 with paroxetine and 24 weeks with buspirone. There was no evidence of an effect for any of the medications tested on abstinence from alcohol use or depression symptoms. There was very low quality evidence that paroxetine was well tolerated, based on drop-out due to treatment-emergent adverse effects. Nevertheless, levels of treatment discontinuation were high, with 43.1% of the participants in the studies withdrawing from medication treatment. Certain adverse effects, such as sexual problems, were commonly reported after treatment with paroxetine and sertraline. The evidence-base for the effectiveness of medication in treating anxiety disorders and comorbid alcohol use disorders is currently inconclusive. There was a small amount of evidence for the efficacy of medication, but this was limited and of very low quality. The majority of the data for the efficacy and tolerability of medication were for SSRIs; there were insufficient data to establish differences in treatment efficacy between medication classes or patient subgroups. There was a small amount of very low quality evidence that medication was well tolerated. There was no evidence that alcohol use was responsive to medication. Large, rigorously conducted RCTs would help supplement the small evidence-base for the efficacy and tolerability of pharmacotherapy for anxiety and comorbid alcohol use disorders. Further research on patient subgroups who may benefit from pharmacological treatment, as well as novel pharmacological interventions, is warranted.

It was not possible to tell whether medication was effective in treating people with anxiety and alcohol use disorders. Although more than twice as many people (57.7%) with social anxiety disorder who were treated with paroxetine in two trials showed signs of clinical improvement compared with people receiving placebo (25.8%), the quality of the evidence was very low. One study reported that buspirone reduced anxiety disorder symptoms after 12 weeks of treatment. None of the other studies found reductions in symptoms. Treatment with medication appeared to be acceptable to participants, but again the quality of the evidence showing this was very low. Certain medication side effects, such as sexual problems, were commonly reported after treatment with paroxetine and sertraline. There was no evidence that treatment had an effect on alcohol use. It was difficult to interpret the findings reported by the studies included in this review. Many participants (43.1% altogether) dropped out of the studies before treatment ended. In addition, outcomes that were reported were either not precise, or appeared to be based on the selective reporting of measures that showed an effect of medication. Funding of two of the studies by drug companies may also have led to reporting of results that favoured the medication.

10.1002/14651858.CD007505.pub2

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cochrane-simplification-train-2728

We identified two RCTs (N=89) eligible for inclusion. These RCTs addressed oral or sublingual immunotherapy, both in adults, with an allergy to apple or peach respectively. Both studies enrolled a small number of participants and used different methods to provide these differing types of immunotherapy. Both studies were judged to be at high risk of bias in at least one domain. Overall, the quality of evidence was judged to be very low due to the small number of studies and participants and possible bias. The studies were clinically heterogeneous and hence we did not pool the results. A study comparing SLIT with placebo for allergy to peach did not detect a significant difference between the number of patients desensitised at six months following a double-blind placebo-controlled food challenge (RR 1.16, 95% confidence interval (CI) 0.49 to 2.74). The second study, comparing OIT versus no treatment for apple allergy, found an effect on desensitisation in favour of the intervention using an oral provocation test at eight months, but results were imprecise (RR 17.50, 95% CI 1.13 to 270.19). Neither study reported data on evidence of immunologic tolerance. In both studies, the incidence of mild and moderate adverse events was higher in the intervention groups than in the controls. In the study comparing SLIT with placebo, patients in the intervention group experienced significantly more local adverse reactions than participants in the control group (RR 3.21, 95% CI 1.51 to 6.82), though there was not a significant difference in the number of participants experiencing systemic adverse reactions (RR 0.81, 95% CI 0.22 to 3.02). In the study of OIT, two of the 25 participants in the intervention group reported relevant side effects, whereas no participants in the control group reported relevant side effects. There is insufficient evidence for using OIT or SLIT to treat allergy to fruit, specifically related to peach and apple. Mild or moderate adverse reactions were reported more frequently in people receiving OIT or SLIT. However, these reactions could be treated successfully with medications.

We found two studies with 89 participants in total. One looked at oral immunotherapy in people with an allergy to apple, comparing it to no treatment, and one looked at sublingual immunotherapy in people with an allergy to peach, comparing it to a placebo. Both studies were in adults. The evidence is current to July 2015. The study of oral immunotherapy for apple allergy found participants who received the intervention were less sensitive to apple than people who did not receive the intervention at eight months. The study of sublingual immunotherapy for peach allergy did not find a difference between the groups in terms of sensitivity at six months. In both studies, there were more side effects in people receiving the treatment, but these were not serious. Overall, the quality of evidence is very low because both studies were small, results were not similar between studies, and there were issues with study design. More research is needed before we can tell if oral and sublingual therapy works for food allergy to fruits.

10.1002/14651858.CD010522.pub2

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cochrane-simplification-train-2729

Three RCTs enrolling 144 participants met our inclusion criteria. Two compared steroid avoidance versus late steroid withdrawal and one compared late steroid withdrawal versus steroid maintenance. All studies included SPK and only one also included PTA. All studies had an overall moderate risk of bias and presented only short-term results (six to 12 months). Two studies (89 participants) compared steroid avoidance or early steroid withdrawal versus late steroid withdrawal. There was no clear evidence of an impact on mortality (2 studies, 89 participants: RR 1.64, 95% CI 0.21 to 12.75), risk of kidney loss censored for death (2 studies, 89 participants: RR 0.35, 95% CI 0.04 to 3.09), risk of pancreas loss censored for death (2 studies, 89 participants: RR 1.05, 95% CI 0.36 to 3.04), or acute kidney rejection (1 study, 49 participants: RR 2.08, 95% CI 0.20 to 21.50), however results were uncertain and consistent with no difference or important benefit or harm of steroid avoidance/early steroid withdrawal. The study that compared late steroid withdrawal versus steroid maintenance observed no deaths, no graft loss or acute kidney rejection at six months in either group and reported uncertain effects on acute pancreas rejection (RR 0.88, 95% CI 0.06 to 13.35). Of the possible adverse effects only infection was reported by one study. There were significantly more UTIs reported in the late withdrawal group compared to the steroid avoidance group (1 study, 25 patients: RR 0.41, 95% CI 0.26 to 0.66). We also identified 13 cohort studies and one RCT which randomised tacrolimus versus cyclosporin. These studies in general showed that steroid-sparing and withdrawal strategies had benefits in lowering HbAc1 and risk of infections (BK virus and CMV disease) and improved blood pressure control without increasing the risk of rejection. However, two studies found an increased incidence of acute pancreas rejection (HR 2.8, 95% CI 0.89 to 8.81, P = 0.066 in one study and 43.3% in the steroid withdrawal group versus 9.3% in the steroid maintenance, P < 0.05 at three years in the other) and one study found an increased incidence of acute kidney rejection (18.7% in the steroid withdrawal group versus 2.8% in the steroid maintenance, P < 0.05) at three years. There is currently insufficient evidence for the benefits and harms of steroid withdrawal in pancreas transplantation in the three RCTs (144 patients) identified. The results showed uncertain results for short-term risk of rejection, mortality, or graft survival in steroid-sparing strategies in a very small number of patients over a short period of follow-up. Overall the data was sparse, so no firm conclusions are possible. Moreover, the 13 observational studies findings generally concur with the evidence found in the RCTs.

This review looked at two strategies - steroid avoidance and steroid withdrawal - to investigate their impact on short- and long-term outcomes. These strategies could be used in adults in the first few days after transplantation when used in combination with more powerful immunosuppressive agents. Twenty-one studies were identified and evaluated in this review although only three RCTs enrolling 144 participants met our inclusion criteria. Steroid avoidance and steroid withdrawal strategies in pancreas and pancreas with kidney transplantation were not apparently associated with increased mortality, graft loss or acute rejection, although more studies are needed.

10.1002/14651858.CD007669.pub2

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cochrane-simplification-train-2730

This review includes a total of 5142 participants (mostly inpatients) from 44 trials conducted between 1988 and 2009 (median study duration ˜ 12 weeks, risk of bias - moderate). We found that incidences of non-compliance were lower in the psychoeducation group in the short term (n = 1400, RR 0.52 CI 0.40 to 0.67, NNT 11 CI 9 to 16). This finding holds for the medium and long term. Relapse appeared to be lower in psychoeducation group (n = 1214, RR 0.70 CI 0.61 to 0.81, NNT 9 CI 7 to 14) and this also applied to readmission (n = 206, RR 0.71 CI 0.56 to 0.89, NNT 5 CI 4 to 13). Scale-derived data also suggested that psychoeducation promotes better social and global functioning. In the medium term, treating four people with schizophrenia with psychoeducation instead of standard care resulted in one additional person showing a clinical improvement. Evidence suggests that participants receiving psychoeducation are more likely to be satisfied with mental health services (n = 236, RR 0.24 CI 0.12 to 0.50, NNT 5 CI 5 to 8) and have improved quality of life. Psychoeducation does seem to reduce relapse, readmission and encourage medication compliance, as well as reduce the length of hospital stay in these hospital-based studies of limited quality. The true size of effect is likely to be less than demonstrated in this review - but, nevertheless, some sort of psychoeducation could be clinically effective and potentially cost beneficial. It is not difficult to justify better, more applicable, research in this area aimed at fully investigating the effects of this promising approach. Note: the 27 new citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.

This review compares the efficacy of psychoeducation added to standard care as a means of helping severely mentally ill people with that of standard care alone. The evidence shows a significant reduction of relapse or readmission rates. There seems to be some suggestion that psychoeducation may improve compliance with medication, but the extent of improvement remains unclear. The findings show a possibility that psychoeducation has a positive effect on a person's well being and promotes better social function. In the medium term, treating four people with schizophrenia with psychoeducation instead of standard care resulted in one additional person showing a clinical improvement. The scarcity of studies made the comparison between the efficacy of different formats (programmes of 10 sessions or less or 11 or more, individual or group sessions) weak.

10.1002/14651858.CD002831.pub2

cochrane-simplification-train-2731

cochrane-simplification-train-2731

We include 57 studies (61 comparisons) in this updated review. We found 31 studies of workplace interventions aimed at individual workers, covering group therapy, individual counselling, self-help materials, nicotine replacement therapy, and social support, and 30 studies testing interventions applied to the workplace as a whole, i.e. environmental cues, incentives, and comprehensive programmes. The trials were generally of moderate to high quality, with results that were consistent with those found in other settings. Group therapy programmes (odds ratio (OR) for cessation 1.71, 95% confidence interval (CI) 1.05 to 2.80; eight trials, 1309 participants), individual counselling (OR 1.96, 95% CI 1.51 to 2.54; eight trials, 3516 participants), pharmacotherapies (OR 1.98, 95% CI 1.26 to 3.11; five trials, 1092 participants), and multiple intervention programmes aimed mainly or solely at smoking cessation (OR 1.55, 95% CI 1.13 to 2.13; six trials, 5018 participants) all increased cessation rates in comparison to no treatment or minimal intervention controls. Self-help materials were less effective (OR 1.16, 95% CI 0.74 to 1.82; six trials, 1906 participants), and two relapse prevention programmes (484 participants) did not help to sustain long-term abstinence. Incentives did not appear to improve the odds of quitting, apart from one study which found a sustained positive benefit. There was a lack of evidence that comprehensive programmes targeting multiple risk factors reduced the prevalence of smoking. 1. We found strong evidence that some interventions directed towards individual smokers increase the likelihood of quitting smoking. These include individual and group counselling, pharmacological treatment to overcome nicotine addiction, and multiple interventions targeting smoking cessation as the primary or only outcome. All these interventions show similar effects whether offered in the workplace or elsewhere. Self-help interventions and social support are less effective. Although people taking up these interventions are more likely to stop, the absolute numbers who quit are low. 2. We failed to detect an effect of comprehensive programmes targeting multiple risk factors in reducing the prevalence of smoking, although this finding was not based on meta-analysed data. 3. There was limited evidence that participation in programmes can be increased by competitions and incentives organized by the employer, although one trial demonstrated a sustained effect of financial rewards for attending a smoking cessation course and for long-term quitting. Further research is needed to establish which components of this trial contributed to the improvement in success rates. 4. Further research would be valuable in low-income and developing countries, where high rates of smoking prevail and smoke-free legislation is not widely accepted or enforced.

For this updated review (first published in 2003), we searched for randomized and quasi-randomized controlled trials, comparing the success rates of those in a work-based stop-smoking programme with those not involved in a work-based stop-smoking programme. The comparison could be between people within a single worksite, or between one or more worksites randomized to a stop-smoking programme or to no programme (cluster-randomized). The study had to include adults (over 18), and could be in any language and reported in any format, published or not. It had to report the numbers stopping smoking for at least six months. We searched for studies in July 2013, and identified ten new trials that fitted our criteria, making a total for this update of 61 comparisons across 57 included studies. We grouped them into two broad categories: those aimed at helping individual smokers, and those that targeted the workplace environment as a whole. The first group includes such methods as individual or group counselling, self help, nicotine replacement therapy (NRT) and other medications, help from workmates or other staff, and helping quitters to stay smoke-free. The second group includes environmental cues (posters, reminders), financial or material incentives, and comprehensive smoking cessation or health promotion programmes. The review found that programmes based on group behaviour therapy (eight trials; 1309 participants), on individual counselling (eight trials; 3516 participants), on medications (five trials; 1092 participants), and on several interventions combined (six trials; 5018 participants) helped people to stop smoking. The chances of stopping smoking using these methods are about the same in the workplace as they are in other settings. This review found that the following do not help people to stop smoking when delivered in the workplace: self-help methods, support from friends, family and workmates, relapse prevention programmes, environmental cues, or comprehensive programmes aimed at changing several high-risk behaviours. Results were mixed for incentives, with one high-quality trial finding a clear benefit for incentives while the remaining five did not. Earlier studies tended to be less well-conducted and reported than recent ones. Fewer than one in five studies randomized their study population by an acceptable method. Two-thirds of the studies checked the accuracy of those who said they had quit by testing their breath, blood or urine. The results were generally in line with findings from other reviews of those ways of quitting in any setting. The 'Summary of findings' table shows that the trials were generally rated as being of moderate to high quality, further confirming the strength of our findings. Future research might examine what features of the large incentives trial made it more successful than other trials in that group. It would also be helpful to have more trials from developing and low-income countries, where smoking rates remain high and anti-smoking laws are not widely enforced.

10.1002/14651858.CD003440.pub4

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cochrane-simplification-train-2732

We included six studies involving 119 participants. We combined studies that evaluated MP in addition to another treatment versus the other treatment alone. Mental practice in combination with other treatment appears more effective in improving upper extremity function than the other treatment alone (Z = 3.48, P = 0.0005; standardised mean difference (SMD) 1.37; 95% confidence interval (CI) 0.60 to 2.15). We attempted subgroup analyses, based on time since stroke and dosage of MP; however, numbers in each group were small. We evaluated the quality of the evidence with the PEDro scale, ranging from 6 to 9 out of 10; we determined the GRADE score to be moderate. There is limited evidence to suggest that MP in combination with other rehabilitation treatment appears to be beneficial in improving upper extremity function after stroke, as compared with other rehabilitation treatment without MP. Evidence regarding improvement in motor recovery and quality of movement is less clear. There is no clear pattern regarding the ideal dosage of MP required to improve outcomes. Further studies are required to evaluate the effect of MP on time post stroke, volume of MP that is required to affect the outcomes and whether improvement is maintained long-term. Numerous large ongoing studies will soon improve the evidence base.

Our review of six studies involving 119 participants provided limited evidence that mental practice, when added to traditional physical rehabilitation treatment, produced improved outcomes compared with the use of traditional rehabilitation treatment alone. The evidence to date shows the improvements are limited to measures of performance of real-life tasks appropriate to the upper limb (e.g. drinking from a cup, manipulating a door knob). It is not clear if mental practice added to physical practice produces improvements in the motor capacity of the upper limb (i.e. the ability to perform selected movements of the upper limb with strength, speed and/or co-ordination). Finally, there is no evidence available detailing either the components of the mental practice (e.g. How long should the mental practice sessions be? How many mental practice sessions are necessary?, etc) or the qualities of the survivor of a stroke (How long since onset of stroke? How much recovery is required?, etc) that are required to obtain a positive outcome. However, there is reason for optimism that some of the questions will be answered as there are several large trials currently ongoing.

10.1002/14651858.CD005950.pub4

cochrane-simplification-train-2733

cochrane-simplification-train-2733

Five trials were identified and included in the meta-analysis. From one of the included trials only preliminary data are reported. The addition of chemotherapy to preoperative RT significantly increased grade III and IV acute toxicity (OR 1.68-10, P = 0.002) and marginally affected postoperative overall morbidity (OR 0.67-1.00, P = 0.05) while no differences were observed in postoperative mortality or anastomotic leak rate. Compared to preoperative RT alone, preoperative CRT significantly increased the rate of complete pathological response (OR 2.12-5.84, P < 0.00001) although this did not translate into a higher sphincter preservation rate (OR 0.92-1.30, P = 0.32). The incidence of local recurrence at five years was significantly lower in the CRT group compared to RT alone (OR 0.39-0.72, P < 0.001). No statistically significant differences were observed in DFS (OR 0.92-1.34, P = 0.27) or OS (OR 0.79-1.14, P = 0.58) at five years. Compared to preoperative RT alone, preoperative CRT enhances pathological response and improves local control in resectable stage II and III rectal cancer, but does not benefit disease free or overall survival. The effects of preoperative CRT on functional outcome and quality of life are incompletely understood and should be addressed in future trials.

It has been proven in clinical studies that this 'preoperative' radiotherapy improves the outcome in rectal cancer patients. Recently, several studies have investigated the combination of radiotherapy with chemotherapy (CRT) before surgery. In theory, adding chemotherapy enhances the antitumour activity of radiotherapy. This meta-analysis has summarized the results of five studies that compared preoperative RT alone with preoperative CRT in rectal cancer patients. All of these studies were randomized, which means that the decision to administer either RT or CRT was determined by chance (ballot draw). The results of the meta-analysis may be summarized as follows. Compared to RT alone, preoperative CRT leads to increased side effects during treatment. Also, postoperative complications are somewhat increased, although the risk of dying from postoperative complications is similar. Preoperative CRT is more effective in causing tumour shrinkage (downstaging), and in preventing local recurrence of the disease. However, addition of chemotherapy did not result in more sphincter preserving surgeries, and did not affect the overall survival in rectal cancer patients.

10.1002/14651858.CD006041.pub3

cochrane-simplification-train-2734

cochrane-simplification-train-2734

Twenty-two trials (3142 episodes in 2372 patients) were included in the analyses. The mortality rate was similar when comparing oral to intravenous antibiotic treatment (RR 0.95, 95% CI 0.54 to 1.68, 9 trials, 1392 patients, median mortality 0, range 0% to 8.8%). Treatment failure rates were also similar (RR 0.96, 95% CI 0.86 to 1.06, all trials). No significant heterogeneity was shown for all comparisons but adverse events. The effect was stable in a wide range of patients. Quinolones alone or combined with another antibiotic were used with comparable results. Adverse reactions, mostly gastrointestinal, were more common with oral antibiotics. Based on the present data, oral treatment is an acceptable alternative to intravenous antibiotic treatment in febrile neutropenic cancer patients (excluding patients with acute leukaemia) who are haemodynamically stable, without organ failure, and do not have pneumonia, infection of a central line or a severe soft-tissue infection. The wide CI for mortality allows the present use of oral treatment in groups of patients with an expected low risk for mortality, and further research should be aimed at clarifying the definition of low risk patients.

This review of randomised controlled trials showed comparable death and failure rates for oral and intravenous antibiotics for low risk patients, those with solid tumours or chronic leukaemia or lymphoma, and independent of age, source of infection and severity of the neutropenia.

10.1002/14651858.CD003992.pub3

cochrane-simplification-train-2735

cochrane-simplification-train-2735

Seven trials assessing 4556 women were identified. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR = 1.00, 95% CI 0.85 to 1.18). This conclusion is also robust to single trial analyses at 4 and 7 years and in one trial across all points in time using a hazard ratio (HR). There was also no significant difference between progestagen therapy and control in terms of the risk of death from endometrial cancer, cardiovascular disease and intercurrent disease. Relapse of disease appeared to be reduced by progestagen therapy in one trial (HR = 0.71, 95% CI 0.52 to 0.97 and 5 year RR = 0.74, 95% CI 0.58 to 0.96), but there was no evidence of a difference in disease recurrence in another trial at 7 years (RR = 1.34, 95% CI 0.79 to 2.27). There is no evidence to support the use of adjuvant progestagen therapy in the primary treatment of endometrial cancer. There have now been several RCTs which have failed to establish a role for adjuvant progestagen therapy after primary treatment for endometrial cancer and therefore, further trials in this field are probably not justified.

Endometrial (womb) cancer is the most common genital tract cancer in developed countries. Progestagen (a hormone) therapy is sometimes used following initial surgery to reduce the risk of recurrence. However, progestagens have been found to reduce one of the protective factors against heart disease and may also make tumours more resistant to radiotherapy. This review found no evidence to support the use of progestagen as an addition to surgery for newly diagnosed endometrial cancer. Progestagen can, however, prevent or delay recurrence of cancer in some patients.

10.1002/14651858.CD001040.pub2

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cochrane-simplification-train-2736

Of the 1888 records identified, 62 randomised trials, including a total of 3428 patients, were eligible for inclusion. All studies were at high or uncertain risk of bias for at least one domain. Network meta-analysis evaluating the rate of pleurodesis failure, suggested talc poudrage to be a highly effective method (ranked second of 16 (95% credible interval (Cr-I) 1 to 5)) and provided evidence that it resulted in fewer pleurodesis failures than eight other methods. The estimated ranks of other commonly used agents were: talc slurry (fourth; 95% Cr-I 2 to 8), mepacrine (fourth; 95% Cr-I 1 to 10), iodine (fifth; 95% Cr-I 1 to 12), bleomycin (eighth; 95% Cr-I 5 to 11) and doxycyline (tenth; 95% Cr-I 4 to 15). The estimates were imprecise as evidenced by the wide credible intervals and both high statistical and clinical heterogeneity. Most of the secondary outcomes, including adverse events, were inconsistently reported by the included studies and the methods used to describe them varied widely. Hence the majority of the secondary outcomes were reported descriptively in this review. We obtained sufficient data to perform network meta-analysis for the most commonly reported adverse events: pain, fever and mortality. The fever network was imprecise and showed substantial heterogeneity, but suggested placebo caused the least fever (ranked first of 11 (95% Cr-I 1 to 7)) and mepacrine and Corynebacterium parvum (C. parvum) appeared to be associated with the most fever (ranked tenth (95% Cr-I 6 to 11) and eleventh (95% Cr-I 7 to 11) respectively). No differences between interventions were revealed by the network meta-analysis of the pain data. The only potential difference in mortality identified in the mortality network was that those receiving tetracycline appeared to have a longer survival than those receiving mitoxantrone (OR 0.16 (95% Confidence Interval (CI) 0.03 to 0.72)). Indwelling pleural catheters were examined in two randomised studies, both of which reported improved breathlessness when compared to talc slurry pleurodesis, despite lower pleurodesis success rates. The risk of bias in a number of the included studies was substantial, for example the vast majority of studies were unblinded, and the methods used for sequence generation and allocation concealment were often unclear. Overall, however, the risk of bias for all studies was moderate. We have not reported the GRADE quality of evidence for the outcomes, as the role of GRADE is not well established in the context of Network Meta-analysis (NMA). Based on the available evidence, talc poudrage is a more effective pleurodesis method in MPE than a number of other frequently used methods, including tetracycline and bleomycin. However further data are required to definitively confirm whether it is more effective than certain other commonly used interventions such as talc slurry and doxycycline, particularly in view of the high statistical and clinical heterogeneity within the network and the high risk of bias of many of the included studies. Based on the strength of the evidence from both direct and indirect comparisons of randomised data of sclerosants administered at the bedside, there is no evidence to suggest large differences between the other highly effective methods (talc slurry, mepacrine, iodine and C. parvum). However, local availability, global experience of these agents and their adverse events, which may not be identified in randomised trials, must also be considered when selecting a sclerosant. Further research is required to delineate the roles of different treatments according to patient characteristics (e.g. according to their prognosis or presence of trapped lung) and to explore patient-centred outcomes, such as breathlessness and quality of life, in more detail. Careful consideration to minimise the risk of bias and standardise outcome measures is essential for future trial design.

We searched databases for trials comparing different interventions in adults with symptomatic MPE to April 2015, written in any language. Since we were only interested in rigorously conducted research, we restricted our search to randomised controlled trials (in which participants are randomly allocated to the methods being tested). We analysed the majority of the data using a technique called 'network meta-analysis' which allows lots of different interventions to be compared in one analysis. This analysis ranks the interventions in order of their effectiveness. We found 62 studies involving 3428 patients. In the network meta-analysis, the use of thoracoscopy to remove the fluid and blow talc into the pleural cavity (talc poudrage) appeared to be more effective in preventing fluid build up than a number of other commonly used methods. However, we could not say definitely that it is better than some other methods such as giving talc or doxycycline through a chest drain. Side effects, quality of life and patient satisfaction were reported inconsistently by the included studies, but are important factors to consider when selecting the best management strategy for a patient. There was enough data to perform network meta-analysis for pain, fever and mortality. We found placebo caused the least fever and Corynebacterium parvum (C. parvum) and mepacrine were likely to cause the most. We found no differences in the pain caused by the interventions evaluated. Only one comparison showed a possible difference, revealing that those receiving tetracycline may live longer than those receiving mitoxantrone. As we only evaluated randomised controlled trials, it is possible some harms of treatments were not identified by this review. Many of the studies were of low quality and the characteristics of the individual studies were quite different to each other. This high risk of bias makes it difficult to reach definite conclusions. The available evidence shows that talc poudrage can stop fluid building up. However, we can not be sure that this is definitely the best method, and further research is needed. It is also important to consider global experience of these agents and knowledge of their safety and side effects when selecting the most appropriate pleurodesis method. Indwelling pleural catheters may help improve patient breathlessness, but may be less good at stopping the fluid coming back. Further research is also required to look at particular patient groups and explore patient-centred outcomes, such as breathlessness and quality of life in more detail. Ideally a fuller understanding of the potential harms of the treatments from the patients' perspective would also be beneficial.

10.1002/14651858.CD010529.pub2

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cochrane-simplification-train-2737

Eleven reports (relating to five possible trials) were found. We included one study (six trial reports) involving 256 women. Four other studies are ongoing. The included trial consisted of three treatment arms: probiotic with dietary intervention, placebo and dietary intervention, and dietary intervention alone; it was at a low risk of bias. The study reported primary outcomes of a reduction in the rate of gestational diabetes mellitus (risk ratio (RR) 0.38, 95% confidence interval (CI) 0.20 to 0.70), with no statistical difference in the rates of miscarriage/intrauterine fetal death (IUFD)/stillbirth/neonatal death (RR 2.00, 95% CI 0.35 to 11.35). Secondary outcomes reported were a reduction in infant birthweight (mean difference (MD) -127.71 g, 95% CI -251.37 to -4.06) in the probiotic group and no clear evidence of increased risk of preterm delivery (RR 3.27, 95% CI 0.44 to 24.43), or caesarean section rate (RR 1.23, 95% CI 0.65 to 2.32). The primary infant outcomes of rates of macrosomia and large-for-gestational age infants were not reported. The following secondary outcomes were not reported: maternal gestational weight gain, pre-eclampsia, and the long-term diagnosis of diabetes mellitus; infant body composition, shoulder dystocia, admission to neonatal intensive care, jaundice, hypoglycaemia and long-term rates of obesity and diabetes mellitus. One trial has shown a reduction in the rate of GDM when women are randomised to probiotics early in pregnancy but more uncertain evidence of any effect on miscarriage/IUFD/stillbirth/neonatal death. There are no data on macrosomia. At this time, there are insufficient studies to perform a quantitative meta-analysis. Further results are awaited from four ongoing studies.

This review was designed to look at whether there is evidence to show if this is true or not. At the moment there is only one randomised controlled study, which involved 256 women. This study does show a lower rate of gestational diabetes mellitus in women who took probiotics from early pregnancy, with the rate of diagnosis of gestational diabetes mellitus being reduced by two-thirds and their babies on average weighed 127 g less at birth. This study did not find differences in the rates of miscarriage, intrauterine or neonatal death or stillbirth. There was no clear evidence of a change in the proportion of women delivered by caesarean section or in the risk of preterm delivery. The study did not report on how much weight the mothers gained during pregnancy or how many babies were large-for-gestational age or that weighed more than 4000 g at birth or on the body composition of the babies. One study is not enough to draw any definite conclusions at the moment. There are other studies underway.

10.1002/14651858.CD009951.pub2

cochrane-simplification-train-2738

cochrane-simplification-train-2738

We included eight studies involving a total of 27,557 participants with non-valvular AF and one or more risk factors for stroke; 26,601 of them were assigned to standard doses groups and included in the primary analysis. The DTIs: dabigatran 110 mg twice daily and 150 mg twice daily (three studies, 12,355 participants), AZD0837 300 mg once per day (two studies, 233 participants) and ximelagatran 36 mg twice per day (three studies, 3726 participants) were compared with the VKA warfarin (10,287 participants). Overall risk of bias and statistical heterogeneity of the studies included were low. The odds of vascular death and ischaemic events were not significantly different between all DTIs and warfarin (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.85 to 1.05). Sensitivity analysis by dose of dabigatran on reduction in ischaemic events and vascular mortality indicated that dabigatran 150 mg twice daily was superior to warfarin although the effect estimate was of borderline statistical significance (OR 0.86, 95% CI 0.75 to 0.99). Sensitivity analyses by other factors did not alter the results. Fatal and non-fatal major bleeding events, including haemorrhagic strokes, were less frequent with the DTIs (OR 0.87, 95% CI 0.78 to 0.97). Adverse events that led to discontinuation of treatment were significantly more frequent with the DTIs (OR 2.18, 95% CI 1.82 to 2.61). All-cause mortality was similar between DTIs and warfarin (OR 0.91, 95% CI 0.83 to 1.01). DTIs were as efficacious as VKAs for the composite outcome of vascular death and ischaemic events and only the dose of dabigatran 150 mg twice daily was found to be superior to warfarin. DTIs were associated with fewer major haemorrhagic events, including haemorrhagic strokes. Adverse events that led to discontinuation of treatment occurred more frequently with the DTIs. We detected no difference in death from all causes.

We included eight studies, identified up to October 2013, evaluating the effect of DTIs versus warfarin in people with non-valvular AF. DTIs included were dabigatran 110 mg or 150 mg twice daily (three studies, 12,355 participants), AZD0837 300 mg once a day (two studies, 233 participants) and ximelagatran 36 mg twice daily (three studies, 3726 participants). Of the total number of participants included in this review 61% were men, and the mean age of participants in all studies was over 70 years. Follow-up periods after the end of study medication ranged from zero to four weeks. We conducted the analyses excluding ximelagatran because this drug was withdrawn from the market owing to toxic effects on the liver. We evaluated the effectiveness of the treatment by the number of vascular deaths and ischaemic events. We evaluated safety by the number of (1) fatal and non-fatal major bleeding events, including haemorrhagic strokes, (2) adverse events other than bleeding and ischaemic events that led to treatment discontinuation, and (3) death from all causes. There was no difference in the number of vascular deaths and ischaemic events between all DTIs combined and warfarin, although dabigatran 150 mg twice daily was superior to warfarin for this outcome. Major bleeding events were less frequent with the DTIs, making them a potentially safer alternative to anticoagulation in people at high risk. The adverse events that led participants to discontinue treatment were more frequent with the DTIs. Death from all causes was similar between DTIs and warfarin. We judged the quality of all eight included studies to be adequate to address the main objectives of the review.

10.1002/14651858.CD009893.pub2

cochrane-simplification-train-2739

cochrane-simplification-train-2739

Twelve RCTs with a total of 585 participants were included. Six trials were double-blinded, placebo-controlled studies, and the other six trials were of less adequate methodology. Most trials were small and had high rates of dropout. Eleven of the 12 included trials described the effects of antioxidants on chronic abdominal pain in chronic pancreatitis. Pain as measured on a visual analogue scale (VAS, scale range 0 to 10) after one to six months was less in the antioxidant group than in the control group (mean difference (MD) -0.33, 95% confidence interval (CI) -0.64 to -0.02, P value 0.04, moderate-quality evidence). The number of pain-free participants was not statistically significantly different (risk ratio (RR) 1.73, 95% CI 0.95 to 3.15, P value 0.07, low-quality evidence). More adverse events were observed in the antioxidant group, both in the parallel trials (RR 4.43, 95% CI 1.60 to 12.29, P value 0.0004, moderate-quality evidence) and in the cross-over trials (RR 5.80, 95% CI 1.56 to 21.53, P value 0.0009, moderate-quality evidence). Adverse events occurred in 16% of participants and were mostly mild (e.g. headache, gastrointestinal complaints), but were sufficient to make participants stop antioxidant use. Other important outcomes such as use of analgesics, exacerbation of pancreatitis and quality of life were rarely reported. One trial from 1991 evaluated the effects of antioxidants on acute pain during exacerbation of chronic pancreatitis and found that a significantly higher proportion of participants in the antioxidant group experienced pain relief. This trial was conducted more than 25 years ago and has not been reproduced since that time. Therefore, additional trials are needed before reliable conclusions can be drawn. Current evidence shows that antioxidants can reduce pain slightly in patients with chronic pancreatitis. The clinical relevance of this small reduction is uncertain, and more evidence is needed. Adverse events in one of six patients may prevent the use of antioxidants. Effects of antioxidants on other outcome measures, such as use of analgesics, exacerbation of pancreatitis and quality of life remain uncertain because reliable data are not available.

This review summarises the evidence from randomised trials on the effects of antioxidants in chronic pancreatitis. Antioxidants are substances that prevent damage to cells caused by toxic byproducts of oxygen in the body. Levels of these byproducts are increased in chronic pancreatitis. Antioxidants constitute a large group that contains many natural and man-made products. Examples include vitamin C, vitamin E, flavonoids (present in tea and cocoa) and many specialised medications. We found 12 randomised trials on this topic. The quality of these trials was mixed, and many had small sample sizes and high rates of dropout. Evidence shows that antioxidants may reduce pain in patients with chronic pancreatitis, but the reported reduction in pain was small. Whether this small decrease really had an impact on patients' complaints is not clear. Given the methodological problems of these trials, a strong conclusion could not be drawn. Use of antioxidants resulted in adverse effects in about 16% of study participants. Most adverse effects were mild, such as headache, nausea and constipation. However, participants who developed these adverse effects tended to stop using antioxidant medication. Other outcomes important for decision making such as use of analgesics, rate of exacerbation of pancreatitis and quality of life, were not very well reported. Therefore, we were unable to reach conclusions on these outcomes.

10.1002/14651858.CD008945.pub2

cochrane-simplification-train-2740

cochrane-simplification-train-2740

There were 8203 citations identified from database searches and reference lists. We included 12 trials with 2605 consumer participants and more than 905 primary care practitioner participants. Eleven trials compared consultation liaison to standard care and one compared consultation liaison to collaborative care, with a case manager co-ordinating mental health care. People with depression were included in eight trials; and one trial each included people with a variety of disorders: depression, anxiety and somatoform disorders; medically unexplained symptoms; and drinking problems. None of the included trials reported separate data for children or older people. There was some evidence that consultation liaison improved mental health up to three months following the start of treatment (two trials, n = 445, NNTB 8, 95% CI 5 to 25) but there was no evidence of its effectiveness between three and 12 months. Consultation liaison also appeared to improve consumer satisfaction (up to three months: one trial, n = 228, NNTB 3, 95% CI 3 to 5; 3 to 12 months: two trials, n = 445, NNTB 8, 95% CI 5 to 17) and adherence (3 to 12 months: seven trials, n = 1251, NNTB 6, 95% CI 4 to 13) up to 12 months. There was also an improvement in the primary care provider outcomes of providing adequate treatment between three to 12 months (three trials, n = 797, NNTB 7, 95% CI 4 to 17) and prescribing pharmacological treatment up to 12 months (four trials, n = 796, NNTB 13, 95% CI 7 to 50). There was also some evidence that consultation liaison may not be as effective as collaborative care in regards to symptoms of mental disorder, disability, general health status, and provision of treatment. The quality of these findings were low for all outcomes however, apart from consumer adherence from three to 12 months, which was of moderate quality. Eight trials were rated a high risk of performance bias because consumer participants were likely to have known whether or not they were allocated to the intervention group and most outcomes were self reported. Bias due to attrition was rated high in eight trials and reporting bias was rated high in six. There is evidence that consultation liaison improves mental health for up to three months; and satisfaction and adherence for up to 12 months in people with mental disorders, particularly those who are depressed. Primary care providers were also more likely to provide adequate treatment and prescribe pharmacological therapy for up to 12 months. There was also some evidence that consultation liaison may not be as effective as collaborative care in terms of mental disorder symptoms, disability, general health status, and provision of treatment. However, the overall quality of trials was low particularly in regards to performance and attrition bias and may have resulted in an overestimation of effectiveness. More evidence is needed to determine the effectiveness of consultation liaison for people with mental disorders particularly for those with mental disorders other than depression.

In this review of studies published up till March 2014, the effectiveness of consultation liaison was compared to standard primary care and other types of mental health care. We included 12 trials with 2605 consumers and more than 905 primary care providers. Consultation liaison was compared to standard care in 11 trials, and compared to collaborative care in one trial. Collaborative care is mental health care co-ordinated by a primary care case manager. There was some evidence that consultation liaison improved mental health, satisfaction with care and adherence to treatment in people with some mental disorders, particularly those with depression, and improved mental health care by primary care providers. There was also some evidence suggesting consultation liaison may not be as effective as collaborative care. However, as the overall quality of trials was low, the effectiveness of these ways of delivering care may have been overestimated. No conclusions can be made regarding the use of consultation liaison with people who have other mental disorders such as schizophrenia or bipolar disorder. There was also no data which could inform practice with specific groups of people such as children and adolescents, and the elderly. More high quality trials of consultation liaison are needed.

10.1002/14651858.CD007193.pub2

cochrane-simplification-train-2741

cochrane-simplification-train-2741

Six trials involving 321 infants in three different settings were included. Compared with beta2-agonist alone, the combination of ipratropium bromide and beta2-agonist was associated with a reduced need for additional treatment, but no difference was seen in treatment response, respiratory rate or oxygen saturation improvement in the emergency department. There was no significant difference in length of hospital stay between ipratropium bromide and placebo; or between ipratropium bromide and beta2-agonist combined compared with beta2-agonist alone. However, combined ipratropium bromide and beta2-agonist compared to placebo showed significantly improved clinical scores at 24 hours. Parents preferred ipratropium bromide over nebulised water or placebo for relief of their children's symptoms at home. A further updated search conducted in June 2005 did not yield any new studies. There is not enough evidence to support the uncritical use of anti-cholinergic therapy for wheezing infants, although parents using it at home were able to identify benefits.

Six trials involving 321 infants in three different settings were reviewed. The review was unable to identify clear benefits in outcomes such as duration of hospitalisation or improvement in oxygenation though there were suggestions that some patients may benefit particularly in recurrently wheezy infants treated at home. Well designed studies are required to clarify the role of these agents in young children with wheeze.

10.1002/14651858.CD001279.pub2

cochrane-simplification-train-2742

cochrane-simplification-train-2742

We identified one randomized controlled trial of high quality, involving 300 patients , comparing SmartCare™ to a written protocol. In this trial, SmartCare™ had no effect on discontinuation time. While SmartCare™ significantly reduced the time to the first SBT (mean difference (MD) -0.34 days, 95% CI -0.60 to -0.08; P = 0.01) it did not reduce the time to the first successful SBT (MD -0.25 days, 95% CI -0.55 to 0.05; P = 0.10) and other clinically important outcomes. SmartCare™ did not demonstrate beneficial effects on most clinically important outcomes including time to successful extubation, total duration of mechanical ventilation, ICU and hospital lengths of stay, and the requirement for tracheostomy. Moreover, SmartCare™ did not favourably impact reintubation, mortality, self-extubation, and the proportion of patients undergoing protracted mechanical ventilation, with a small numbers of events in this single trial. There is a paucity of evidence from randomized controlled trials to support or refute use of automated weaning and SBT systems in discontinuing invasive mechanical ventilation in adult postoperative patients. In a single large trial of high methodologic quality, while the use of SmartCare™ to adjust ventilator settings and conduct SBTs shortened the time to undergoing the first SBT, it did not reduce the time to the first successful SBT or the rate of tracheostomy compared to a written protocol implemented by physicians. SmartCare™ did not demonstrate beneficial effects on clinically important outcomes including time to mechanical ventilation discontinuation, time to successful discontinuation, total duration of mechanical ventilation, and ICU and hospital lengths of stay. Additional well-designed, adequately powered randomized controlled trials are needed to clarify the role for SmartCare™ on important outcomes in patients who predominantly require short term ventilation and in specific postoperative patient populations.

In a single large trial of high methodologic quality that involved 300 patients, use of a system (SmartCare™) that automatically adjusted ventilator settings and conducted tests of patients' ability to breathe spontaneously there was no clear benefit of SmartCare™. While it reduced the time to undergo the first test of spontaneous breathing, it did not reduce the time to the first successful spontaneous breathing test compared to a written weaning protocol applied by physicians. There was no clear benefit of SmartCare™ on other clinically important outcomes including the time to successful discontinuation of artificial ventilation , the total duration of mechanical ventilation, the time spent in the intensive care unit and hospital, and the requirement for tracheostomy (an airway inserted into the trachea). Further studies are needed to clarify the role of SmartCare™ in the postoperative setting, in general, and in specific patient populations.

10.1002/14651858.CD008639.pub2

cochrane-simplification-train-2743

cochrane-simplification-train-2743

We identified four RCTs with 148 participants in total. In the first one, of 14 participants with moderate or severe myasthenia gravis, improvement after one month was not significantly greater for participants treated with plasma exchange and prednisone than for those treated with prednisone alone. A randomised controlled cross-over trial of 12 participants with moderate to severe myasthenia gravis found no statistically significant difference in the efficacy of plasma exchange or intravenous immunoglobulins after four weeks. A trial including 87 participants with myasthenia gravis exacerbation found no statistically significant difference between plasma exchange and immunoglobulin after two weeks. The fourth RCT, with 35 participants, showed a statistically significant difference in favour of plasma exchange before thymectomy. However these trials, except the third, are at high risk of bias and have a weak statistical power. No adequate RCTs have been performed to determine whether plasma exchange improves the short- or long-term outcome for chronic myasthenia gravis or myasthenia gravis exacerbation. However, many studies with case series report short-term benefit from plasma exchange in myasthenia gravis, especially in myasthenic crisis. In severe exacerbations of myasthenia gravis one RCT did not show a significant difference between plasma exchange and intravenous immunoglobulin. Further research is need to compare plasma exchange with alternative short-term treatments for myasthenic crisis or before thymectomy and to determine the value of long-term plasma exchange for treating myasthenia gravis.

Four randomised controlled trials were identified. In the first one, of 14 participants with moderate or severe myasthenia gravis, the myasthenic muscular score after one month was not significantly different for participants treated with plasma exchange and prednisone than for those treated with prednisone alone but there can be only low statistical confidence in the results of this study because of its small size. A randomised controlled cross-over trial of only 12 participants reported the same efficacy, after four weeks, of plasma exchange or intravenous immunoglobulins for the treatment of moderate to severe myasthenia gravis, but because of bias and a very weak statistical power the data prevent any conclusion. The third, including 87 participants, showed the same efficacy, after two weeks, of plasma exchange or intravenous immunoglobulins for the treatment of myasthenia gravis exacerbation. The fourth randomised controlled trial involving 35 participants reported a benefit from plasma exchange before thymectomy but this trial was heavily biased. No trial addressed the new subtype with antibodies to a muscle specific kinase. Further research is needed to determine the value of long-term plasma exchange for treating myasthenia gravis and to compare plasma exchange with alternative short-term treatments for myasthenic crisis or before thymectomy in both types of autoimmune myasthenia.

10.1002/14651858.CD002275

cochrane-simplification-train-2744

cochrane-simplification-train-2744

There were three randomized controlled trials that met our inclusion criteria recruited HIV-negative participants with chancroid (two trials with 143 participants) and primary syphilis (one trial with 30 participants). The syphilis study, carried out in the US between 1995 and 1997, randomized participants to receive a single 2.0 g oral dose of azithromycin (11 participants); two 2.0 g oral doses of azithromycin administered six to eight days apart (eight participants); or benzathine penicillin G administered as either 2.4 million units intramuscular injection once or twice seven days apart (11 participants). No participant in the trial seroconverted during 12 months of follow-up. The chancroid trials, conducted in Kenya by 1990, found no significant differences in HIV seroconversion rates during four to 12 weeks of follow-up between 400 and 200 mg single oral doses of fleroxacin (one trial, 45 participants; RR 3.00; 95% CI 0.29 to 30.69), or between 400 mg fleroxacin and 800 mg sulfamethoxazole plus 160 mg trimethoprim (one trial, 98 participants; RR 0.33; 95% CI 0.04 to 3.09). Adverse events reported were mild to moderate in severity, and included Jarisch-Herxheimer reactions and gastrointestinal symptoms. The differences between the treatment arms in the incidence of adverse events were not significant. The quality of this evidence on the effectiveness of genital ulcer disease treatment in reducing sexual acquisition of HIV, according to GRADE methodology, is of very low quality. At present, there is insufficient evidence to determine whether curative treatment of genital ulcer disease would reduce the risk of HIV acquisition. The very low quality of the evidence implies that the true effect of genital ulcer disease treatment on sexual acquisition of HIV may be substantially different from the effect estimated from currently available data. However, genital ulcer diseases are public health problems in their own right and patients with these conditions should be treated appropriately; whether the treatment reduces the risk of HIV infection or not.

This review assessed whether giving treatment for diseases that present with ulcers in the genital region would reduce sexual acquisition of HIV. Three studies were identified involving 173 HIV-negative patients with genital ulcers. These studies did not provide sufficient evidence that treatment of genital ulcer diseases reduces sexual acquisition of HIV infection. However, genital ulcer diseases are public health problems in their own right and patients with these conditions should be treated appropriately; whether the treatment reduces the risk of HIV infection or not.

10.1002/14651858.CD007933.pub2

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cochrane-simplification-train-2745

We included one RCT with 34 participants who were randomly assigned to receive IVIg or placebo once daily in addition to azathioprine and prednisolone for remission maintenance. There were no significant differences between adjuvant IVIg and adjuvant placebo in mortality, serious adverse events, time to relapse, open-label rescue therapy, and infection rates. The fall in disease activity score, derived from patient-reported symptoms, was slightly greater in the IVIg group than in the placebo group at one month (MD 2.30; 95% Confidence interval (CI) 1.12 to 3.48, P < 0.01) and three months (MD 1.80; 95% CI 0.35 to 3.25, P = 0.01). There was a significant increase in total adverse events in the IVIg group (relative risk (RR) 3.50; 95% CI 1.44 to 8.48, P < 0.01). There is insufficient evidence from one RCT that IVIg adjuvant therapy provides a therapeutic advantage compared with the combination of steroids and immunosuppressants for patients with WG. Given the high cost of IVIg (one dose at 2 g/kg for a 70 kg patient = $8,400), it should be limited to treat WG in the context of a well conducted RCT powered to detect patient-relevant outcomes.

We found one small randomized trial in which 34 participants were randomized to receive IVIg or placebo once daily in addition to azathioprine and prednisolone for remission maintenance. This trial did not provide enough evidence to determine if IVIg has an advantage over corticosteroids and immunosuppressants for the treatment of Wegener's granulomatosis.

10.1002/14651858.CD007057.pub3

cochrane-simplification-train-2746

cochrane-simplification-train-2746

Previous versions of this review included no trials. From the 2015 search, we identified three cross-over trials that could be included. The 2017 search found no new studies relevant to this review. The included trials randomised 47 inpatients with chronic mental illnesses in the USA and China. Trials were published in the 1990s and were of short duration (six to 10 weeks). Overall, the risk of bias was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, and attrition and outcome data were not fully reported. Findings were sparse, no study reported on the primary outcome 'no clinically important improvement in tardive dyskinesia symptoms,' but two small studies (37 participants) found no difference on the tardive dyskinesia symptoms scale Abnormal Involuntary Movement Scale (AIMS) scores between diltiazem or flunarizine and placebo after three to four weeks' treatment (MD -0.71, 95% CI -2.68 to 1.26, very low quality evidence). Only one study randomising 20 participants reported on adverse events, and reported that there were no adverse events with flunarizine or with placebo (very low quality evidence). One study with 18 participants reported no events of deterioration in mental state with diltiazem or with placebo (very low quality evidence). No studies reported on acceptability of treatment or on social confidence, social inclusion, social networks or personalised quality of life outcomes designated important to patients. Available evidence from randomised controlled trials is extremely limited and very low quality, conclusions cannot be drawn. The effects of calcium channel blockers for antipsychotic-induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well-designed randomised trials.

We searched for clinical trials (up to April 2017) using Cochrane Schizophrenia's specialised register of trials. The review includes three small, short trials published in the 1990s. The trials randomised 47 people with schizophrenia or other chronic mental illnesses who had also developed tardive dyskinesia because they were taking antipsychotic medicines. The treatments the participants received were the calcium channel blockers, flunarizine, nifedipine or diltiazem hydrochloride or placebo (dummy treatment). A small set of very low quality data were available from three small and poorly reported trials. Currently, it is uncertain whether calcium channel blockers are helpful in the treatment of tardive dyskinesia that is caused by taking antipsychotic medicines. Therefore, the use of calcium channel blockers for this purpose remains experimental. Evidence was limited and small scale. It is not possible to recommend these drugs as a treatment for antipsychotic-induced tardive dyskinesia. To fully investigate whether calcium channel blockers have any positive effects, there would have to be more well-designed, conducted and reported clinical trials. This plain language summary was adapted by the review authors from a summary originally written by Ben Gray, Senior Peer Researcher, McPin Foundation (mcpin.org/).

10.1002/14651858.CD000206.pub4

cochrane-simplification-train-2747

cochrane-simplification-train-2747

We identified three eligible studies; two describing ICU patients (N = 358), and one describing relatives of ICU patients (N = 30). The study involving relatives of ICU patients was a substudy of family members from one of the ICU patient studies. There was a mixed risk of bias within the included studies. Blinding of participants to allocation was not possible and blinding of the outcome assessment was not adequately achieved or reported. Overall the quality of the evidence was low to very low. The patient diary intervention was not identical between studies. However, each provided a prospectively prepared, day-to-day description of the participants' ICU admission. No study adequately reported on risk of PTSD as described using a clinical interview, family or caregiver anxiety or depression, health-related quality of life or costs. Within a single study there was no clear evidence of a difference in risk for developing anxiety (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.07 to 1.19) or depression (RR 0.38, 95% CI 0.12 to 1.19) in participants who received ICU diaries, in comparison to those that did not receive a patient diary. However, the results were imprecise and consistent with benefit in either group, or no difference. Within a single study there was no evidence of difference in median post-traumatic stress symptomatology scores (diaries 24, SD 11.6; no diary 24, SD 11.6) and delusional ICU memory recall (RR 1.04, 95% CI 0.84 to 1.28) between the patients recovering from ICU admission who received patient diaries, and those who did not. One study reported reduced post-traumatic stress symptomatology in family members of patients recovering from admission to ICU who received patient diaries (median 19; range 14 to 28), in comparison to no diary (median 28; range 14 to 38). Currently there is minimal evidence from RCTs of the benefits or harms of patient diaries for patients and their caregivers or family members. A small study has described their potential to reduce post-traumatic stress symptomatology in family members. However, there is currently inadequate evidence to support their effectiveness in improving psychological recovery after critical illness for patients and their family members.

The evidence is current to January 2014. We identified three eligible studies; two describing 358 ICU patients, and one describing 30 relatives of ICU patients. These were included in the review. The study involving relatives of ICU patients was a substudy of family members from one of the ICU patient studies. All people included in the studies were adults based in Europe and the UK, with a mixed severity of critical illness requiring admission to an ICU. We found no studies that had reported the risk of post-traumatic stress disorder in patients recovering from admission to ICU using a structured clinical interview. The other primary outcome measures of anxiety and depression were described in one study of 36 patients. In this study no clear evidence of a difference was seen in anxiety and depression when patient diaries were used for people recovering from ICU admission, in comparison to no diaries. Post-traumatic stress symptoms in family members and caregivers were reduced in another study of 30 people when patient diaries were used, in comparison to no diaries. Current research has not adequately assessed the safety and effectiveness of patient diaries. Adverse events associated with the use of diaries have not been reported. It has not been established whether patient diaries are an effective practice or whether they may cause harm. The overall quality of the evidence to support the use of diaries to promote recovery for patients and caregivers or families recuperating from critical illness is low or very low. This is because of the small amount of research and the methodological quality of studies. There is no evidence to support their use and it has not been established whether they cause benefit or harm.

10.1002/14651858.CD010468.pub2

cochrane-simplification-train-2748

cochrane-simplification-train-2748

We included nine RCTs with a total of 534 participants with cirrhosis and ascites. One RCT had a low risk of bias for mortality and a high risk of bias for the remaining outcomes. All included trials had a high risk of bias for non-mortality outcomes. In total, 473 participants had type 1 hepatorenal syndrome. Seven RCTs specifically evaluated terlipressin and albumin. Terlipressin was associated with a beneficial effect on mortality when including all RCTs (RR 0.85, 95% CI 0.73 to 0.98; 534 participants; number needed to treat for an additional beneficial outcome (NNTB) 10.3 people; low-quality evidence). Trial Sequential Analysis including all RCTs also found a beneficial effect of terlipressin. Additional analyses showed a beneficial effect of terlipressin and albumin on reversal of hepatorenal syndrome (RR 0.63, 95% CI 0.48 to 0.82; 510 participants; 8 RCTs; NNTB 4 people; low-quality evidence). Terlipressin increased the risk of serious cardiovascular adverse events (RR 7.26, 95% CI 1.70 to 31.05; 234 participants; 4 RCTs), but it had no effect on the risk of serious adverse events when analysed as a composite outcome (RR 0.91, 95% CI 0.68 to 1.21; 534 participants; 9 RCTs; number needed to treat for an additional harmful outcome 24.5 people; low-quality evidence). Non-serious adverse events were mainly gastrointestinal, including diarrhoea (RR 5.76, 95% CI 2.19 to 15.15; 240 participants; low-quality evidence) and abdominal pain (RR 1.54, 95% CI 0.97 to 2.43; 294 participants; low-quality evidence). We identified one ongoing trial on terlipressin versus placebo in participants with cirrhosis, ascites, and hepatorenal syndrome type 1. Three RCTs reported funding from a pharmaceutical company. The remaining trials did not report funding or did not receive funding from pharmaceutical companies. This review suggests that terlipressin may be associated with beneficial effects on mortality and renal function in people with cirrhosis and type 1 hepatorenal syndrome, but it is also associated with serious adverse effects. We downgraded the strength of the evidence due to methodological issues including bias control, clinical heterogeneity, and imprecision. Consequently, additional evidence is needed.

The review includes nine randomised clinical trials (RCTs) and a total of 534 participants. The trials originated from six countries. Seven trials included only participants with type 1 hepatorenal syndrome. Two trials included a total of 96 participants with type 1 or type 2 hepatorenal syndrome. Three RCTs reported funding from a pharmaceutical company. The remaining trials did not report funding or did not receive funding from pharmaceutical companies. People who received terlipressin had a lower risk of dying than people who received inactive placebo or no treatment. Terlipressin was also associated with a beneficial effect on renal function. Terlipressin increased the risk of serious circulation and heart problems (so-called cardiovascular events). Other adverse events included diarrhoea and abdominal pain. The analyses mainly included people with type 1 hepatorenal syndrome. No beneficial or harmful effects of terlipressin were found when analysing participants with type 2 hepatorenal syndrome (possibly due to the small number of participants). We considered the evidence to be of low quality.

10.1002/14651858.CD005162.pub4

cochrane-simplification-train-2749

cochrane-simplification-train-2749

We included 14 trials that included 1063 women in the intervention groups and 1065 women in the control groups. Thirteen studies compared endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle versus no injury, and one study compared endometrial injury on the day of oocyte retrieval versus no injury. Overall, eight of the 14 included studies were deemed to be at high risk of bias in at least one domain. In studies comparing endometrial injury performed between day 7 of the previous cycle and day 7 of the ET cycle versus no intervention or a sham procedure, endometrial injury was associated with an increase in live birth or ongoing pregnancy rate: RR 1.42, 95% confidence interval (CI) 1.08 to 1.85; P value 0.01; nine RCTs; 1496 women; I² = 53%; moderate-quality evidence. In other words, moderate-quality evidence suggests that if 26% of women achieve live birth without endometrial injury, between 28% and 48% will achieve live birth with endometrial injury. A sensitivity analysis removing the studies at high risk of bias showed no difference in effect. There was no evidence of an effect on miscarriage, however the evidence is of low-quality: RR 0.99, 95% CI 0.63 to 1.53; P value 0.06; eight RCTs; 500 clinical pregnancies; I² = 10%; low-quality evidence. Endometrial injury was also associated with an increased clinical pregnancy rate: RR 1.34, 95% CI 1.21 to 1.61; P value 0.002; 13 RCTs; 1972 women; I² = 45%; moderate-quality evidence. This suggests that if 30% of women achieve clinical pregnancy without endometrial injury, between 33% and 48% will achieve clinical pregnancy with this intervention. Endometrial injury was associated with increased pain, however the evidence was of very low quality. One study reported pain on a VAS scale: MD 4.60, 95% CI 3.98 to 5.22; P value < 0.00001; one RCT; 158 women. Two studies reported the number of pain complaints after the procedure; one recorded no events in either group, and the other reported that endometrial injury increased pain complaints: OR 8.65, 95% CI 2.49 to 30.10; P value 0.0007; one RCT; 101 women. Results from the only randomised controlled trial (RCT) comparing endometrial injury on the day of oocyte retrieval versus no injury, reported that this endometrial injury markedly decreased live birth (RR 0.31, 95% CI 0.14 to 0.69; P value 0.004; 156 women; low-quality evidence) and clinical pregnancy (RR 0.36, 95% CI 0.18 to 0.71; P value 0.003; one RCT; 156 women; low-quality evidence). Moderate-quality evidence indicates that endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle is associated with an improvement in live birth and clinical pregnancy rates in women with more than two previous embryo transfers. There is no evidence of an effect on miscarriage, multiple pregnancy or bleeding. The procedure is mildly painful. Endometrial injury on the day of oocyte retrieval is associated with a reduction of clinical and ongoing pregnancy rates. Although current evidence suggests some benefit of endometrial injury, we need evidence from well-designed trials that avoid instrumentation of the uterus in the preceding three months, do not cause endometrial damage in the control group, stratify the results for women with and without recurrent implantation failure (RIF) and report live birth.

Cochrane authors included 14 clinical trials (2128 women) evaluating the effects of endometrial injury on outcomes of ART. Thirteen of these trials studied endometrial injury during the menstrual cycle before embryo transfer. One trial studied endometrial injury on the day of oocyte retrieval, which is just a few days before the day the embryo is transferred into the womb. Whether participants had undergone previous embryo transfers varied among the included studies. The evidence is current to January 2015. The included studies suggest that endometrial injury performed sometime during the month before the start of ovarian stimulation as part of ART improves the chances that a woman will achieve live birth and clinical pregnancy. Moderate-quality evidence suggests that if 26% of women achieve live birth without endometrial injury, between 28% and 48% will achieve live birth with this intervention. Contrary to this, endometrial injury performed on the day the eggs are picked up reduces the chances of pregnancy. We are still uncertain about the effect of endometrial injury on adverse events such as miscarriage, multiple pregnancy or vaginal bleeding. However, the endometrial injury procedure does appear to cause some pain, although this is short lived. Evidence that endometrial injury performed in the cycle before ART increases the probability of live birth and clinical pregnancy is of moderate quality. For all other outcomes the evidence is of low or very low quality. The quality of the evidence is reduced because insufficient participants were included in the studies, and because a large proportion of the included studies have important limitations in the methods that they used.

10.1002/14651858.CD009517.pub3

cochrane-simplification-train-2750

cochrane-simplification-train-2750

Six trials were included. Based on similar designs, trials clustered in three categories. (1) MLD + standard physiotherapy versus standard physiotherapy (one trial) showed significant improvements in both groups from baseline but no significant between-groups differences for per cent reduction. (2) MLD + compression bandaging versus compression bandaging (two trials) showed significant per cent reductions of 30% to 38.6% for compression bandaging alone, and an additional 7.11% reduction for MLD (MD 7.11%, 95% CI 1.75% to 12.47%; two RCTs; 83 participants). Volume reduction was borderline significant (P = 0.06). LE volume was not significant. Subgroup analyses was significant showing that participants with mild-to-moderate BCRL were better responders to MLD than were moderate-to-severe participants. (3) MLD + compression therapy versus nonMLD treatment + compression therapy (three trials) were too varied to pool. One of the trials compared compression sleeve plus MLD to compression sleeve plus pneumatic pump. Volume reduction was statistically significant favoring MLD (MD 47.00 mL, 95% CI 15.25 mL to 78.75 mL; 1 RCT; 24 participants), per cent reduction was borderline significant (P=0.07), and LE volume was not significant. A second trial compared compression sleeve plus MLD to compression sleeve plus self-administered simple lymphatic drainage (SLD), and was significant for MLD for LE volume (MD -230.00 mL, 95% CI -450.84 mL to -9.16 mL; 1 RCT; 31 participants) but not for volume reduction or per cent reduction. A third trial of MLD + compression bandaging versus SLD + compression bandaging was not significant (P = 0.10) for per cent reduction, the only outcome measured (MD 11.80%, 95% CI -2.47% to 26.07%, 28 participants). MLD was well tolerated and safe in all trials. Two trials measured function as range of motion with conflicting results. One trial reported significant within-groups gains for both groups, but no between-groups differences. The other trial reported there were no significant within-groups gains and did not report between-groups results. One trial measured strength and reported no significant changes in either group. Two trials measured QoL, but results were not usable because one trial did not report any results, and the other trial did not report between-groups results. Four trials measured sensations such as pain and heaviness. Overall, the sensations were significantly reduced in both groups over baseline, but with no between-groups differences. No trials reported cost of care. Trials were small ranging from 24 to 45 participants. Most trials appeared to randomize participants adequately. However, in four trials the person measuring the swelling knew what treatment the participants were receiving, and this could have biased results. MLD is safe and may offer additional benefit to compression bandaging for swelling reduction. Compared to individuals with moderate-to-severe BCRL, those with mild-to-moderate BCRL may be the ones who benefit from adding MLD to an intensive course of treatment with compression bandaging. This finding, however, needs to be confirmed by randomized data. In trials where MLD and sleeve were compared with a nonMLD treatment and sleeve, volumetric outcomes were inconsistent within the same trial. Research is needed to identify the most clinically meaningful volumetric measurement, to incorporate newer technologies in LE assessment, and to assess other clinically relevant outcomes such as fibrotic tissue formation. Findings were contradictory for function (range of motion), and inconclusive for quality of life. For symptoms such as pain and heaviness, 60% to 80% of participants reported feeling better regardless of which treatment they received. One-year follow-up suggests that once swelling had been reduced, participants were likely to keep their swelling down if they continued to use a custom-made sleeve.

We found six trials published through May, 2013, totaling 208 participants. When women were treated with a course of intensive compression bandaging, their swelling went down about 30% to 37%. When MLD was added to the intensive course of compression bandaging, their swelling went down another 7.11%. Thus, MLD may offer benefit when added to compression bandaging. Examining this finding more closely showed that this significant reduction benefit was observed in people with mild-to-moderate lymphedema when compared to participants with moderate-to-severe lymphedema. Thus, our findings suggest that individuals with mild-to-moderate BCRL are the ones who may benefit from adding MLD to an intensive course of treatment with compression bandaging. This finding, however, needs to be confirmed by further research. When women were given a standard elastic compression sleeve plus MLD and compared to women who received a standard compression sleeve plus a nonMLD treatment, results were mixed (sometimes favoring MLD and sometimes favoring neither treatment.) One-year follow-up suggests that once swelling had been reduced, participants were likely to keep their swelling down if they continued to use a custom-made sleeve. MLD is safe and well tolerated. Findings were contradictory for function (range of motion), with one trial showing benefit and the other not. Two trials measured quality of life, but neither trial presented results comparing the treatment group to the control, so findings are inconclusive. No trial measured cost of care. Trials were small ranging from 24 to 45 participants. Most trials appeared to randomize participants adequately. However, in four trials the person measuring the swelling knew what treatment the participants were receiving, and this could have biased results.

10.1002/14651858.CD003475.pub2

cochrane-simplification-train-2751

cochrane-simplification-train-2751

This review includes 26 studies (33,849 participants). Overall, we judged 13 studies to be at low risk of bias, three at high risk, and the remainder at unclear risk. Settings and recruitment procedures varied across studies, but most studies were conducted in high-income countries. There was moderate-certainty evidence, limited by inconsistency, that automated text messaging interventions were more effective than minimal smoking cessation support (RR 1.54, 95% CI 1.19 to 2.00; I2 = 71%; 13 studies, 14,133 participants). There was also moderate-certainty evidence, limited by imprecision, that text messaging added to other smoking cessation interventions was more effective than the other smoking cessation interventions alone (RR 1.59, 95% CI 1.09 to 2.33; I2 = 0%, 4 studies, 997 participants). Two studies comparing text messaging with other smoking cessation interventions, and three studies comparing high- and low-intensity messaging, did not show significant differences between groups (RR 0.92 95% CI 0.61 to 1.40; I2 = 27%; 2 studies, 2238 participants; and RR 1.00, 95% CI 0.95 to 1.06; I2 = 0%, 3 studies, 12,985 participants, respectively) but confidence intervals were wide in the former comparison. Five studies compared a smoking cessation smartphone app with lower-intensity smoking cessation support (either a lower-intensity app or non-app minimal support). We pooled the evidence and deemed it to be of very low certainty due to inconsistency and serious imprecision. It provided no evidence that smartphone apps improved the likelihood of smoking cessation (RR 1.00, 95% CI 0.66 to 1.52; I2 = 59%; 5 studies, 3079 participants). Other smartphone apps tested differed from the apps included in the analysis, as two used contingency management and one combined text messaging with an app, and so we did not pool them. Using complete case data as opposed to using data from all participants randomised did not substantially alter the findings. There is moderate-certainty evidence that automated text message-based smoking cessation interventions result in greater quit rates than minimal smoking cessation support. There is moderate-certainty evidence of the benefit of text messaging interventions in addition to other smoking cessation support in comparison with that smoking cessation support alone. The evidence comparing smartphone apps with less intensive support was of very low certainty, and more randomised controlled trials are needed to test these interventions.

We included 26 randomised controlled studies (involving over 33,000 people) that compared smoking quit rates in people who received text messages or smartphone apps to help them quit, with people who did not receive these programmes. We were interested in studies that measured smoking for six months or longer. We found that text messaging programmes may be effective in supporting people to quit, increasing quit rates by 50% to 60%. This was the case when they were compared to minimal support or were tested as an addition to other forms of stop-smoking support. There was not enough evidence to determine the effect of smartphone apps. Most of the studies were of high quality, although three studies had high drop out rates. We are moderately confident in the results of the text messaging interventions, but there were some issues with unexplained differences between study findings and for some comparisons there was not much data. We have low confidence in the results concerning smartphone apps, and more studies are needed in this field.

10.1002/14651858.CD006611.pub5

cochrane-simplification-train-2752

cochrane-simplification-train-2752

Three RCTs were identified. A qualitative approach with no meta analysis was performed because of variety in interventions between included studies. Interventions compared were antibiotics to no antibiotics, single to double compound antibiotic therapy and short to long IV administration. None of the studies found significant difference between the tested interventions. Risk of bias varied from low to high. The newest RCT overall had the best quality and statistical power. The newest evidence from one RCT says there is no significant difference between antibiotics versus no antibiotics in the treatment of uncomplicated diverticulitis. Previous RCTs have only suggested a non-inferiority between different antibiotic regimes and treatment lengths. This new evidence needs confirmation from more RCTs before it can be implicated safely in clinical guidelines. Ongoing RCTs will be published in the years to come and more are needed. The role of antibiotics in the treatment of complicated diverticulitis has not been investigated yet.

We found 3 randomized controlled trials (RCTs) on the use of antibiotics for uncomplicated diverticulitis tested on hospitalised patients. The newest trial investigating the actual need for antibiotics when compared to no antibiotics, a second investigated two different antibiotic cures and a third investigated the length of IV antibiotic treatment. None of the studies found a statistical difference in the tested antibiotic regimes. The newest trial had the overall best quality and had the biggest groups of patients making it the overall best trial. It found no difference in the occurrence of surgery needing complications like abscesses and perforations of the big bowel. Antibiotics can cause serious adverse events for patients like allergic reactions and can even cause other life threatening infections of the bowel. Ultimately, there is a growing antibiotic resistance meaning that the drugs loose their ability to function as bactericidals. This causes limitations in the clinical use of antibiotics when they are needed for treating patients with infections. Therefore there exists strong arguments for limiting the use of antibiotics. The trial that showed no effect of antibiotics is very new and needs confirmation from other similar trials. Ongoing trials will in the next few years be published on the subject.

10.1002/14651858.CD009092.pub2

cochrane-simplification-train-2753

cochrane-simplification-train-2753

Three randomised controlled trials (1039 women) published between 1922 and 2005 fulfilled the prespecified criteria. In the earliest trial, 389 women were alternately allocated to receive either skin preparation and perineal shaving or clipping of vulval hair only. In the second trial, which included 150 participants, perineal shaving was compared with the cutting of long hairs for procedures only. In the third and most recent trial, 500 women were randomly allocated to shaving of perineal area or cutting of perineal hair. The primary outcome for all three trials was maternal febrile morbidity; no differences were found (risk ratio (RR) 1.14, 95% confidence interval (CI) 0.73 to 1.76). No differences were found in terms of perineal wound infection (RR 1.47, 95% CI 0.80 to 2.70) and perineal wound dehiscence (RR 0.33, 95% CI 0.01 to 8.00) in the most recent trial involving 500 women, which was the only trial to assess these outcomes. In the smallest trial, fewer women who had not been shaved had Gram-negative bacterial colonisation compared with women who had been shaved (RR 0.83, 95% CI 0.70 to 0.98). There were no instances of neonatal infection in either group in the one trial that reported this outcome. There were no differences in maternal satisfaction between groups in the larger trial reporting this outcome (mean difference (MD) 0.00, 95% CI -0.13 to 0.13). No trial reported on perineal trauma. One trial reported on side-effects and these included irritation, redness, burning and itching. The overall quality of evidence ranged from very low (for the outcomes postpartum maternal febrile morbidity and neonatal infection) to low (for the outcome maternal satisfaction and wound infection). There is insufficient evidence to recommend perineal shaving for women on admission in labour.

Three controlled trials that involved a total of 1039 women were reported on between 1922 and 2005. They each used an antiseptic skin preparation and compared perineal shaving with cutting vulval hairs. The overall quality of evidence ranged from very low (for the outcomes postpartum maternal febrile morbidity and neonatal infection) to low (for the outcomes wound infection and maternal satisfaction). When the findings of the trials were combined, no differences were found, with and without shaving, on the number of mothers who experiencing high body temperatures after the birth. One trial also looked at perineal wound infection, the incidence of open wounds and maternal satisfaction immediately after a perineal repair had been completed and found no difference between groups. Most of the side-effects attributable to shaving occurred later, as described by one of the trials. These included irritation, redness, multiple superficial scratches from the razor and burning and itching of the vulva. One trial assessed maternal satisfaction and found no difference between groups. Other outcomes such as pain, embarrassment or discomfort during hair regrowth, were not reported. The present review found no evidence of any clinical benefit with perineal shaving. Not routinely shaving women before labour appeared safe.

10.1002/14651858.CD001236.pub2

cochrane-simplification-train-2754

cochrane-simplification-train-2754

We added seven studies during this update, bringing the total to 15 studies, involving 989 participants. The interventions involved various memory retraining techniques, such as computerised programmes and training on internal and external memory aids. Control groups varied in format from assessment-only groups, discussion and games, non-specific cognitive retraining, and attention or visuospatial training. The risk of bias of the included studies was generally low, but we found eight studies to have high risk of bias related to certain aspects of their methodology. We found significant effect of intervention on objective assessments of memory in both the immediate and long-term follow-ups: standardised mean difference (SMD) 0.23 (95% confidence interval (CI) 0.05 to 0.41) and SMD 0.26 (95% CI 0.03 to 0.49), respectively. We also found significant effect of intervention for quality of life in the immediate follow-up (SMD 0.23 (95% CI 0.05 to 0.41)). These findings showed that the intervention group performed significantly better than the control group. We also found a significant difference for activities of daily living (ADL) in the long-term follow-up (SMD -0.33 (95% CI -0.63 to -0.03)), showing that the control groups had significantly less difficulty completing ADLs than the intervention groups. We found no significant effects, either immediate or long-term, on subjective reports of memory problems (SMD 0.04 (95% CI -0.19 to 0.27) and SMD 0.04 (95% CI -0.19 to 0.27)); on mood (SMD 0.02 (95% CI -0.16 to 0.20) and SMD -0.01 (95% CI -0.21 to 0.20)); and on immediate follow-up for ADL (SMD -0.13 (95% CI -0.60 to 0.33)) and in the long term for quality of life (SMD 0.16 (95% CI -0.03 to 0.36)). We could not complete a sensitivity analysis of intention-to-treat in comparison with per-protocol analysis, due to insufficient information from the included papers. However, a sensitivity analysis of high- versus low-risk studies suggested that while quality of the trials did not affect most outcomes, differences were seen in the objective memory outcomes (both at immediate and long term) and quality of life (immediate) outcome, with studies with higher risk of bias inflating the overall effect size estimates for these outcomes, and the test of overall effect changing from being statistically significant to not significant when studies at high risk of bias were excluded. This suggests that lower-quality studies may have positively influenced the outcomes. There is some evidence to support the effectiveness of memory rehabilitation on memory function, as well as on quality of life. However, the evidence is limited and does not extend to subjective reports of memory functioning or mood. Furthermore, the objective measures used are not ecologically valid measures, and thus potentially limit generalisability of these findings into daily life. Further robust RCTs of high methodological quality and better quality of reporting, using ecologically valid outcome assessments, are still needed.

This review included 15 studies with 989 participants involving various types of memory retraining techniques, some using computer programs or memory aids such as diaries or calendars. The results of this review showed some evidence to support the use of memory rehabilitation in people with MS. Those participants who had memory rehabilitation had better memory functioning compared to those who did not receive memory rehabilitation, and this difference between groups was found after the intervention was completed and for some time thereafter. However, this outcome was usually measured on assessments that were abstract and did not reflect people’s daily life. Those participants who received memory rehabilitation also showed better quality of life, but this effect was not maintained long term. We also found that those participants who did not receive the memory rehabilitation were better at completing activities of daily living, but these differences between groups were small. The groups who did and did not receive memory rehabilitation did not differ in terms of their subjective reports of memory problems or mood. There are still relatively few large, good-quality studies to base our findings on, so more are needed.

10.1002/14651858.CD008754.pub3

cochrane-simplification-train-2755

cochrane-simplification-train-2755

Twenty-three published and unpublished studies (6061 participants) were included in the review. There was a significant change in forced expiratory volume in 1 second (FEV1) in favour of salmeterol 50 mcg twice daily (BID) of 51 mls (95% confidence intervals (CI) 32 to 70), end of study morning peak expiratory flow (PEF) 14.89 L/min (95% CI 10.86 to 18.91). Supplemental short-acting bronchodilator usage was reduced by just under one puff per day. There were significant differences in the total, activity and impact domain scores of the St George's respiratory questionnaire in favour of salmeterol 50 mcg BID. Findings from other health status measurements and symptom scores were conflicting. There was no significant difference in exercise tolerance. The number of participants experiencing exacerbations was significantly reduced with salmeterol 50 mcg treatment compared with placebo (numbers needed to treat to benefit 24). This review shows that the treatment of patients with COPD with salmeterol 50 mcg produces modest increases in lung function. There were varying effects for other important outcomes such as health related quality of life or reduction in symptoms. However, there was a consistent reduction in exacerbations which may help people with COPD who suffer frequent deterioration of symptoms prompting healthcare utilisation. The strength of evidence for the use of salmeterol 100 mcg, formoterol 12 mcg, 18 mcg, 24 mcg was insufficient to provide clear indications for practice.

This review aims to determine the effectiveness of long-acting beta-agonists, salmeterol or formoterol, in the treatment of COPD (emphysema/chronic bronchitis). These drugs improve airflow in the lungs, and enable people with COPD to get on with their daily activities. Twenty-four studies (6061 participants) reported the effects of LABAs in people with COPD. People taking salmeterol 50 mcg daily do have fewer exacerbations than those on placebo, and some improvement in lung function and certain quality of life scores. The findings were not consistent enough to support a general recommendation for the use of these drugs in the group of people with COPD with minimal variation in their lung function, although there is some evidence of improvement in important outcomes and these findings require further exploration in additional trials.

10.1002/14651858.CD001104.pub2

cochrane-simplification-train-2756

cochrane-simplification-train-2756

We included six trials involving 359,078 adult women and men. One trial was at low risk of bias in all six specific domains assessed. Two trials examined the effect of multiple rounds of chlamydia screening on C. trachomatis transmission. A cluster-controlled trial in women and men in the general population in the Netherlands found no change in chlamydia test positivity after three yearly invitations (intervention 4.1% vs control 4.3%, RR 0.96, 95% CI 0.84 to 1.09, 1 trial, 317,304 participants at first screening invitation, low quality evidence). Uptake of the intervention was low (maximum 16%). A cluster-randomised trial in female sex workers in Peru found a reduction in chlamydia prevalence after four years (adjusted RR 0.72, 95% CI 0.54 to 0.98, 1 trial, 4465 participants, low quality evidence). Four RCTs examined the effect of chlamydia screening on PID in women 12 months after a single screening offer. In analysis of four trials according to the intention-to-treat principle, the risk of PID was lower in women in intervention than control groups, with little evidence of between-trial heterogeneity (RR 0.68, 95% CI 0.49 to 0.94, I2 7%, 4 trials, 21,686 participants, moderate quality evidence). In a sensitivity analysis, the estimated effect of chlamydia screening in two RCTs at low risk of detection bias (RR 0.80, 95% CI 0.55 to 1.17) was compatible with no effect and was lower than in two RCTs at high or unclear risk of detection bias (RR 0.42, 95% CI 0.22 to 0.83). The risk of epididymitis in men invited for screening, 12 months after a single screening offer, was 20% lower risk for epididymitis than in those not invited; the confidence interval was wide and compatible with no effect (RR 0.80, 95% CI 0.45 to 1.42, 1 trial, 14,980 participants, very low quality evidence). We found no RCTs of the effects of chlamydia screening in pregnancy and no trials that measured the harms of chlamydia screening. Evidence about the effects of screening on C. trachomatis transmission is of low quality because of directness and risk of bias. There is moderate quality evidence that detection and treatment of chlamydia infection can reduce the risk of PID in women at individual level. There is an absence of RCT evidence about the effects of chlamydia screening in pregnancy. Future RCTs of chlamydia screening interventions should determine the effects of chlamydia screening in pregnancy, of repeated rounds of screening on the incidence of chlamydia-associated PID and chlamydia reinfection in general and high risk populations.

The evidence is up to date as of February 2016. We found six trials involving 359,078 adult women and men in Denmark, the Netherlands, Peru, the UK and the United States. Two trials examined the effect of chlamydia screening on levels of chlamydia infection. In the Netherlands, investigators invited women and men aged 15 to 29 every year for three years to have a chlamydia test. In Peru, mobile teams visited 20 cities to offer women sex workers tests for chlamydia over a period of four years. With regard to the level of chlamydia infection, in the Netherlands there was no difference in women and men who had been invited to have yearly chlamydia screening tests compared with women and men who received only one invitation. Only 16% of those invited to be screened had a test in the first year and only 10% had a test in the third year. In Peru, female sex workers in cities with mobile teams had lower levels of chlamydia infection than those in cities without mobile teams. Four trials provided comparable data on PID. The risk of PID was 32% lower in women who were invited to have a single chlamydia screening test than in women who were not invited. When we removed two trials with lower quality evidence, the protective effect of chlamydia screening decreased. I was found no effect on epididymitis in men. The effect of register-based chlamydia screening on C. trachomatis transmission in young adults in the general population is uncertain. We are moderately sure that chlamydia screening can reduce the risk of PID, but we are not sure by how much because of our concerns about quality in some trials.

10.1002/14651858.CD010866.pub2

cochrane-simplification-train-2757

cochrane-simplification-train-2757

We included 39 randomised controlled trials involving 2599 randomised participants. We included participants of either gender, aged from the first year of life through to 55 years (only six studies assessed adults), who had mild to severe eczema. Trials were undertaken in primary and secondary healthcare settings, mainly in Europe or Asia. Duration of treatment ranged from four weeks to six months, and duration of follow-up after end of treatment ranged from zero to 36 months. We selected no standard dose: researchers used a variety of doses and concentrations of probiotics. The probiotics used were bacteria of the Lactobacillus and Bifidobacteria species, which were taken alone or combined with other probiotics, and were given with or without prebiotics. Comparators were no treatment, placebo, and other treatments with no probiotics. For all results described in this abstract, the comparator was no probiotics. Active treatment ranged from six weeks to three months for all of the following results, apart from the investigator-rated eczema severity outcome, for which the upper limit of active treatment was 16 weeks. With regard to score, the higher the score, the more severe were the symptoms. All key results reported in this abstract were measured at the end of active treatment, except for adverse events, which were measured during the active treatment period. Probiotics probably make little or no difference in participant- or parent-rated symptoms of eczema (13 trials; 754 participants): symptom severity on a scale from 0 to 20 was 0.44 points lower after probiotic treatment (95% confidence interval (CI) -1.22 to 0.33; moderate-quality evidence). Trial sequential analysis shows that target sample sizes of 258 and 456, which are necessary to demonstrate a minimum mean difference of -2 and -1.5, respectively, with 90% power, have been exceeded, suggesting that further trials with similar probiotic strains for this outcome at the end of active treatment may be futile. We found no evidence suggesting that probiotics make a difference in QoL for patients with eczema (six studies; 552 participants; standardised mean difference (SMD) 0.03, 95% CI -0.36 to 0.42; low-quality evidence) when measured by the participant or the parent using validated disease-specific QoL instruments. Probiotics may slightly reduce investigator-rated eczema severity scores (24 trials; 1596 participants). On a scale of 0 to 103 for total Severity Scoring of Atopic Dermatitis (SCORAD), a score combining investigator-rated eczema severity score and participant scoring for eczema symptoms of itch and sleep loss was 3.91 points lower after probiotic treatment than after no probiotic treatment (95% CI -5.86 to -1.96; low-quality evidence). The minimum clinically important difference for SCORAD has been estimated to be 8.7 points. We noted significant to extreme levels of unexplainable heterogeneity between the results of individual studies. We judged most studies to be at unclear risk of bias; six studies had high attrition bias, and nine were at low risk of bias overall. We found no evidence to show that probiotics make a difference in the risk of adverse events during active treatment (risk ratio (RR) 1.54, 95% CI 0.90 to 2.63; seven trials; 402 participants; low-quality evidence). Studies in our review that reported adverse effects described gastrointestinal symptoms. Evidence suggests that, compared with no probiotic, currently available probiotic strains probably make little or no difference in improving patient-rated eczema symptoms. Probiotics may make little or no difference in QoL for people with eczema nor in investigator-rated eczema severity score (combined with participant scoring for eczema symptoms of itch and sleep loss); for the latter, the observed effect was small and of uncertain clinical significance. Therefore, use of probiotics for the treatment of eczema is currently not evidence-based. This update found no evidence of increased adverse effects with probiotic use during studies, but a separate adverse events search from the first review revealed that probiotic treatment carries a small risk of adverse events. Results show significant, unexplainable heterogeneity between individual trial results. Only a small number of studies measured some outcomes. Future studies should better measure QoL scores and adverse events, and should report on new probiotics. Researchers should also consider studying subgroups of patients (e.g. patients with atopy or food allergies, adults) and standardising doses/concentrations of probiotics given.

We included 39 randomised controlled clinical trials (RCTs) with 2599 participants, which we identified in searches up to January 2017. These studies included people of either gender and of all ages, although most studies assessed children who had been told by a healthcare professional that they had eczema. Participants had eczema ranging from mild to severe, and RCTs compared treatment with live micro-organisms (probiotics) of varying dose and concentration, taken by mouth, versus no treatment, placebo, or another treatment with no probiotics. The probiotics included were bacteria of the Lactobacillus and Bifidobacteria species taken alone or in combination with other probiotics for a period ranging from four weeks up to six months. We did not look at studies that were seeking to prevent eczema. Most studies were done in Europe, and some were done in Asia, Australia, and New Zealand - all in a medical setting. Most studies were conducted at a single centre. Reviewers applied no language restrictions on study selection. Ten studies were funded by companies supplying the probiotics, and another four studies did not declare the source of funding. Please note that results in this summary are based on the following: a comparison of probiotic against no probiotic; treatment over six weeks to three months, except for the investigator-rated eczema severity outcome, for which participants were treated longer (16 weeks); and outcomes measured at the end of the treatment period, apart from adverse events, which were assessed throughout treatment. Unless otherwise stated, outcomes were measured by participants or parents. The included studies assessed a variety of probiotics of differing concentrations or doses. With regard to score, the higher the score, the more severe were the symptoms. We found that currently available probiotics probably make little or no difference in reducing eczema symptoms, such as itching and sleep loss (moderate-quality evidence). However, we did find that these probiotics may slightly reduce the severity of eczema scored by patients and their healthcare professionals in combination (low-quality evidence), although it is uncertain if such a change is meaningful for patients. In terms of patient quality of life, we found no evidence that probiotics make a difference (low-quality evidence). We found no evidence of an increase in adverse events; those reported in included studies that were related to treatment were tummy and gut upset with diarrhoea, constipation, vomiting, and colic pains (low-quality evidence). Analysis suggests that further probiotic studies assessing the effects of eczema symptoms may not be worthwhile, as they are unlikely to change the outcome at the end of active treatment. The quality of evidence supporting our key findings was low, apart from one moderate rating for participant-rated symptoms of eczema. Reasons for this include variability between studies, which could not be explained, and not enough available data.

10.1002/14651858.CD006135.pub3

cochrane-simplification-train-2758

cochrane-simplification-train-2758

From an initial 1388 citations, we identified 43 studies in 40 papers. Of those, 29 studies with 10,044 participants compared six prokinetics with placebo for the outcome of absence of symptoms or symptom improvement. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR of remaining dyspeptic = 0.81, 95% CI 0.74 to 0.89; number needed to treat for an additional beneficial outcome (NNTB) =7, very low-quality evidence) with considerable heterogeneity; I2 = 91% (P < 0.00001). After removing cisapride from the analysis, the effect of prokinetics in global symptom improvement still persisted, compared to placebo (RR 0.87, 95% CI 0.80 to 0.94), but was still based on very low-quality evidence. The result showed persistence of significant improvement in subgroups of studies at unclear or at low risk of bias (RR 0.86, 95% CI 0.80-0.92), and in subgroups by molecules of cisapride (RR 0.71, 95% CI 0.54 to 0.93; NNTB = 4), acotiamide (RR 0.94, 95% CI 0.91 to 0.98; NNTB = 20) and tegaserod(RR 0.89, 95% CI 0.82 to 0.96; NNTB = 14). Ten studies compared different types of prokinetics with each other and the most commonly used comparator was domperidone, 10 mg three times a day (eight of the 10 studies). There was a significantly better post-treatment symptom score in other prokinetics, compared to domperidone (SMD -0.19, 95% CI -0.35 to -0.03, very low-quality evidence), but no difference in reducing global symptom (RR 0.94, 95% CI 0.83 to 1.07), and mean difference symptom scores (SMD -0.13, 95% CI -0.31 to 0.05). We found five studies that assessed quality of life, but there was no benefit in improving quality of life with prokinetic treatment (SMD 0.11, 95% CI -0.10 to 0.33; participants = 1774). The adverse events in individual prokinetics was not different from placebo (RR 1.09, 95% CI 0.95 to 1.25; participants = 3811; studies = 17). However, when we looked at the adverse effects by each prokinetic, there were overall greater adverse effects in the active treatment group with cisapride (RR 1.31, 95% CI 1.03 to 1.65; P = 0.03). The most common side effects were diarrhoea, abdominal discomfort and nausea. The funnel plot was asymmetric (Egger's test, P = 0.02) implying reporting bias or other small-study effects may be, in part, driving the benefit of prokinetics compared to placebo in this meta-analysis. The GRADE assessment of the quality of the evidence in each outcome are mostly low or very low due to concerns around risk of bias in study design, unexplained heterogeneity and possible publication bias. Due to low, or very low, quality of evidence, we are unable to say whether prokinetics are effective for the treatment of functional dyspepsia . We are uncertain which of the individual prokinetic drugs is the most effective as well as whether prokinetics can improve quality of life. Apart from cisapride, prokinetics are well-tolerated. Good quality RCTs are needed to verify the efficacy of prokinetics.

We included 43 studies that compared prokinetics with either placebo (powder that has the appearance similar to drug) or another prokinetic for treatment of functional dyspepsia. The studies were limited to those which assessed only adults who presented with upper abdominal discomfort but who did not have a specific cause after investigation. We are uncertain whether prokinetics reduce dyspeptic symptoms, compared to no prokinetic treatment. We are also uncertain which prokinetics had the most efficacy in reducing dyspeptic symptoms, improving post-treatment symptom scores, or improving the mean difference of symptom score. We are uncertain whether prokinetic treatment can improve quality of life. We are uncertain whether prokinetics (except cisapride) differ from no prokinetic in producing unpleasant symptoms. The most common unpleasant symptoms from prokinetics were diarrhoea, abdominal discomfort and nausea. The quality of the evidence was graded as low or very low. We need more research to prove the benefit of prokinetics for treatment in people with functional dyspepsia.

10.1002/14651858.CD009431.pub3

cochrane-simplification-train-2759

cochrane-simplification-train-2759

We found only two RCTs that compared oral L-acetylcarnitine (LAC) with oral placebo in children with FXS. The studies included a total of 83 participants, all of them male, who were treated and followed for one year. The age of participants at the start of treatment ranged from 6 to 13 years, with a mean age of 9 years. Neither study provided information on randomisation, allocation concealment procedures, or blinding of outcome assessment, and we received no responses from the authors we emailed for clarification. We therefore rated studies as being at unclear risk of bias on these domains. We judged both studies to be at low risk of bias for blinding of participants and personnel, incomplete outcome data, and selective reporting, but to be at high risk of other bias, as at least one study was funded by a drug company, and in both studies people working for the company were part of the research team. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the quality of the available evidence. Overall, the quality of the evidence was low due to the imprecision of results and high risk of other bias. Regarding the primary outcome of psychological and learning capabilities, both studies assessed the effect of interventions on children's verbal and non-verbal intellectual functioning using the Wechsler Intelligence Scale for Children - Revised. The authors did not provide detailed data on those results but said that they found no important differences between treatment and placebo. Both studies evaluated the impact of the treatment on hyperactive behaviour using the Conners' Abbreviated Parent-Teacher Questionnaire. In one study, teachers' assessments of the children found no clear evidence of a difference (mean difference (MD) 0.50, 95% confidence interval (CI) -5.08 to 6.08, n = 51; low-quality evidence). The other study stated that there were no differences between treated and untreated participants, but did not provide detailed data for inclusion in the meta-analysis. Parents' assessments favoured LAC in one study (MD -0.57, 95% CI -0.94 to -0.19, n = 17; low-quality evidence), but not in the other (MD -2.80, 95% CI -7.61 to 2.01, n = 51; low-quality evidence), though changes were not large enough to be considered clinically relevant. Regarding social skills, one study reported no clear evidence of a difference in Vineland Adaptive Behavior composite scores (MD 8.20, 95% CI -0.02 to 16.42, n = 51; low-quality evidence), yet results in the socialisation domain favoured LAC (MD 11.30, 95% CI 2.52 to 20.08, n = 51; low-quality evidence). Both studies assessed the safety of the active treatment and recorded no side effects. Neither of the included studies assessed the secondary outcome of caregiver burden. Low-quality evidence from two small trials showed that when compared to placebo, LAC may not improve intellectual functioning or hyperactive behaviour in children with FXS.

We searched the scientific literature for all randomised trials published up to May 2015 and found only two trials to include in the review. The trials recruited a total of 83 boys (6 to 13 years of age) who were treated for a maximum of one year. We found no clear evidence of important differences in verbal and non-verbal intellectual functioning between treatment with LAC and placebo. Regarding hyperactive behaviour, teachers' assessments found no clear evidence of differences between treatment with LAC and placebo. Parents' assessments showed some differences between treatments favouring LAC, but changes were not large enough to be considered clinically relevant. Only one study assessed social skills, and it reported no clear evidence of a difference between LAC and placebo in adaptive behaviour, though results in the socialisation domain favoured LAC. No side effects were reported, and no study reported on the secondary outcome of caregiver burden. The available evidence is of low quality. Risk of bias for these studies is unclear regarding the procedures used to randomise participants to LAC or placebo, to conceal treatment allocation, and to blind assessors to the results of the treatments. At least one of the studies was funded by a drug manufacturer with a commercial interest in the results. One of the studies was also funded by charitable monies.

10.1002/14651858.CD010012.pub2

cochrane-simplification-train-2760

cochrane-simplification-train-2760

We included 17 trials (with 2434 patients) in this updated review. The original review included 11 trials. The total geometric mean duration of mechanical ventilation in the protocolized weaning group was on average reduced by 26% compared with the usual care group (N = 14 trials, 95% confidence interval (CI) 13% to 37%, P = 0.0002). Reductions were most likely to occur in medical, surgical and mixed ICUs, but not in neurosurgical ICUs. Weaning duration was reduced by 70% (N = 8 trials, 95% CI 27% to 88%, P = 0.009); and ICU length of stay by 11% (N = 9 trials, 95% CI 3% to 19%, P = 0.01). There was significant heterogeneity among studies for total duration of mechanical ventilation (I2 = 67%, P < 0.0001) and weaning duration (I2 = 97%, P < 0.00001), which could not be explained by subgroup analyses based on type of unit or type of approach. There is evidence of reduced duration of mechanical ventilation, weaning duration and ICU length of stay with use of standardized weaning protocols. Reductions are most likely to occur in medical, surgical and mixed ICUs, but not in neurosurgical ICUs. However, significant heterogeneity among studies indicates caution in generalizing results. Some study authors suggest that organizational context may influence outcomes, however these factors were not considered in all included studies and could not be evaluated. Future trials should consider an evaluation of the process of intervention delivery to distinguish between intervention and implementation effects. There is an important need for further development and research in the neurosurgical population.

Study characteristics: This updated Cochrane review included 17 studies involving 2434 critically ill men and women who were being cared for in medical, surgical, neurosurgical and mixed medical/surgical intensive care units (ICUs). The studies compared the use of protocols to wean patients from the ventilator against usual practice. They were conducted in ICUs in America, Europe, Asia and Australia. The ICUs cared for patients with heart conditions, breathing difficulties, head injuries, trauma and following major surgery. In 13 studies, clinicians used weaning protocols to guide them to reduce the ventilator support. In four studies ventilator support was reduced automatically by programmed computers following a protocol. Results: In comparison with usual practice without protocols, the average total time spent on the ventilator was reduced by 26%. The duration of weaning was reduced by 70% and length of stay in the ICU reduced by 11%. Using protocols did not result in any additional harms. We found considerable variation in the types of protocols used, the criteria for considering when to start weaning, the medical conditions of the patients and usual practice in weaning. This means that we cannot say exactly which protocols will work best for particular patients, but we do know they have not been beneficial in neurosurgical patients. Quality of evidence: We graded the quality of the available evidence as moderate for duration of ventilation and harmful effects, and low for the duration of weaning and ICU length of stay. The reasons for our grading were that results were not consistent across the studies, and studies lacked sufficient detail about usual care practices.

10.1002/14651858.CD006904.pub3

cochrane-simplification-train-2761

cochrane-simplification-train-2761

We included six RCTs with a total of 750 participants. Each trial was conducted in a different country: Denmark, Germany, India, Japan, UK, and United States. Additionally, we identified two ongoing trials not due to be completed until 2016. Among the six trials included in this review, we judged one to be at high risk of bias. The remaining five trials were judged to be at either low or uncertain risk of biases. Five trials compared only two intervention groups and one trial had a three-arm comparison of oral corticosteroids or intravenous corticosteroids with placebo. Of the five trials with only two intervention groups, two trials compared oral corticosteroids versus placebo, two trials compared intravenous corticosteroids with placebo, and one trial compared intravenous dexamethasone with intravenous methylprednisolone plus oral prednisolone. Three trials evaluating oral corticosteroids used varying doses of corticosteroids versus placebo. In the meta-analyses to assess visual acuity, the risk ratio (RR) was 1.00 (95% confidence interval (CI) 0.82 to 1.23; participants = 398) at one month; 0.92 (95% CI 0.77 to 1.11; participants = 355) at six months; and 0.93 (95% CI 0.70 to 1.24; participants = 368) at one year. In the meta-analyses of two trials evaluating corticosteroids with total dose greater than 3000 mg administered intravenously, the RR of normal visual acuity (defined as 20/20 Snellen fraction or equivalent) in the intravenous corticosteroids group compared with the placebo group was 1.05 (95% CI 0.88 to 1.26; participants = 346) at six months. The RR of contrast sensitivity in the normal range for the same comparison was 1.11 (95% CI 0.92 to 1.33; participants = 346) at six months follow-up. The RR of normal visual field for this comparison was 1.08 (95% CI 0.96 to 1.21; 346 participants) at six months; and 1.01 (95% CI 0.86 to 1.19; participants = 316) at one year. Four trials reported adverse events primarily related to gastrointestinal symptoms and sleep disturbance; one trial reported minor adverse event of acne. There is no conclusive evidence of benefit in terms of recovery to normal visual acuity, visual field or contrast sensitivity six months after initiation with either intravenous or oral corticosteroids at the doses evaluated in trials included in this review.

For this systematic review, we identified six trials conducted in Denmark, Germany, India, Japan, United Kingdom, and United States, which included 750 participants. These trials compared corticosteroid treatment with placebo or another treatment; they varied in the way corticosteroids were given and the dose. Two trials compared oral corticosteroids versus placebo; three trials compared intravenous corticosteroids versus placebo; one trial compared two types of intravenous corticosteroids; and one trial with three groups compared oral corticosteroids versus intravenous corticosteroids versus placebo. Participants in all six trials were followed up for at least three months. Outcomes of visual acuity, contrast sensitivity in the normal range and visual field were assessed at 1, 6, and 12 months. Quality of life also was assessed and reported in one trial. The information is current as of 7 April 2015. There was no available evidence of beneficial effect from oral or intravenous corticosteroids compared with placebo for the visual acuity, visual field, and contrast sensitivity outcomes. Adverse effects, although not consistently reported, included dermatological symptoms, endocrinological disorders, gastrointestinal problems, headache, fever, sleep disturbance and psychiatric problems. Severe adverse events were reported in the intravenous steroid treatment group of one trial. The investigators of three trials concluded that minor adverse events were more common in steroid groups than in the placebo group. Out of six trials included in this review, we assessed one trial to have high risk of bias due to including a subset of participants who were allowed to choose their intervention. The remaining five trials were of either low or uncertain risk of biases.

10.1002/14651858.CD001430.pub4

cochrane-simplification-train-2762

cochrane-simplification-train-2762

Two RCTs with a total of 144 participants met the selection criteria. Both trials compared simvastatin versus placebo in older people (older than 50 or 60 years) with high risk of developing AMD (drusen present on examination). Overall, we judged the quality of the evidence to be low, as we downgraded all outcomes due to limitations in the designs of the trials and insufficient outcome reporting. The larger trial, with 114 participants, was conducted in Australia and used a higher dose (40 mg daily) of simvastatin for three years. Participants and study personnel in this trial were adequately masked, however data were missing for 30% of participants at three years' follow-up. The smaller trial, with 30 participants, was conducted in Italy and used a lower dose (20 mg) of simvastatin for three months. This trial reported insufficient details to assess the risk of bias. Neither trial reported data for change in visual acuity. Low-quality evidence from the smaller trial, with 30 participants, did not show a statistically significant difference between the simvastatin and placebo groups in visual acuity values at three months of treatment (decimal visual acuity 0.21 ± 0.56 in simvastatin group and 0.19 ± 0.40 in placebo group) or 45 days after the completion of treatment (decimal visual acuity 0.20 ± 0.50 in simvastatin group and 0.19 ± 0.48 in placebo group). The lack of a difference in visual acuity was not explained by lens or retina status, which remained unchanged during and after the treatment period for both groups. Preliminary analyses of 42 participants who had completed 12 months' follow-up in the larger trial did not show a statistically significant difference between simvastatin and the placebo groups for visual acuity, drusen score, or visual function (effect estimates and confidence intervals were not available). Complete data for these outcomes at three years' follow-up were not reported. At three years, low-quality evidence showed an effect of simvastatin in slowing progression of AMD compared with placebo to be uncertain (odds ratio 0.51, 95% confidence interval 0.23 to 1.09). One trial did not report adverse outcomes. The second trial reported no difference between groups in terms of adverse events such as death, muscle aches, and acute hepatitis. Evidence from currently available RCTs is insufficient to conclude that statins have a role in preventing or delaying the onset or progression of AMD.

We included two trials (144 total participants) in this review. Participants included men and women, most of whom were older than 50 years, who had good visual acuity. Participants were either susceptible to or had been diagnosed with an early stage of AMD. Both trials compared simvastatin with placebo. The larger trial, with 114 participants and conducted in Australia, used a higher dose of 40 mg per day and had a treatment period of three years. The smaller trial, with 30 participants and conducted in Italy, used a lower dose of 20 mg per day and had a treatment period of three months. The evidence provided in this review was up-to-date as of March 2016. Neither trial provided sufficient evidence to determine whether statins are effective in delaying the onset or progression of AMD. Information was lacking for outcomes related to vision, quality of life, and adverse events. The overall quality of the evidence was low. In the smaller trial, the number of participants enrolled and the short treatment period may not have been sufficient for detecting the effect of statins on AMD, which develops over time. In the larger trial, 30% of participants did not attend the three-year follow-up visit, and the amount of missing data hindered our ability to draw any reliable conclusions for this trial.

10.1002/14651858.CD006927.pub5

cochrane-simplification-train-2763

cochrane-simplification-train-2763

The original review included 10 studies with 996 participants. This updated review included 15 studies (1509 participants); 11 assessed naproxen sodium and four naproxen. In nine studies (784 participants) using 500/550 mg naproxen or naproxen sodium the NNT for at least 50% pain relief over four to six hours was 2.7 (95% CI 2.3 to 3.2). No dose response was demonstrated over the range 200/220 mg to 500/550 mg, but limited data was identified. Median time to use of rescue medication was 8.9 hours for naproxen 500/550 mg and 2.0 hours for placebo. Use of rescue medication was significantly less common with naproxen than placebo. Associated adverse events were generally of mild to moderate severity and rarely led to withdrawal. Doses equivalent to 500 mg and 400 mg naproxen administered orally provided effective analgesia to adults with moderate to severe acute postoperative pain. About half of participants treated with these doses experienced clinically useful levels of pain relief, compared to 15% with placebo, and half required additional medication within nine hours, compared to two hours with placebo. Associated adverse events did not differ from placebo.

This review assessed evidence from 1509 participants in 15 randomised, double blind, placebo-controlled clinical trials of naproxen or naproxen sodium (a non-steroidal anti-inflammatory drug) in adults with moderate to severe acute postoperative pain. At doses equivalent to 500 mg and 400 mg, orally administered naproxen provides effective analgesia. About half of those treated experienced at least half pain relief over four to six hours, and the effects lasted, on average, up to nine hours. Associated adverse events did not differ from placebo, but these studies are of limited use for studying adverse effects.

10.1002/14651858.CD004234.pub3

cochrane-simplification-train-2764

cochrane-simplification-train-2764

A total of six RCTs (326 patients) evaluating therapeutic discontinuation in patients with quiescent CD were eligible for inclusion. In four RCTs azathioprine monotherapy was discontinued, and in two RCTs azathioprine was discontinued from a combination therapy regimen consisting of azathioprine with infliximab. No studies of biologic monotherapy withdrawal were eligible for inclusion. The majority of studies received unclear or low risk of bias ratings, with the exception of three open-label RCTs, which were rated as high risk of bias for blinding. Four RCTs (215 participants) compared discontinuation to continuation of azathioprine monotherapy, while two studies (125 participants) compared discontinuation of azathioprine from a combination regimen to continuation of combination therapy. Continuation of azathioprine monotherapy was shown to be superior to withdrawal for risk of clinical relapse. Thirty-two per cent (36/111) of azathioprine withdrawal participants relapsed compared to 14% (14/104) of participants who continued with azathioprine therapy (RR 0.42, 95% CI 0.24 to 0.72, GRADE low quality evidence). However, it is uncertain if there are any between-group differences in new CD-related complications (RR 0.34, 95% CI 0.06 to 2.08, GRADE low quality evidence), adverse events (RR 0.88, 95% CI 0.67 to 1.17, GRADE low quality evidence), serious adverse events (RR 3.29, 95% CI 0.35 to 30.80, GRADE low quality evidence) or withdrawal due to adverse events (RR 2.59, 95% CI 0.35 to 19.04, GRADE low quality evidence). Common adverse events included infections, mild leukopenia, abdominal symptoms, arthralgias, headache and elevated liver enzymes. No differences between azathioprine withdrawal from combination therapy versus continuation of combination therapy were observed for clinical relapse. Among patients who continued combination therapy with azathioprine and infliximab, 48% (27/56) had a clinical relapse compared to 49% (27/55) of patients discontinued azathioprine but remained on infliximab (RR 1.02, 95% CI 0.68 to 1.52, P = 0.32; GRADE low quality evidence). The effects on adverse events (RR 1.11, 95% CI 0.44 to 2.81, GRADE low quality of evidence) or serious adverse events are uncertain (RR 1.00, 95% CI 0.21 to 4.66; GRADE very low quality of evidence). Common adverse events in the combination therapy studies included infections, liver test elevations, arthralgias and infusion reactions. The effects of withdrawal of immunosuppressant therapy in people with quiescent Crohn's disease are uncertain. Low quality evidence suggests that continuing azathioprine monotherapy may be superior to withdrawal for avoiding clinical relapse, while very low quality evidence suggests that there may be no difference in clinical relapse rates between discontinuing azathioprine from a combination therapy regimen, compared to continuing combination therapy. It is unclear whether withdrawal of azathioprine, initially administered alone or in combination, impacts on the development of CD-related complications, adverse events, serious adverse events or withdrawal due to adverse events. Further high-quality research is needed in this area, particularly double-blind RCTs in which biologic therapy or an immunosuppressant other than azathioprine is withdrawn.

We performed a comprehensive literature review and identified six randomized controlled trials (an experiment in which participants are randomly assigned to receive two or more interventions and the results are compared) that involved a total of 326 participants. Four of the six studies assigned patients who had been receiving azathioprine alone to either continue or discontinue therapy (215 participants). Two of the six studies assigned patients who had been receiving azathioprine in addition to infliximab to continue therapy or discontinue azathioprine (111 participants). Clinical relapse occurred in 13% (14/104) of patients who continued azathioprine monotherapy compared to 32% (36/111) of patients who discontinued azathioprine monotherapy. No differences were observed for Crohn's disease-related complications, side effects, serious side effects and withdrawal due to side effects. Common side effects included infections, mild decrease in the number of white blood cells, abdominal symptoms, joint pain, headache and elevated liver enzymes. Among patients who continued combination therapy with azathioprine and infliximab, 48% (27/56) had a clinical relapse compared to 49% (27/55) of patients discontinued azathioprine but remained on infliximab. No differences in side effects, serious side effects or withdrawal due to side effects were observed. Common side effects reported in the combination therapy studies included infections, liver test elevations, joint pain and infusion reactions (a hypersensitivity reaction to the biologic medication). Overall, the quality of evidence for each outcome was low due to a high risk of study bias and small numbers of patients evaluated. The effects of withdrawal of immunosuppressant therapy in people with Crohn's disease in remission are uncertain. Low quality evidence suggests that continuing azathioprine monotherapy may be superior to withdrawal of azathioprine for avoiding clinical relapse in people with Crohn's disease in remission. Low quality evidence suggests that stopping the immunosuppressive after combination therapy does not seem to impact on the risk of relapsing. It is unclear whether the withdrawal of azathioprine, initially administered alone or in combination, impacts on the development of Crohn's disease-related complications, side effects, serious side effects, or withdrawal from the studies due to side effects. Additional research is needed in this area to better inform clinical practice, particularly high-quality randomized controlled trials examining outcomes when biologic therapy is withdrawn.

10.1002/14651858.CD012540.pub2

cochrane-simplification-train-2765

cochrane-simplification-train-2765

We included eight studies examining the blood pressure lowering efficacy of carvedilol and labetalol in 1493 hypertensive patients. Five of the included studies were parallel design; three were cross-over design. The two largest included studies were unpublished carvedilol studies. The estimates of BP lowering effect (systolic BP/diastolic BP millimeters of mercury; SPB/DBP mm Hg) were -4 mm Hg (95% confidence intervals (CI) -6 to -2)/-3 mm Hg (95% CI -4 to -2) for carvedilol (>1000 subjects) and -10 mm Hg (95% CI -14 to -7)/-7 mm Hg (95% CI -9 to -5) for labetalol (110 subjects). The effect of labetalol is likely to be exaggerated due to high risk of bias. Carvedilol, within the recommended dose range, did not show a significant dose response effect for SBP or DBP. Carvedilol had little or no effect on pulse pressure (-1 mm Hg) and did not change BP variability. Overall, once and twice the starting dose of carvedilol and labetalol lowered BP by -6 mm Hg (95% CI -7 to -4) /-4 mm Hg (95% CI -4 to -3) (low quality evidence) and lowered heart rate by five beats per minute (95% CI -6 to -4) (low quality evidence). Five studies (N = 1412) reported withdrawal due to adverse effects; the risk ratio was 0.88 (95% CI 0.54 to 1.42) (moderate quality evidence). This review provides low quality evidence that in patients with mild to moderate hypertension, dual receptor blockers lowered trough BP by an average of -6/-4 mm Hg and reduced heart rate by five beats per minute. Due to the larger sample size from the two unpublished studies, carvedilol provided a better estimate of BP lowering effect than labetalol. The BP lowering estimate from combining carvedilol once and twice the starting doses is -4/-3 mm Hg. Doses higher than the recommended starting dose did not provide additional BP reduction. Higher doses of dual receptor blockers caused more bradycardia than lower doses. Based on indirect comparison with other classes of drugs, the blood pressure lowering effect of dual alpha- and beta-receptor blockers is less than non-selective, beta1 selective and partial agonist beta blockers, as well as thiazides and drugs inhibiting the renin angiotensin system. Dual blockers also had little or no effect on reducing pulse pressure, which is similar to the other beta-blocker classes, but less than the average reduction of pulse pressure seen with thiazides and drugs inhibiting the renin angiotensin system. Patients taking dual receptor blockers were not more likely to withdraw from the study compared to patients taking placebo.

We found eight clinical studies in October 2014, that examined the blood pressure lowering effect of carvedilol and labetalol in 1493 participants with high blood pressure. These people were randomly assigned to receive either a fixed dose of dual receptor blockers or a placebo for 3 to 12 weeks. On average, dual receptor blockers lowered systolic BP by six points, diastolic BP by four points and heart rate by five beats per minute in patients with mild to moderate high blood pressure. There were more data on the effects of carvedilol. On average, carvedilol lowered systolic BP by four points and diastolic BP by three points. Higher doses of dual receptor blockers caused more slowing of heart rate but not more lowering of BP. The BP lowering effect of dual receptor blockers was less than other classes of BP lowering drugs. Patients taking dual receptor blockers were not more likely to withdraw from the study compared to patients taking placebo. The quality of the evidence was judged to be low due to various types of bias that could exaggerate the effect. A low quality of evidence means future research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

10.1002/14651858.CD007449.pub2

cochrane-simplification-train-2766

cochrane-simplification-train-2766

We included eight studies (24 reports, 258 participants). Because duration of the included studies was too short (1 to 26 weeks) to test the effect of salt restriction on endpoints such as mortality, cardiovascular events or CKD progression, changes in salt intake on blood pressure and other secondary risk factors were applied. Three studies were parallel RCTs and five were cross-over studies. Selection bias was low in five studies and unclear in three. Performance and detection biases were low in two studies and unclear in six. Attrition and reporting biases were low in four studies and unclear in four. One study had the potential for high carryover effect; three had high risk of bias from baseline characteristics (change of medication or diet) and two studies were industry funded. There was a significant reduction in 24 hour sodium excretion associated with low salt interventions (range 52 to 141 mmol) (8 studies, 258 participants: MD -105.86 mmol/d, 95% CI -119.20 to -92.51; I2 = 51%). Reducing salt intake significantly reduced systolic blood pressure (8 studies, 258 participants: MD -8.75 mm Hg, 95% CI -11.33 to -6.16; I2 = 0%) and diastolic blood pressure (8 studies, 258 participants: MD -3.70 mm Hg, 95% CI -5.09 to -2.30; I2 = 0%). One study reported restricting salt intake reduced the risk of oedema by 56%. Salt restriction significantly increased plasma renin activity (2 studies, 71 participants: MD 1.08 ng/mL/h, 95% CI 0.51 to 1.65; I2 = 0%) and serum aldosterone (2 studies, 71 participants: 6.20 ng/dL (95% CI 3.82 to 8.58; I2 = 0%). Antihypertensive medication dosage was significantly reduced with a low salt diet (2 studies, 52 participants): RR 5.48, 95% CI 1.27 to 23.66; I2 = 0%). There was no significant difference in eGFR (2 studies, 68 participants: MD -1.14 mL/min/1.73 m2, 95% CI -4.38 to 2.11; I2 = 0%), creatinine clearance (3 studies, 85 participants): MD -4.60 mL/min, 95% CI -11.78 to 2.57; I2 = 0%), serum creatinine (5 studies, 151 participants: MD 5.14 µmol/L, 95% CI -8.98 to 19.26; I2 = 59%) or body weight (5 studies, 139 participants: MD -1.46 kg; 95% CI -4.55 to 1.64; I2 = 0%). There was no significant change in total cholesterol in relation to salt restriction (3 studies, 105 participants: MD -0.23 mmol/L, 95% CI -0.57 to 0.10; I2 = 0%) or symptomatic hypotension (2 studies, 72 participants: RR 6.60, 95% CI 0.77 to 56.55; I2 = 0%). Salt restriction significantly reduced urinary protein excretion in all studies that reported proteinuria as an outcome, however data could not be meta-analysed. We found a critical evidence gap in long-term effects of salt restriction in people with CKD that meant we were unable to determine the direct effects of sodium restriction on primary endpoints such as mortality and progression to end-stage kidney disease (ESKD). We found that salt reduction in people with CKD reduced blood pressure considerably and consistently reduced proteinuria. If such reductions could be maintained long-term, this effect may translate to clinically significant reductions in ESKD incidence and cardiovascular events. Research into the long-term effects of sodium-restricted diet for people with CKD is warranted, as is investigation into adherence to a low salt diet.

We searched the literature for studies that looked at the effects of restricting salt in the diets of people with CKD up to January 2015. We found eight studies that involved 258 people which met our inclusion criteria. Study participants included people in the early stages of CKD (six studies), who were on peritoneal dialysis (one study), or were kidney transplant recipients (one study). The average study duration was six weeks, and ranged from one to 26 weeks. We did not find any studies that measured the effect of salt intake on the incidence of death, heart disease, or need to begin dialysis. We found that reducing salt intake reduced 24 hour sodium excretion, blood pressure. One study reported restricting salt intake reduced the risk of oedema (swelling). Antihypertensive medication dosage was significantly reduced with a low salt diet. There was no significant difference in kidney function measures or body weight. There was no significant change in total cholesterol or hypotension. Long-term effects of salt restriction in people with CKD is lacking that meant we were unable to determine the direct effects of sodium restriction on primary endpoints such as mortality and progression to end-stage kidney disease (ESKD). Research into the long-term effects of sodium-restricted diet for people with CKD is warranted, as is investigation into adherence to low salt diet.

10.1002/14651858.CD010070.pub2

cochrane-simplification-train-2767

cochrane-simplification-train-2767

Rates of developing postoperative ileus were comparable between study groups (RR 0.47, 95% CI 0.17 to 1.29, P = 0.14, 3 RCTs, 279 women, I² = 0%, moderate-quality evidence). When we considered the rates of nausea or vomiting or both, there was no evidence of a difference between the study groups (RR 1.03, 95% CI 0.64 to 1.67, P = 0.90, 4 RCTs, 484 women, I² = 73%, moderate-quality evidence). There was no evidence of a difference between the study groups in abdominal distension (RR 1.07, 95% CI 0.77 to 1.47, 2 RCTs, 301 women, I² = 0%) or a need for postoperative nasogastric tube placement (RR 0.48, 95% CI 0.13 to 1.80, 1 RCT, 195 women). Early feeding was associated with shorter time to the presence of bowel sound (MD -0.32 days, 95% CI -0.61 to -0.03, P = 0.03, 2 RCTs, 338 women, I² = 52%, moderate-quality evidence) and faster onset of flatus (MD -0.21 days, 95% CI -0.40 to -0.01, P = 0.04, 3 RCTs, 444 women, I² = 23%, moderate-quality evidence). In addition, women in the early feeding group resumed a solid diet sooner (MD -1.47 days, 95% CI -2.26 to -0.68, P = 0.0003, 2 RCTs, 301 women, I² = 92%, moderate-quality evidence). There was no evidence of a difference in time to the first passage of stool between the two study groups (MD -0.25 days, 95% CI -0.58 to 0.09, P = 0.15, 2 RCTs, 249 women, I² = 0%, moderate-quality evidence). Hospital stay was shorter in the early feeding group (MD -0.92 days, 95% CI -1.53 to -0.31, P = 0.003, 4 RCTs, 484 women, I² = 68%, moderate-quality evidence). Infectious complications were less common in the early feeding group (RR 0.20, 95% CI 0.05 to 0.73, P = 0.02, 2 RCTs, 183 women, I² = 0%, high-quality evidence). In one study, the satisfaction score was significantly higher in the early feeding group (MD 11.10, 95% CI 6.68 to 15.52, P < 0.00001, 143 women, moderate-quality evidence). Early postoperative feeding after major abdominal gynaecologic surgery for either benign or malignant conditions appeared to be safe without increased gastrointestinal morbidities or other postoperative complications. The benefits of this approach include faster recovery of bowel function, lower rates of infectious complications, shorter hospital stay, and higher satisfaction.

We assessed evidence on the following outcomes: 1. Nausea, vomiting, cramping abdominal pain, bloating, abdominal distension, wound complication, deep venous thrombosis, urinary tract infection, pneumonia. 2. Time to first: bowel sound, gas, stool, start of regular diet. 3. Length of hospital stay Early feeding was defined as having fluids or food within 24 hours of surgery. Delayed feeding was defined as having fluids or food 24 hours after surgery, and only if there are bowel sounds, passage of gas or stool, and a feeling of hunger. The evidence is current to April 2014 We included five published studies of 631 women, mainly with gynaecologic cancer. Recovery of bowel function was faster in those with early feeding. There was no difference in rates of nausea or vomiting, abdominal distension, need for a postoperative nasogastric tube or time to first bowel movement, but early feeding was associated with a shorter time to bowel sounds and onset of gas. The early feeding group resumed a solid diet 1½ days sooner than those having delayed feeding and the hospital stay was one day shorter. Also, the early feeding group were more satisfied with the feeding schedule, although only one study reported this. Early feeding appeared safe, without increased postoperative complications and with fewer infectious complications overall. Most of the evidence was moderate quality. The main limitation was lack of blinding, which could influence the findings for subjective outcomes such as self-reported symptoms, hospital stay, patients' satisfaction and quality of life. The evidence suggests that eating and drinking on the first day after abdominal gynaecologic surgery is safe and could reduce the length of hospital stay.

10.1002/14651858.CD004508.pub4

cochrane-simplification-train-2768

cochrane-simplification-train-2768

We included only one non-randomised study published 30 years ago in the review. This study included 77 participants who had gastric ulcer and in whom medical therapy (histamine H2 receptor blockers, antacids, and diet) had failed after an average duration of treatment of 29 months. The authors do not state whether these were recurrent or refractory ulcers. It appears that the participants did not have previous complications such as bleeding or perforation. Of the 77 included participants, 37 participants continued to have medical therapy while 40 participants received surgical therapy (antrectomy with or without vagotomy; subtotal gastrectomy with or without vagotomy; vagotomy; pyloroplasty and suture of the ulcer; suture or closure of ulcer without vagotomy or excision of the ulcer; proximal gastric or parietal cell vagotomy alone; suture or closure of the ulcer with proximal gastric or parietal cell vagotomy). Whether to use medical or surgical treatment was determined by participant's or treating physician's preference. The study authors reported that two participants in the medical treatment group (2 out of 37; 5.4%) had gastric cancer, which was identified by repeated biopsy. They did not report the proportion of participants who had gastric cancer in the surgical treatment group. They also did not report the implications of the delayed diagnosis of gastric cancer in the medical treatment group. They did not report any other outcomes of interest for this review (that is health-related quality of life (using any validated scale), adverse events and serious adverse events, peptic ulcer bleeding, peptic ulcer perforation, abdominal pain, and long-term mortality). We found no studies that provide the relative benefits and harms of medical versus surgical treatment for recurrent or refractory peptic ulcers. Studies that evaluate the natural history of recurrent and refractory peptic ulcers are urgently required to determine whether randomised controlled trials comparing medical versus surgical management in patients with recurrent or refractory peptic ulcers or both are necessary. Such studies will also provide information for the design of such randomised controlled trials. A minimum follow-up of two to three years will allow the calculation of the incidence of complications and gastric cancer (in gastric ulcers only) in recurrent and refractory peptic ulcers. In addition to complications related to treatment and disease, health-related quality of life and loss of productivity should also be measured.

We found no randomised controlled trials, and identified only one non-randomised study published 30 years ago, on this topic. This study included 77 participants who had stomach ulcer and in whom medical therapy had failed after an average treatment duration of 29 months. Medical therapy included histamine H2 receptor blockers (medicines that block the action of the chemical histamine, resulting in a decreased production of stomach acid, such as ranitidine), antacids, and diet. It must be highlighted that this form of medical treatment is not considered to be as effective as treatment with proton pump inhibitors. The authors do not state whether these were recurrent or refractory ulcers. Of the 77 included participants, 37 participants continued to have medical therapy, while 40 participants received surgical therapy. Whether to use medical or surgical treatment was determined by participant's or treating physician's preference. The evidence is current to September 2015. The study authors reported that two participants in the medical treatment group (5%) had stomach cancer, which was identified after repeated examinations using a camera to look inside the body (an endoscope), in this case, the stomach and small intestine. They did not report the percentage of participants who had stomach cancer in the surgical treatment group. They also did not report the implications of the delayed diagnosis of stomach cancer in the medical treatment group. They did not report any other outcomes of interest (measures by which one treatment can be considered better than another) for this review (that is health-related quality of life, treatment-related complications, peptic ulcer-related complications, abdominal pain, and long-term deaths). There is thus no study that provides the relative benefits and harms of medical versus surgical treatment for recurrent or refractory peptic ulcers. Studies on this topic are urgently required. Since the only study that compared medical and surgical treatment in people with refractory or recurrent ulcers did not report any of the outcomes in a sufficiently detailed manner, we were not able to assess the quality of evidence in a formal way.

10.1002/14651858.CD011523.pub2

cochrane-simplification-train-2769

cochrane-simplification-train-2769

Three trials with a total of 81 patients were included in the analysis. Forty patients were randomized to azathioprine and forty-one to placebo. A pooled estimate was calculated for two outcomes. A statistically significant benefit was observed for azathioprine when compared to placebo for tender joint scores. The standardized weighted mean difference between treatment and placebo was -0.98 (95% CI -1.45, -0.50). Withdrawals from adverse reactions were significantly higher in the azathioprine group OR=4.56 (95% CI 1.16, 17.85). Azathioprine appears to have a statistically significant benefit on the disease activity in joints of patients with RA. This evidence however is based on a small number of patients, included in older trials. Its effects on long-term functional status and radiological progression were not assessed due to lack of data. Toxicity is shown to be higher and more serious than that observed with other disease-modifying anti-rheumatic drugs (DMARDs). Given this high risk to benefit ratio, there is no evidence to recommend the use of azathioprine over other DMARDs.

Azathioprine is a drug that suppresses the immune system. This review includes three trials with a total of 81 patients. Forty patients were given azathioprine and forty-one were given placebo. Patients taking azathioprine had lower tender joint scores when compared to patients taking placebo. Significantly more patients in the azathioprine group withdrew from the studies due to adverse reactions compared to patients in the placebo group. This evidence is based on a small number of patients in older trials. These findings suggest that several other drugs should be used before considering azathioprine for a patient with rheumatoid arthritis.

10.1002/14651858.CD001461

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cochrane-simplification-train-2770

Six trials were included, involving 606 participants. Five trials included comparisons of ultrasound therapy with sham ultrasound; and three trials included single comparisons of ultrasound with three other treatments. The assessment of risk of bias was hampered by poor reporting of trial methods and results. None of the five placebo-controlled trials (sham ultrasound) demonstrated statistically significant differences between true and sham ultrasound therapy for any outcome measure at one to four weeks of follow-up. The pooled risk ratio for general improvement at one week was 1.04 (random-effects model, 95% confidence interval 0.92 to 1.17) for active versus sham ultrasound. The differences between intervention groups were generally small, between zero and six per cent, for most dichotomous outcomes. The evidence from the five small placebo-controlled trials included in this review does not support the use of ultrasound in the treatment of acute ankle sprains. The potential treatment effects of ultrasound appear to be generally small and of probably of limited clinical importance, especially in the context of the usually short-term recovery period for these injuries. However, the available evidence is insufficient to rule out the possibility that there is an optimal dosage schedule for ultrasound therapy that may be of benefit.

The review aimed to look at the evidence from studies testing the use of ultrasound in clinical practice. Six trials were included in the review. Poor reporting of trial methods made it difficult to assess the risk of bias of the included studies. The six trials involved a total of 606 participants with acute ankle sprains of relatively short duration. Five trials compared ultrasound therapy with sham ultrasound (machine turned off). Three of the six trials included single comparisons of ultrasound with three other treatments. The main results were from the review of the five placebo-controlled trials (sham ultrasound). These found that ultrasound therapy does not seem to enhance recovery or help to reduce pain and swelling after an ankle sprain, or improve the ability to stand on the affected foot and ankle. Most ankle sprains heal quickly. While ultrasound may still improve recovery in a small way, this potential benefit is probably too small to be important.

10.1002/14651858.CD001250.pub2

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cochrane-simplification-train-2771

Eleven trials (550 women) compared corticosteroids with placebo or no treatment. There was no difference in the risk of maternal death (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.28 to 3.21), maternal death or severe maternal morbidity (RR 0.27, 95% CI 0.03 to 2.12), or perinatal/infant death (RR 0.64, 95% CI 0.21 to 1.97). The only clear effect of treatment on individual outcomes was improved platelet count (standardized mean difference (SMD) 0.67, 95% CI 0.24 to 1.10). The effect on platelet count was strongest for women who commenced treatment antenatally (SMD 0.80, 95% CI 0.25 to 1.35). Two trials (76 women) compared dexamethasone with betamethasone. There was no clear evidence of a difference between groups in respect to perinatal/infant death (RR 0.95, 95% CI 0.15 to 6.17) or severe perinatal/infant morbidity or death (RR 0.64, 95% CI 0.27 to 1.48). Maternal death and severe maternal morbidity were not reported. In respect to platelet count, dexamethasone was superior to betamethasone (MD 6.02, 95% CI 1.71 to 10.33), both when treatment was commenced antenatally (MD 8.10, 95% CI 6.23 to 9.97) and postnatally (MD 3.70, 95% CI 0.96 to 6.44). There was no clear evidence of any effect of corticosteroids on substantive clinical outcomes. Those receiving steroids showed significantly greater improvement in platelet counts which was greater for those receiving dexamethasone than those receiving betamethasone. There is to date insufficient evidence of benefits in terms of substantive clinical outcomes to support the routine use of steroids for the management of HELLP. The use of corticosteroids may be justified in clinical situations in which increased rate of recovery in platelet count is considered clinically worthwhile.

Infant health may also be poor, primarily due to premature birth and growth restriction.This review examined the effect of treating women with HELLP syndrome using corticosteroids (which can reduce inflammation). The results of this review did not indicate that there was a clear effect on the health of pregnant women when treated with corticosteroids, or their babies. Corticosteroids did appear to improve some components of the women's blood tests, but it is not clear that this had an effect on their overall health. The review identified 11 randomized controlled trials involving 550 women that compared corticosteroid (dexamethasone, betamethasone, or prednisolone) given during pregnancy, just after delivery or in the postnatal period, or both before and after birth, with placebo or no treatment. Two further trials showed that there was no clear difference between dexamethasone and betamethasone on the substantive clinical outcomes for women or their infants. Dexamethasone did improve maternal platelet count and some biochemical measures to a greater extent than betamethasone.

10.1002/14651858.CD008148.pub2

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cochrane-simplification-train-2772

We included 23 trials involving 1886 people in this updated review. Twenty-two of these trials investigated the addition of medication to treat the identified dysfunction, with most agents studied in only single studies. One study investigated switching to an alternative antidepressant. In men, data for the phosphodiesterase inhibitors sildenafil (three studies, 255 participants) and tadalafil (one study, 54 participants) indicated they led to a greater improvement in erectile function than placebo. Combined data from three sildenafil studies found benefit over placebo on International Index of Erectile Function ratings of ability to achieve (MD 1.04, 95% CI 0.65 to 1.44), and maintain erections (MD 1.18, 95% CI 0.78 to 1.59). A single point improvement on these ratings is equivalent to an improvement in frequency from 'sometimes' to 'most times'. Men receiving tadalafil were more likely to report improved erectile function (RR 11.50, 95% CI 3.03 to 43.67). For women it remains uncertain whether sildenafil is more effective than placebo. Unpublished data could reduce this uncertainty. Data from three studies in men and women of bupropion 150 mg twice daily indicate a benefit over placebo on rating scale scores (SMD 1.60, 95% CI 1.40 to 1.81), but response rates in two studies of bupropion 150 mg once daily demonstrated no statistically significant difference in effect (RR 0.62, 95% CI 0.09 to 4.41). Other augmentation strategies failed to demonstrate significant improvements in sexual dysfunction compared with placebo. One trial involving 75 people with sexual dysfunction due to sertraline assessed the effect of changing antidepressant. Switching to nefazodone was significantly less likely to result in the re-emergence of sexual dysfunction than restarting sertraline (RR 0.34, 95% CI 0.19 to 0.60), however, nefazodone is no longer available for clinical use. There is an absence of randomised trials assessing the effects of switching to currently-available antidepressant agents with lower rates of adverse sexual effects, the role of psychological or mechanical interventions, or of techniques such as drug holidays. We identified no data for any of the strategies included in the trials assessed that indicated that they led to a worsening of psychiatric symptoms. However, the relatively small numbers assessed for many of the interventions studied means that the possibility of such an effect cannot confidently be excluded in all cases. Given the small numbers of studies assessing most of the strategies assessed, the presence of any unpublished trials could have substantial effects on estimates of effect. In some cases, only results from particular items or subscales within ratings scales are available. It is likely that this could act to bias estimates of effect obtained, increasing apparent effectiveness. The evidence currently available is rather limited. For men with antidepressant-induced erectile dysfunction, the addition of sildenafil or tadalafil appears to be an effective strategy. For women with antidepressant-induced sexual dysfunction the addition of bupropion at higher doses appears to be the most promising approach studied so far.

This systematic review investigated different ways to manage such sexual dysfunction. We included 23 randomised studies, with a total of 1886 participants who had developed their sexual problems while taking antidepressant medication. Twenty-two of these studies looked at the addition of further medication to the ongoing treatment for depression. For men with antidepressant-induced erectile dysfunction, the addition of sildenafil (Viagra; three studies, 255 participants) or tadalafil (Cialis; one study, 54 participants) appeared to improve the situation. For women with antidepressant-induced sexual dysfunction the addition of bupropion (Wellbutrin, Zyban; three studies, 482 participants) at higher doses appears to be the most promising approach studied so far, but further data from randomised trials are likely to be required before it can be recommended confidently. We did not find evidence that any intervention led to a worsening of psychiatric symptoms; however, we cannot be confident of this for many of the interventions studied, as only small numbers of participants have been studied so far.

10.1002/14651858.CD003382.pub3

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cochrane-simplification-train-2773

Twelve trials were eligible for inclusion. Three of these trials, involving a total of 909 patients, compared ICS plus systemic corticosteroids versus oral corticosteroid therapy alone. There was no demonstrated benefit of ICS therapy when used in addition to oral corticosteroid therapy in the trials. Relapses were reduced; however, this was not statistically significant with the addition of ICS therapy (OR 0.68; 95% CI 0.46 to 1.02; 3 studies; N = 909). In addition, no statistically significant differences were demonstrated between the two groups for relapses requiring admission, quality of life, symptom scores or adverse effects. Nine trials, involving a total of 1296 patients compared high-dose ICS therapy alone versus oral corticosteroid therapy alone after ED discharge. There were no significant differences demonstrated between ICS therapy alone versus oral corticosteroid therapy alone for relapse rates (OR 1.00; 95% CI 0.66 to 1.52; 4 studies; N = 684), admissions to hospital, or in the secondary outcomes of beta2-agonist use, symptoms or adverse events. However, the sample size was not adequate to exclude the possibility of either treatment being significantly inferior and people with severe asthma were excluded from these trials. There is insufficient evidence that ICS therapy provides additional benefit when used in combination with standard systemic corticosteroid therapy upon ED discharge for acute asthma. There is some evidence that high-dose ICS therapy alone may be as effective as oral corticosteroid therapy when used in mild asthmatics upon ED discharge; however, the confidence intervals were too wide to be confident of equal effectiveness. Further research is needed to clarify whether ICS therapy should be employed in acute asthma treatment following ED discharge. The review does not suggest any reason to stop usual treatment with ICS following ED discharge, even if a course of oral corticosteroids are prescribed.

This review of trials found that there was insufficient evidence that inhaling corticosteroids as well as taking the drugs orally is better than oral use alone, after emergency department treatment for an asthma attack. There is also insufficient evidence that taking ICS alone is as good as taking them orally, although there is some evidence to support using ICS alone for mild asthma attacks after emergency department discharge. More research is needed.

10.1002/14651858.CD002316.pub2

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cochrane-simplification-train-2774

We included 15 trials. Seven studies reported from 2010 to 2014 were added to eight from the original 2001 review. Newer trials compared immediate postplacental insertion versus early (10 minutes to 48 hours) or standard insertion (during the postpartum visit). Of four with full reports, three were small trials. The other three studies had conference abstracts. The eight early trials examined immediate insertion of different devices or insertion techniques. Most studies were published in the 1980s, some with limited reporting. Our sensitivity analysis included trials with sufficient outcome data and moderate or high quality evidence. Four newer trials comparing insertion times met the inclusion criteria. Two studies used the levonorgestrel-releasing intrauterine system (LNG-IUS) after vaginal delivery. The other two trials placed IUC after cesarean section; one used the CuT 380A intrauterine device (IUD) and the other used the LNG-IUS. A pilot trial compared immediate insertion versus early or standard insertion. In groups comparing immediate versus early insertion (N = 30), all women had the LNG-IUS inserted. By six months, the groups had the same expulsion rate and did not differ significantly in IUC use. For immediate versus standard insertion, we conducted meta-analyses of four trials. Insertion rates did not differ significantly between study arms. However, the trial from Uganda showed insertion was more likely for the immediate group, although the estimate was imprecise. In the meta-analysis, expulsion by six months was more likely for the immediate group, but the confidence interval was wide (OR 4.89, 95% CI 1.47 to 16.32; participants = 210; studies = 4). IUC use at six months was more likely with immediate insertion than with standard insertion (OR 2.04, 95% CI 1.01 to 4.09; participants = 243; studies = 4). Study arms did not differ in use at 3 or 12 months in individual small trials. Recent trials compared different insertion times after vaginal or cesarean delivery. Evidence was limited because studies with full reports generally had small sample sizes. Overall, the quality of evidence was moderate; abstracts and older studies had limited reporting. Ongoing trials will add to the evidence, although some are small. Trials of adequate power are needed to estimate expulsion rates and side effects. The benefit of effective contraception immediately after delivery may outweigh the disadvantage of increased risk for expulsion. Frequent prenatal visits during the third trimester provide the opportunity to discuss effective contraceptive methods and desired timing for initiation. Clinical follow-up can help detect early expulsion, as can educating women about expulsion signs and symptoms.

Until 1 April 2015, we ran computer searches for randomized trials of IUC inserted within 10 minutes of placenta (afterbirth) delivery. We wrote to researchers to find more studies. Trials could compare different times for insertion as well as types of IUC and ways to insert the device. We found 15 trials. Seven recent studies compared IUC insertion right after childbirth versus early insertion (before hospital discharge) or later insertion (weeks after discharge). Four had full reports, although three were small studies. Insertion was as likely to occur when placed right after childbirth as when planned for later placement, except in a study from Uganda. For the four trials overall, the IUC came out more often on its own when placed right after childbirth than when inserted weeks later. Use at six months was more likely with insertion right after childbirth than weeks later. In single studies, the groups did not differ in use at 3 months or 12 months. Eight older studies looked at types of IUC put in right after childbirth. Changing IUC design did not seem to affect whether IUC stayed in or whether it was used later on. Inserting IUC by hand or with a holding instrument did not seem to make a difference. We found newer trials with full reports that compared placement times. The studies were of good quality. Ongoing trials will provide additional data, although some sample sizes are small. Larger studies would provide better information on whether the IUC came out on its own and on whether side effects occurred.

10.1002/14651858.CD003036.pub3

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cochrane-simplification-train-2775

After conducting initial searches and screening the titles and abstracts of the identified literature, 77 full text papers were retrieved and read. Ultimately three studies were included. Two controlled before-after studies were conducted in hospital settings (one in the UK and one in the Netherlands) and one cluster randomised controlled trial was conducted in a primary care setting (in the USA). The study conducted in primary care reported that physicians were receptive to the screening intervention, but the intervention did not result in any improvements in the malnutrition detection rate or nutritional intervention rate. The two studies conducted in hospitals had important methodological limitations. One study reported that as a result of the intervention, the recording of patients' weight increased in the intervention wards. No significant changes were observed in the referral rates to dietitians or care at meal time. The third study reported weight gains and a reduction in hospital acquired infection rate in the intervention hospital. They found no significant differences in length of stay, pressure sores, malnutrition and treatment costs per patient between the two hospitals. Current evidence is insufficient to support the effectiveness of nutritional screening, although equally there is no evidence of no effect. Therefore, more high quality studies should be conducted to assess the effectiveness of nutritional screening in different settings.

We searched for studies evaluating the effects of nutritional screening as a main intervention in hospital and primary care settings on patient outcomes such as mortality, illness, health related quality of life, and change in BMI or weight. We also searched for studies evaluating process outcomes like identification of patients requiring nutritional care, data recording (e.g. weight and BMI), or referral of patients to dietitians or similar. Three studies met our inclusion criteria, but they were very dissimilar in their design, setting, intervention and outcomes. One study found that primary care physicians were receptive to the intervention but it did not result in any improvement in detection rate and nutritional intervention rate. Two studies were conducted in hospitals: one reported that patients’ weight documentation increased as a result of the intervention, and the other reported significant weight gains and reduction in hospital acquired infection rate in the intervention hospital. Both of these studies suffered from limitations in their design, and it was not possible to rule out the impact of confounding factors on their findings. As a result, we conclude that evidence on the effectiveness of nutritional screening is insufficient. Therefore, further high quality studies should be conducted to assess the effectiveness of nutritional screening programmes in hospitals and communities.

10.1002/14651858.CD005539.pub2

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cochrane-simplification-train-2776

We identified two double-blind RCTs of gabapentin treatment in ALS for inclusion in this review. We found no eligible RCTs of baclofen or other GABA modulators. The selected studies were phase II and phase III trials, which lasted six and nine months, respectively. They were highly comparable because both were comparisons of oral gabapentin and placebo, performed by the same investigators. The trials enrolled 355 participants with ALS: 80 in the gabapentin group and 72 in the placebo group in the first (phase II) trial and 101 in the gabapentin group and 102 in the placebo group in the second (phase III) trial. Neither trial was long enough to report survival at one year, which was our primary outcome. We found little or no difference in estimated one-year survival between the treated group and the placebo group (78% versus 77%, P = 0.63 by log-rank test; high-quality evidence). We also found little or no difference in the rate of decline of MVIC expressed as arm megascore, or rate of FVC decline (high-quality evidence). One trial investigated monthly decline in the ALSFRS and quality of life measured using the 12-Item Short Form Survey (SF-12) and found little or no difference between groups (moderate-quality evidence). The trials reported similar adverse events. Complaints that were clearly elevated in those taking gabapentin, based on analyses of the combined data, were light-headedness, drowsiness, and limb swelling (high-quality evidence). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. We assessed the overall risk of bias in the included trials as low. According to high-quality evidence, gabapentin is not effective in treating ALS. It does not extend survival, slow the rate of decline of muscle strength, respiratory function and, based on moderate-quality evidence, probably does not improve quality of life or slow monthly decline in the ALSFRS. Other GABA modulators have not been studied in randomized trials.

A systematic search of the medical literature found two randomized trials of gabapentin compared with placebo (inactive treatment). The same team of scientists performed both trials, which were sponsored by the manufacturer. The trials involved a total of 355 people with ALS. Treatment with gabapentin lasted six and nine months. We found no trials of baclofen or other GABA modulators in ALS that met our selection criteria. We assessed the gabapentin trials as well run and well conducted. Neither of the trials were long enough to for us to report survival at one year. Combined results from the two studies (based on 274 participants) provided high-quality evidence of little or no difference in estimated one-year survival, the rate of decline in respiratory function, or rate of decline in arm strength in people treated with gabapentin compared to those treated with placebo. One trial (128 participants) measured quality of life and monthly decline in function (measured by the ALS Functional Rating Scale). There was little or no difference in the ALS Functional Rating Scale (ALSFRS) or quality of life between the gabapentin group and the placebo group. People who received gabapentin had more light-headedness, drowsiness, and limb swelling than those taking placebo when we combined data from both trials (353 participants). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. In conclusion, high-quality evidence indicates that gabapentin does not extend survival or slow the rate of decline of muscle strength or respiratory function. Moderate-quality evidence shows no effect on quality of life or decline in ALSFRS. Other GABA modulators have not been studied in randomized trials. The evidence is current to August 2016.

10.1002/14651858.CD006049.pub2

cochrane-simplification-train-2777

cochrane-simplification-train-2777

We included 38 randomised controlled trials involving 1907 participants (1114 cell therapy, 793 controls) in this review update. Twenty-three trials were at high or unclear risk of selection bias. Other sources of potential bias included lack of blinding of participants (12 trials) and full or partial commercial sponsorship (13 trials). Cell therapy reduced the incidence of long-term mortality (≥ 12 months) (risk ratio (RR) 0.42, 95% confidence interval (CI) 0.21 to 0.87; participants = 491; studies = 9; I2 = 0%; low-quality evidence). Periprocedural adverse events associated with the mapping or cell/placebo injection procedure were infrequent. Cell therapy was also associated with a long-term reduction in the incidence of non-fatal myocardial infarction (RR 0.38, 95% CI 0.15 to 0.97; participants = 345; studies = 5; I2 = 0%; low-quality evidence) and incidence of arrhythmias (RR 0.42, 95% CI 0.18 to 0.99; participants = 82; studies = 1; low-quality evidence). However, we found no evidence that cell therapy affects the risk of rehospitalisation for heart failure (RR 0.63, 95% CI 0.36 to 1.09; participants = 375; studies = 6; I2 = 0%; low-quality evidence) or composite incidence of mortality, non-fatal myocardial infarction, and/or rehospitalisation for heart failure (RR 0.64, 95% CI 0.38 to 1.08; participants = 141; studies = 3; I2 = 0%; low-quality evidence), or long-term left ventricular ejection fraction when measured by magnetic resonance imaging (mean difference -1.60, 95% CI -8.70 to 5.50; participants = 25; studies = 1; low-quality evidence). This systematic review and meta-analysis found low-quality evidence that treatment with bone marrow-derived stem/progenitor cells reduces mortality and improves left ventricular ejection fraction over short- and long-term follow-up and may reduce the incidence of non-fatal myocardial infarction and improve New York Heart Association (NYHA) Functional Classification in people with chronic ischaemic heart disease and congestive heart failure. These findings should be interpreted with caution, as event rates were generally low, leading to a lack of precision.

We included 38 randomised controlled trials involving more than 1900 participants in this review, with 14 trials of chronic ischaemic heart disease, 17 trials of ischaemic heart failure secondary to heart disease, and seven trials of refractory or intractable angina. The mean age of participants ranged from 55 to 70 years, and the proportion of male participants ranged from 51% to 100%. Results indicated that treatment with bone marrow-derived cells can lead to a reduction in deaths in participants followed for at least 12 months. Adverse events occurring around the time of treatment were generally rare. Participants who received cell treatment also experienced fewer heart attacks and arrhythmias when compared to those who received no cells. However, cell therapy does not appear to reduce the risk of rehospitalisation for heart failure or the combined risk of death, non-fatal heart attack, or rehospitalisation, and did not result in any improvement over standard treatment in tests of heart function. These results suggest that cell therapy may be of benefit in people with chronic ischaemic heart disease or heart failure, or both. The quality of the evidence was low, as the number of included studies and participants is not currently high enough to draw robust conclusions. Thirteen studies received commercial funding, of which four were fully commercially sponsored, and 12 studies did not report that participants were blinded to the treatment they received. Further research involving a larger number of participants is required to confirm our results.

10.1002/14651858.CD007888.pub3

cochrane-simplification-train-2778

cochrane-simplification-train-2778

Of the 12 RCTs included, the effect of patient education on primary end points was reported in only five. Pooling of outcome data was precluded by marked, mainly clinical, heterogeneity. One of the RCTs showed reduced incidence of foot ulceration (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.14 to 0.66) and amputation (RR 0.33, 95% CI 0.15 to 0.76) during one-year follow-up of diabetes patients at high risk of foot ulceration after a one-hour group education session. However, one similar study, with lower risk of bias, did not confirm this finding (RR amputation 0.98, 95% CI 0.41 to 2.34; RR ulceration 1.00, 95% CI 0.70 to 1.44). Three other studies, also did not demonstrate any effect of education on the primary end points, but were most likely underpowered. Patients' foot care knowledge was improved in the short term in five of eight RCTs in which this outcome was assessed, as was patients' self-reported self-care behaviour in the short term in seven of nine RCTs. Callus, nail problems and fungal infections improved in only one of five RCTs. Only one of the included RCTs was at low risk of bias. In some trials, foot care knowledge and self reported patient behaviour seem to be positively influenced by education in the short term. Yet, based on the only two sufficiently powered studies reporting the effect of patient education on primary end points, we conclude that there is insufficient robust evidence that limited patient education alone is effective in achieving clinically relevant reductions in ulcer and amputation incidence.

Foot ulcers not only lead to physical disability and loss of quality of life but also to economic burden (healthcare costs, industrial disability). The aim is therefore to prevent foot ulcers occurring. This review of high-level studies found that educating people with diabetes about the need to look after their feet seems to improve people's foot care knowledge and behaviour in the short term. There is insufficient evidence that education alone, without any additional preventive measures, will effectively reduce the occurrence of ulcers and amputations.

10.1002/14651858.CD001488.pub5

cochrane-simplification-train-2779

cochrane-simplification-train-2779

We found four randomised clinical trials including 496 adult participants diagnosed with variceal haemorrhage due to cirrhotic portal hypertension. The overall risk of bias in all the trials was judged at high risk. All the trials were conducted in the United States of America (USA). Two of the trials randomised participants to selective surgical shunts versus TIPS. The other two trials randomised participants to non-selective surgical shunts versus TIPS. The diagnosis of liver cirrhosis was by clinical and laboratory findings. We are uncertain whether there is a difference in all-cause mortality at 30 days between surgical portosystemic shunts compared with TIPS (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.44 to 1.99; participants = 496; studies = 4). We are uncertain whether there is a difference in encephalopathy between surgical shunts compared with TIPS (RR 0.56, 95% CI 0.27 to 1.16; participants = 496; studies = 4). We found evidence suggesting an increase in the occurrence of the following harms in the TIPS group compared with surgical shunts: all-cause mortality at five years (RR 0.61, 95% CI 0.42 to 0.90; participants = 496; studies = 4); variceal rebleeding (RR 0.18, 95% CI 0.07 to 0.49; participants = 496; studies = 4); reinterventions (RR 0.13, 95% CI 0.06 to 0.28; participants = 496; studies = 4); and shunt occlusion (RR 0.14, 95% CI 0.04 to 0.51; participants = 496; studies = 4). We could not perform an analysis of health-related quality of life but available evidence appear to suggest improved health-related quality of life in people who received surgical shunt compared with TIPS. We downgraded the certainty of the evidence for all-cause mortality at 30 days and five years, irreversible shunt occlusion, and encephalopathy to very low because of high risk of bias (due to lack of blinding); inconsistency (due to heterogeneity); imprecision (due to small sample sizes of the individual trials and few events); and publication bias (few trials reporting outcomes). We downgraded the certainty of the evidence for variceal rebleeding and reintervention to very low because of high risk of bias (due to lack of blinding); imprecision (due to small sample sizes of the individual trials and few events); and publication bias (few trials reporting outcomes). The small sample sizes and few events did not allow us to produce meaningful trial sequential monitoring boundaries, suggesting plausible random errors in our estimates. We found evidence suggesting that surgical portosystemic shunts may have benefit over TIPS for treatment of refractory or recurrent variceal haemorrhage in people with cirrhotic portal hypertension. Given the very low-certainty of the available evidence and risks of random errors in our analyses, we have very little confidence in our review findings.

We found four randomised clinical trials in which 496 adult participants were allowed to receive either a surgical shunt or a radiologic shunt. There were problems with the design of the trials as they had small number of participants and used different shunt types. We judged all four trials at high risk of bias (trials may have overestimated the true effect of shunts treatment). We found no difference in the number of participants who died within 30 days of treatment, and the number that developed encephalopathy (disease of the brain due to toxins bypassing the liver to reach the brain), when surgical shunts were compared with radiologic shunt. We found evidence suggesting more harms with radiologic shunt when we considered the number of participants that died five years after treatment; or had repeat bleeding; or required repeated treatment; or had shunt blockage; that appeared to be more in the radiologic shunt group. Surgical shunts appear to be better than radiologic shunt for treating persistent and repeated bleeding due to varices in people with liver cirrhosis. Given the very low certainty of the evidence due to problems with design of the trials and inadequate number of participants, we are unsure if our conclusion is correct. Future trials with better design and adequate number of participants will likely produce results that are reliable.

10.1002/14651858.CD001023.pub3

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cochrane-simplification-train-2780

We included nine trials, with 316 participants in total, that compared the effects of naloxone versus placebo or no drug in newborn infants exposed to maternal opioid analgesia prior to delivery. None of the included trials investigated infants born to mothers who had used a prescribed or non-prescribed opioid during pregnancy. None of these trials specifically recruited infants with cardiorespiratory or neurological depression. The main outcomes reported were measures of respiratory function in the first six hours after birth. There is some evidence that naloxone increases alveolar ventilation. The trials did not assess the effect on the primary outcomes of this review (admission to a neonatal unit and failure to establish breastfeeding). The existing evidence from randomised controlled trials is insufficient to determine whether naloxone confers any important benefits to newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opioid. Given concerns about the safety of naloxone in this context, it may be appropriate to limit its use to randomised controlled trials that aim to resolve these uncertainties.

We found nine completed trials that compared giving to newborn babies, whose mothers had received opioids during labour, either naloxone or a placebo ('dummy drug'). These trials were conducted more than 30 years ago and they were generally very small including only about 300 infants in total. Most of the trials did not use reliable methods consistently. Evidence is up-to-date as of February 2018. The trials reported the effects of naloxone on the baby's breathing but did not assess the effect on the need for babies to be cared for in a neonatal unit (separated from their mother), whether they needed help with breathing, or on breastfeeding success. None of the trials assessed long-term development. We did not find any trials including babies born to mothers who had used opioids (whether prescribed or non-prescribed) during pregnancy. The available evidence was not sufficient to determine whether giving naloxone to babies whose mothers received opioids during birth was helpful or harmful.

10.1002/14651858.CD003483.pub3

cochrane-simplification-train-2781

cochrane-simplification-train-2781

We found no RCT and thus no available data for evaluation of the primary outcome (mortality) nor secondary outcomes or adverse effects. Therefore, we conducted no statistical analysis. A total of 73 observational studies reported on various clinically relevant outcomes following catheter removal or catheter retention. Most of these excluded, observational studies reported a beneficial effect of catheter removal in patients with candidaemia. None of the observational studies reported results in favour of retaining a catheter. However, the observational studies were very heterogeneous with regards to population, pathogens and interventions. Furthermore, they suffered from confounding by indication and an overall high risk of bias. As a consequence, we are not able to provide recommendations or to draw firm conclusions because of the difficulties involved in interpreting the results of these observational studies (very low quality of evidence, GRADE - Grades of Recommendation, Assessment, Development and Evaluation Working Group). Despite indications from observational studies in favour of early catheter removal, we found no eligible RCTs or quasi-RCTs to support these practices and therefore could draw no firm conclusions. At this stage, RCTs have provided no evidence to support the benefit of early or late catheter removal for survival or other important outcomes among patients with candidaemia; no evidence with regards to assessment of harm or benefit with prompt central venous catheter removal and subsequent re-insertion of new catheters to continue treatment; and no evidence on optimal timing of insertion of a new central venous catheter.

We found no clinical trials with a randomized controlled design that evaluated this topic and measured the number of deaths or any of our secondary outcomes. We identified 73 observational studies that delivered descriptive data on catheter management and survival in people with bloodstream infections caused by Candida. We identified no randomized controlled trials for statistical analyses and assessments. Therefore, we can present no results on the effect of catheter removal on survival when Candida is found in the bloodstream. A total of 73 observational studies reported relevant outcomes after the catheter was removed or was kept in place. In all, 40 studies reported a beneficial effect of catheter removal in patients with candidaemia, and 34 presented results showing no clear differences between groups. No studies reported results in favour of retaining the catheter. We found no reports on the harmful effects of removing a catheter and re-inserting a new catheter. No randomized controlled trials met the inclusion criteria. Consequently, we cannot assess the quality of evidence.

10.1002/14651858.CD011195.pub2

cochrane-simplification-train-2782

cochrane-simplification-train-2782

We included three RCTs (n=277) with 24-28 weeks follow-up. Three combinations of minerals were investigated: potassium-magnesium, calcium-magnesium, and calcium-potassium. One trial investigated combinations of calcium-magnesium and of calcium-potassium, and for each found a statistically non-significant increase in both SBP and DBP. All three trials investigated the potassium-magnesium combination. None of the trials provided mortality or morbidity data. The potassium-magnesium combination compared to control resulted in statistically non-significant reductions in both SBP (mean difference = -4.6 mmHg, 95% CI: -9.9 to 0.7) and DBP (mean difference = -3.8 mmHg, 95% CI: -9.5 to 1.8), although the results were heterogeneous (I2=68% and 85% for SBP and DBP respectively). A sensitivity analysis using alternative reported values which accounted for missing data had very little effect on DBP but resulted in a larger, statistically significant reduction in SBP (mean difference = -5.8 mmHg, 95% CI: -10.5 to -1.0). The quality of the trials was not well reported. We found no robust evidence that supplements of any combination of potassium, magnesium or calcium reduce mortality, morbidity or BP in adults. More trials are needed to investigate whether the combination of potassium & magnesium is effective.

This review found no robust evidence to suggest that combinations of potassium, calcium or magnesium can reduce high blood pressure (BP) in adults. Only three trials assessing a total of 277 participants were found. The only combination assessed by all three trials was potassium and magnesium, demonstrating a statistically non-significant reduction in BP among people receiving this combination. One trial assessed both calcium & magnesium and calcium & potassium and found that neither combination had very much effect on BP. None of the trials were of high quality, so their results may not be reliable. Very few mild adverse effects were reported. These were of short duration and participants did not have to stop taking their treatment.

10.1002/14651858.CD004805.pub2

cochrane-simplification-train-2783

cochrane-simplification-train-2783

Two small RCTs (total 42 patients) met the inclusion criteria and were included in the review. One study (18 patients) compared four weeks of treatment with a glutamine-enriched polymeric diet (42% amino acid composition) to a standard polymeric diet (4% amino acid composition) with low glutamine content in paediatric patients (< 18 years of age) with active Crohn's disease. The other study (24 patients) compared glutamine-supplemented total parenteral nutrition to non-supplemented total parenteral nutrition in adult patients (> 18 years of age) with acute exacerbation of inflammatory bowel disease. The paediatric study was rated as low risk of bias. The study in adult patients was rated as unclear risk of bias for blinding and low risk of bias for all other items. It was not possible to pool data for meta-analysis because of significant differences in study populations, nature of interventions, and the way outcomes were assessed. Data from one study showed no statistically significant difference in clinical remission rates at four weeks. Forty-four per cent (4/9) of patients who received a glutamine-enriched polymeric diet achieved remission compared to 56% (5/9) of patients who received a standard low-glutamine polymeric diet (RR 0.80, 95% CI 0.31 to 2.04). A GRADE analysis indicated that the overall quality of evidence for this outcome was low due to serious imprecision (9 events). In both included studies, no statistically significant changes in intestinal permeability were found between patients who received glutamine supplementation and those who did not. Neither study reported on clinical response, quality of life or growth in children. Adverse event data were not well documented. There were no serious adverse events in the paediatric study. The study in adult patients reported three central catheter infections with positive blood cultures in the glutamine group compared to none in the control group (RR 7.00, 95% CI 0.40 to 122.44). Currently there is insufficient evidence to allow firm conclusions regarding the efficacy and safety of glutamine for induction of remission in Crohn's disease. Data from two small studies suggest that glutamine supplementation may not be beneficial in active Crohn's disease but these results need to be interpreted with caution as they are based on small numbers of patients. This review highlights the need for adequately powered randomised controlled trials to investigate the efficacy and safety of glutamine for induction of remission in Crohn's disease.

The researchers identified two randomised controlled trials (total 42 participants) that investigated the role of glutamine for the treatment of active Crohn's disease. One study (18 patients) compared four weeks of treatment with a glutamine-enriched polymeric diet (42% amino acid composition) to a standard polymeric diet (4% amino acid composition) with low glutamine content in paediatric patients (< 18 years of age) with active Crohn's disease. Participants were encouraged to consume the diet orally. If this was not possible the diet was administered via a fine-bore nasogastric tube. The other study (24 participants) compared glutamine-supplemented total parenteral nutrition (TPN) to non-supplemented TPN in adult patients (> 18 years of age) with sudden worsening of inflammatory bowel disease. The TPN diet was administered intravenously via a central catheter (a thin tube) for at least one week. Both studies were generally high quality. Neither study demonstrated any beneficial effects for glutamine. Side effects were not well documented in the two studies. There were no serious side effects noted in the paediatric study. The study in adult patients reported three central catheter-related blood infections in the glutamine group compared to none in the non-glutamine control group. Currently, there is insufficient evidence to allow any firm conclusions regarding the effectiveness and harms of glutamine for the treatment of active Crohn's disease.

10.1002/14651858.CD007348.pub2

cochrane-simplification-train-2784

cochrane-simplification-train-2784

We included 18 RCTs involving 1014 infants. All studies were small and at high risk of bias, often presenting major shortcomings across multiple design factors (e.g. selection, performance, attrition, lack of washout period). Three studies compared simethicone with placebo, and one with Mentha piperita; four studies compared herbal agents with placebo; two compared sucrose or glucose with placebo; five compared dicyclomine with placebo; and two compared cimetropium - one against placebo and the other at two different dosages. One multiple-arm study compared sucrose and herbal tea versus no treatment. Simethicone. Comparison with placebo revealed no difference in daily hours of crying reported for simethicone at the end of treatment in one small, low-quality study involving 27 infants. A meta-analysis of data from two cross-over studies comparing simethicone with placebo showed no difference in the number of of infants who responded positively to treatment (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.73 to 1.23; 110 infants, low-quality evidence). One small study (30 participants) compared simethicone with Mentha piperita and found no difference in crying duration, number of crying episodes or number of responders. Herbal agents. We found low-quality evidence suggesting that herbal agents reduce the duration of crying compared with placebo (mean difference (MD) 1.33, 95% CI 0.71 to 1.96; three studies, 279 infants), with different magnitude of benefit noted across studies (I² = 96%). We found moderate-quality evidence indicating that herbal agents increase response over placebo (RR 2.05, 95% CI 1.56 to 2.70; three studies, 277 infants). Sucrose. One very low-quality study involving 35 infants reported that sucrose reduced hours spent crying compared with placebo (MD 1.72, 95% CI 1.38 to 2.06). Dicyclomine. We could consider only one of the five studies of dicyclomine (48 infants) for the primary comparison. In this study, more of the infants given dicyclomine responded than than those given placebo (RR 2.50, 95% CI 1.17 to 5.34). Cimetropium bromide. Data from one very low-quality study comparing cimetropium bromide with placebo showed reduced crying duration among infants treated with cimetropium bromide (MD -30.20 minutes per crisis, 95% CI -39.51 to -20.89; 86 infants). The same study reported that cimetropium increased the number of responders (RR 2.29, 95% CI 1.44 to 3.64). No serious adverse events were reported for all of the agents considered, with the exception of dicyclomine, for which two of five studies reported relevant adverse effects (longer sleep 4%, wide-eyed state 4%, drowsiness 13%). At the present time, evidence of the effectiveness of pain-relieving agents for the treatment of infantile colic is sparse and prone to bias. The few available studies included small sample sizes, and most had serious limitations. Benefits, when reported, were inconsistent. We found no evidence to support the use of simethicone as a pain-relieving agent for infantile colic. Available evidence shows that herbal agents, sugar, dicyclomine and cimetropium bromide cannot be recommended for infants with colic. Investigators must conduct RCTs using standardised measures that allow comparisons among pain-relieving agents and pooling of results across studies. Parents, who most often provide the intervention and assess the outcome, should always be blinded.

We found 18 randomised controlled trials (studies in which participants were randomly assigned to one of two or more treatment groups) involving 1014 infants with infantile colic. The evidence is current to May 2016. Infants were eight to 16 weeks old, and males and females were equally represented. All infants had colic, defined in one of two ways. Some studies defined it as inconsolable crying in otherwise healthy infants, lasting longer than three hours per day for more than three days a week for longer than three weeks. Other studies defined colic as attacks of screaming and crying (usually in the afternoon, or in the early evening) during which the infant failed to respond to any amount of comforting by adults. Four studies explored the effects of simethicone (a drug used to reduce excess gas in the intestinal tract); four studies looked at herbal agents (plant-derived remedies that might have relaxing properties that reduce cramps and pains in the bowel); two studies looked at sugar; and five studies explored the effects of dicyclomine and two the effects of cimetropium bromide (drugs that relieve bowel muscle spasms). One study compared sucrose and herbal tea in a group of infants who received no treatment for colic. Sixteen of 18 studies compared the intervention with a placebo. Among the other two studies, one compared simethicone with Mentha piperita, and the other compared two different dosages of cimetropium. Included studies received funding from different sources: a public institution (two studies), academic funds (one study) and private companies (three studies). Three studies received no funding. Nine studies did not report whether the study received funding. In four studies that reported no funds and no details about funds, private companies supplied the products (pain-relieving agents). Available data provide no evidence that sugar, dicyclomine and cimetropium are effective interventions in the treatment of colic. Some evidence suggests that, compared with placebo or no treatment, herbal agents may reduce crying time. However, because the quality of these studies was very poor and the extent of the benefit observed was variable, these results should be interpreted with caution. The same is true for sugar, dicyclomine and cimetropium, for which we judged the quality of evidence as low or very low. Studies that tested simethicone reported no benefit from administration of this drug over placebo. Two studies reported side effects for dicyclomine, for example, difficulty awakening, wide-eyed state and drowsiness. Studies of other pain-relieving agents reported no side effects as a result of treatment. Low-quality evidence indicates that infants with colic may benefit from treatment with sugar and cimetropium, and that herbal agents may reduce crying time. Moderate-quality evidence suggests that these agents increase the number of children experiencing improvement in symptoms. Overall, evidence is insufficient to allow firm conclusions about the benefits and side effects of the pain-relieving agents examined for treatment of crying due to infantile colic.

10.1002/14651858.CD009999.pub2

cochrane-simplification-train-2785

cochrane-simplification-train-2785

We included one randomized controlled trial on pharmacological interventions with 95 participants. No studies were found for non-pharmacological interventions. Concerning the proportion of participants with seizure freedom, no significant differences were found for the comparisons of levetiracetam (LEV) versus lamotrigine (LTG) (risk ratio (RR) 1.20, 95% confidence interval (CI) 0.53 to 2.71), LEV versus phenobarbital (PB) (RR 1.01, 95% CI 0.47 to 2.19), or LTG versus PB (RR 0.84, 95% CI 0.35 to 2.02). It seemed that LEV could improve cognition and LTG could relieve depression, while PB and LTG could worsen cognition, and LEV and PB could worsen mood. Unclear risk of bias was found in allocation, blinding and selective reporting. We judged the quality of the evidence to be very low. This review does not provide sufficient evidence to support LEV, PB or LTG for the treatment of epilepsy in people with AD. Regarding efficacy and tolerability, no significant differences were found between LEV, PB and LTG. Large randomized controlled trials with a double-blind, parallel-group design are required to determine the efficacy and tolerability of treatment for epilepsy in people with AD.

We searched scientific databases for clinical trials comparing medication and non-medication-based treatments for epilepsy in people with Alzheimer's disease. We wanted to evaluate how well the treatment worked and if it had any side effects. We included and analyzed one randomized controlled trial (a clinical study where people are randomly put into one or two or more treatment groups) with 95 participants. Concerning the proportion of participants with seizure freedom, no significant differences were found between the antiepileptic drugs (levetiracetam versus lamotrigine, levetiracetam versus phenobarbital, and lamotrigine versus phenobarbital). It seemed that levetiracetam could improve cognition (thinking) and lamotrigine could relieve depression; while phenobarbital and lamotrigine could worsen cognition, and levetiracetam and phenobarbital could worsen mood. The quality of the evidence from the study was very low and results should be interpreted with caution. Large randomized controlled trials, which have a double-blind parallel-group design, are required to determine how effective and well tolerated treatments are for epilepsy in people with Alzheimer's disease. The evidence is current to July 2018.

10.1002/14651858.CD011922.pub3

cochrane-simplification-train-2786

cochrane-simplification-train-2786

Eight studies involving 290 participants were included. Two trials examined the effects of captopril, the rest were single trials on single drugs. All comparisons were with placebo. The methodological quality of most trials was poor. Enalapril was associated with a small increase in the frequency of attacks per week (difference in means 0.8; 95% CI 0.43 to 1.17). The difference between the intervention groups on a subjective improvement score was non-significant. There was a significant effect of buflomedil on the frequency of attacks per week (weighted mean difference (WMD) -8.8; 95% CI -17.55 to -0.09), but there was no evidence of effect on the severity score. The proportion with fewer attacks was significantly higher on moxisylyte than on placebo (relative risk (RR) 4.33; 95% CI 1.36 to 13.81). For captopril, beraprost, dazoxiben and ketanserin there was no evidence of an effect on the frequency, severity or duration of attacks. Beraprost and moxisylyte gave significantly more adverse effects than placebo. Poor methodological quality, small sample sizes and the limited data available resulted in low precision of the statistical results and limited value of the overall results .The overall results show that there is no evidence for an effect of vasodilator drugs on primary Raynaud's phenomenon.

The review looked at the effectiveness of other drugs that can be taken by mouth. These were drugs that increase blood flow (vasodilators). The evidence from randomised controlled trials is limited. The review authors identified eight controlled studies. These were published between 1980 and 1996 and involved a total of 290 participants randomly assigned to the vasodilator drug or placebo. The length of treatment varied from two weeks to six months. Only two trials looked at the same drug, the angiotensin converting enzyme (ACE) inhibitor captopril so most of the findings were from single trials. Taking enalapril resulted in a small increase in the frequency of attacks in a week. Buflomedil reduced the frequency of attacks but without a clear effect on their severity. Moxisylyte (thymoxamine) also reduced attacks but both beraprost and moxisylyte produced more adverse effects than with placebo. For captopril, beraprost, dazoxiben and ketanserin there was no evidence of an effect on the frequency, severity or duration of attacks. The methodological quality of most trials was poor and they were small. The outcomes were subjective and were reported on scales that were not well described or validated. This makes the clinical importance of the results difficult to assess, especially if the placebo response is high.

10.1002/14651858.CD006687.pub3

cochrane-simplification-train-2787

cochrane-simplification-train-2787

We identified 47 studies (4 of which are new to this review), involving approximately 1,223,856 children. Studies took place in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most of the studies included equal numbers of girls and boys and lasted about a year. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for vitamin A compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-quality evidence). This result was sensitive to choice of model, and a random-effects meta-analysis showed a different summary estimate (24% reduction: RR 0.76, 95% CI 0.66 to 0.88); however, the confidence intervals overlapped with that of the fixed-effect model. Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 participants; high-quality evidence). There was no significant effect for VAS on mortality due to measles, respiratory disease, and meningitis. VAS reduced incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies; 77,946 participants; low-quality evidence) and measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies; 19,566 participants; moderate-quality evidence). However, there was no significant effect on incidence of respiratory disease or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies; 10,541 participants; moderate-quality evidence). Vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children. Therefore, we suggest maintaining the policy of universal supplementation for children under five years of age in populations at risk of VAD. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented vitamin A deficiency, it would be unethical to conduct placebo-controlled trials.

This review includes 47 RCTs representing 1,223,856 children. Studies took place in 19 countries: 30 (63%) in Asia, 16 of which were in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. The average age of children was about 33 months. Most of the studies included equal numbers of boys and girls and lasted about a year. The quality of the included studies was variable; however, it was unlikely that death rates were influenced by potential errors in the conduct of the studies. Data on the effect of VAS for the prevention of death were available from 19 of the included studies, and the combined results indicate that vitamin A reduces overall risk of death and death due to diarrhoea by 12%. Vitamin A does not specifically reduce death due to measles, respiratory infections, or meningitis, but it can reduce new occurrences of diarrhoea and measles. Giving oral synthetic vitamin A to children at risk of VAD reduces the risk of night blindness. It also improves levels of vitamin A in their blood. The only reported side effect was risk of vomiting within 48 hours of taking vitamin A in large doses, as recommended by the World Health Organization. We rated the overall quality of the evidence using the GRADE approach, which considers methodological flaws within studies, consistency in reporting of results across studies, extent to which results apply to other settings, and effectiveness of treatments. Based on these criteria, we judged the overall quality of the evidence to be high for benefits of VAS against overall risk of death and death due to diarrhoea. For the rest of the outcomes, we rated the evidence as low or moderate. One large, recently conducted study, which included about 1 million children, did not show any effect of VAS; however, when this study was combined with other, well-conducted studies, VAS still had beneficial effects for the prevention of death and illness. In summary, VAS can reduce risk of illness and death in children aged 6 to 59 months of age who are at risk of VAD.

10.1002/14651858.CD008524.pub3

cochrane-simplification-train-2788

cochrane-simplification-train-2788

This review includes 18 randomised controlled trials (14 new to this version), reported in 26 papers, involving 928 children and adolescents with RAP between the ages of 6 and 18 years. The interventions were classified into four types of psychosocial therapy: cognitive behavioural therapy (CBT), hypnotherapy (including guided imagery), yoga, and written self-disclosure. The studies were carried out in the USA, Australia, Canada, the Netherlands, Germany, and Brazil. The majority of the studies were small and short term; only two studies included more than 100 participants, and only five studies had follow-up assessments beyond six months. Small sample sizes and the degree of assessed risk of performance and detection bias in many studies led to the overall quality of the evidence being rated as low to very low for all outcomes. For CBT compared to control, we found evidence of treatment success postintervention (odds ratio (OR) 5.67, 95% confidence interval (CI) 1.18 to 27.32; Z = 2.16; P = 0.03; 4 studies; 175 children; very low-quality evidence), but no evidence of treatment success at medium-term follow-up (OR 3.08, 95% CI 0.93 to 10.16; Z = 1.85; P = 0.06; 3 studies; 139 children; low-quality evidence) or long-term follow-up (OR 1.29, 95% CI 0.50 to 3.33; Z = 0.53; P = 0.60; 2 studies; 120 children; low-quality evidence). We found no evidence of effects of intervention on pain intensity scores measured postintervention (standardised mean difference (SMD) -0.33, 95% CI -0.74 to 0.08; 7 studies; 405 children; low-quality evidence), or at medium-term follow-up (SMD -0.32, 95% CI -0.85 to 0.20; 4 studies; 301 children; low-quality evidence). For hypnotherapy (including studies of guided imagery) compared to control, we found evidence of greater treatment success postintervention (OR 6.78, 95% CI 2.41 to 19.07; Z = 3.63; P = 0.0003; 4 studies; 146 children; low-quality evidence) as well as reductions in pain intensity (SMD -1.01, 95% CI -1.41 to -0.61; Z = 4.97; P < 0.00001; 4 studies; 146 children; low-quality evidence) and pain frequency (SMD -1.28, 95% CI -1.84 to -0.72; Z = 4.48; P < 0.00001; 4 studies; 146 children; low-quality evidence). The only study of long-term effect reported continued benefit of hypnotherapy compared to usual care after five years, with 68% reporting treatment success compared to 20% of controls (P = 0.005). For yoga therapy compared to control, we found no evidence of effectiveness on pain intensity reduction postintervention (SMD -0.31, 95% CI -0.67 to 0.05; Z = 1.69; P = 0.09; 3 studies; 122 children; low-quality evidence). The single study of written self-disclosure therapy reported no benefit for pain. There was no evidence of effect from the pooled analyses for any type of intervention on the secondary outcomes of school performance, social or psychological functioning, and quality of daily life. There were no adverse effects for any of the interventions reported. The data from trials to date provide some evidence for beneficial effects of CBT and hypnotherapy in reducing pain in the short term in children and adolescents presenting with RAP. There was no evidence for the effectiveness of yoga therapy or written self-disclosure therapy. There were insufficient data to explore effects of treatment by RAP subtype. Higher-quality, longer-duration trials are needed to fully investigate the effectiveness of psychosocial interventions. Identifying the active components of the interventions and establishing whether benefits are sustained in the long term are areas of priority. Future research studies would benefit from employing active control groups to help minimise potential bias from wait-list control designs and to help account for therapist and intervention time.

As of June 2016, we identified 18 randomised controlled trials (a type of scientific experiment in which people are randomly assigned to one of two or more treatments), which included 928 children and adolescents between the ages of 6 and 18 years. These studies compared a range of psychosocial therapy to usual care or some form of non-therapy control (such as education or breathing exercises). We identified four different kinds of psychosocial therapy: cognitive behavioural therapy, hypnotherapy, yoga, and written self-disclosure (a therapy that involves writing down thoughts and feelings about something distressing). The duration of the included studies ranged from five days to three months. The studies were conducted in the USA, Australia, Canada, the Netherlands, Germany, and Brazil. We found that cognitive behavioural therapy and hypnotherapy may be effective in terms of reducing pain in the short term. There was little evidence of long-term benefit. There was no evidence that either therapy had a beneficial effect on quality of life, daily activities, or psychological outcomes such as anxiety and depression. Yoga therapy and written self-disclosure as a therapy had no effect on pain, quality of life, or daily activities. No adverse effects were reported from any of these therapies. We rated the overall quality of the evidence as low to very low for all outcomes. Many of the studies had small sample sizes or weaknesses in their study design. The authors reported no conflicts of interest in relation to funding. Cognitive behavioural therapy and hypnotherapy warrant consideration by clinicians as part of the management strategy for children with recurrent abdominal pain. The overall quality of the evidence was low to very low. More high-quality research is needed to evaluate the particular aspects of the therapies that are effective and to establish whether benefits are maintained over time.

10.1002/14651858.CD010971.pub2

cochrane-simplification-train-2789

cochrane-simplification-train-2789

We included 5 RCTs involving a total of 103 participants; all of the trials used a within-participant design. The interventions and outcomes were too varied to be combined statistically. All trials used the pulsed dye laser for comparisons. None of the studies focused on participant satisfaction, which was one of our primary outcomes, but participant preference was evaluated in three of five studies. Participants preferred the pulsed dye laser to intense pulsed light based on the clinical effect. They marginally preferred the Neodymium:YAG (yttrium-aluminium-garnet) (Nd:YAG) laser to the pulsed dye laser due to shorter lasting purpura, and pulsed dye laser in conjunction with cooling was preferred to treatment with pulsed dye laser alone. All trials examined short-term efficacy of less than six months after treatments with the pulsed dye laser, intense pulsed light, and Nd:YAG laser. The pulsed dye laser was evaluated in all five trials. Depending upon the setting of the pulsed dye laser, this resulted in more than 25% reduction in redness. This was after 1 to 3 treatments for up to 4 to 6 months postoperatively in 50% to 100% of the participants. There was only one study each of intense pulsed light and Nd:YAG laser. Two trials had no occurrence of long-term adverse effects, i.e. six months after treatment. Three trials reported pigmentary alterations in 3% to 24% of the participants, with the highest percentage occurring in Chinese participants with darker skin types. In one study one participant experienced scarring of the skin caused by a too-high dose of the laser used. Short-term side-effects included pain, crusting, and blistering in the first two weeks after treatment. The pulsed dye laser leads to clinically relevant clearance of port-wine stains. A limited number of RCTs evaluated the efficacy from intense pulsed light and other laser types. High-quality RCTs are needed to assess individual efficacy from different lasers and light sources, as well as participant satisfaction.

None of the studies focused on participant satisfaction which was our primary outcome. Depending upon the setting of the pulsed dye laser, more than 25% lightening (i.e. by reduction in redness) of port-wine stains occurred. This was after 1 to 3 treatments for up to 4 to 6 months postoperatively in 50% to 100% of the participants of the trials. Substantial evidence is lacking for other laser types and intense pulsed light. Side-effects were rare in the included trials, but 3 trials reported pigmentary alterations in 3% to 24% of the participants, with the highest percentage occurring in Chinese participants with darker skin types. In one study one participant experienced scarring of the skin due to a too-high dose of the laser used. Short-term side-effects included pain, crusting, and blistering in the first two weeks after treatment. Two trials reported no occurrence of long-term adverse effects, i.e. six months after treatment.

10.1002/14651858.CD007152.pub2

cochrane-simplification-train-2790

cochrane-simplification-train-2790

Twenty four studies, including 2147 participants, met the inclusion criteria. Comparing any dopamine agonist versus placebo, we found no differences for any of the outcomes considered: dropout (moderate quality of evidence), abstinence (low quality of evidence), severity of dependence (low quality of evidence), adverse events (moderate quality of evidence). This was also observed when single dopamine agonists were compared against placebo. Comparing amantadine versus antidepressants, we found low quality of evidence that antidepressants performed better for abstinence (RR 0.25, 95% CI 0.12 to 0.53) based on two studies with 44 participants. No differences were found for dropout or adverse events, for both moderate quality of evidence. The major flaws of the included studies concerned selection bias because most studies did not report information about sequence generation (80%) and allocation concealment methods (86%): half of the included studies were judged at unclear risk of performance bias and 62.5% at unclear risk of detection bias for what concerns subjective outcomes. Current evidence from RCTs does not support the use of dopamine agonists for treating cocaine misuse. This absence of evidence may leave to clinicians the alternative of balancing the possible benefits against the potential adverse effects of the treatment. Even the potential benefit of combining a dopamine agonist with a more potent psychosocial intervention, which was suggested by the previous Cochrane Review (Soares 2003), is not supported by the results of this Cochrane Review update.

We searched scientific databases and internet resources to identify randomised controlled trials (where participants are allocated at random to any dopamine agonist drug or placebo or another type of drug aimed to reduce use of cocaine. We also assessed dropout from treatment and frequency of side effects. We included adults of any gender, age or ethnicity. We included 24 studies with 2147 participants, who were all addicted to cocaine. Most were men (82.%)with an average age of 37 years. The mean duration of the included trials was seven weeks (range 1.5 to 16 weeks) Twenty-two studies were conducted in USA, one in Brazil and one in Spain; all but four were outpatients. The included trials studied the following drugs: amantadine, bromocriptine, L dopa/Carbidopa, pergolide, cabergoline hydergine, and pramipexole. All compared dopamine agonist versus placebo. Four studies compared amantidine versus antidepressants. No differences were found between the drugs and placebo for any of the outcomes considered: dropout (moderate quality of evidence), abstinence (low quality of evidence), severity of dependence (low quality of evidence), adverse events (moderate quality of evidence). Antidepressants was found to be better than the dopamine agonist amantidine for abstinence, but this was based on two studies with very few participants and low quality of evidence. There is no current evidence supporting the clinical use of dopamine agonist medications in the treatment of cocaine misuse. The evidence is current to 12 January 2015.

10.1002/14651858.CD003352.pub4

cochrane-simplification-train-2791

cochrane-simplification-train-2791

We included two studies with 72 participants. Overall, the two studies were at moderate risk of bias. The evidence was derived from group mean data and completer analysis (very low quality evidence overall). We rated the quality of all outcomes according to GRADE as very low due to indirectness, imprecision and potential reporting bias. The primary outcomes in our review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Nabilone was compared to placebo and to amitriptyline in one study each. Study sizes were 32 and 40 participants. One study used a cross-over design and one used a parallel group design; study duration was four or six weeks. Both studies used nabilone, a synthetic cannabinoid, with a bedtime dosage of 1 mg/day. No study reported the proportion of participants experiencing at least 30% or 50% pain relief or who were very much improved. No study provided first or second tier (high to moderate quality) evidence for an outcome of efficacy, tolerability and safety. Third tier (very low quality) evidence indicated greater reduction of pain and limitations of HRQoL compared to placebo in one study. There were no significant differences to placebo noted for fatigue and depression (very low quality evidence). Third tier evidence indicated better effects of nabilone on sleep than amitriptyline (very low quality evidence). There were no significant differences between the two drugs noted for pain, mood and HRQoL (very low quality evidence). More participants dropped out due to adverse events in the nabilone groups (4/52 participants) than in the control groups (1/20 in placebo and 0/32 in amitriptyline group). The most frequent adverse events were dizziness, nausea, dry mouth and drowsiness (six participants with nabilone). Neither study reported serious adverse events during the period of both studies. We planned to create a GRADE 'Summary of findings' table, but due to the scarcity of data we were unable to do this. We found no relevant study with herbal cannabis, plant-based cannabinoids or synthetic cannabinoids other than nabilone in fibromyalgia. We found no convincing, unbiased, high quality evidence suggesting that nabilone is of value in treating people with fibromyalgia. The tolerability of nabilone was low in people with fibromyalgia.

In April 2016 we searched for reports of clinical trials that used cannabis products to treat symptoms in adults with fibromyalgia. We found two small, moderate quality studies, of four and six weeks long, including 72 participants. Both studies tested nabilone, a synthetic (man-made) cannabis product, comparing it with placebo (a dummy pill) or amitriptyline (an antidepressant frequently used in the treatment of fibromyalgia). Nabilone did not convincingly relieve fibromyalgia symptoms (pain, sleep, fatigue) better than placebo or amitriptyline (very low quality evidence). Compared with placebo and amitriptyline, more people experienced side effects and left the study due to side effects (very low quality evidence). There were no serious side effects reported. We found no relevant study with herbal cannabis, plant-based cannabinoids or other synthetic cannabinoids than nabilone in fibromyalgia. There was not enough high quality evidence available to draw any robust conclusions. We found no studies on medical cannabis in fibromyalgia.

10.1002/14651858.CD011694.pub2

cochrane-simplification-train-2792

cochrane-simplification-train-2792

Nine randomized, double-blind, placebo controlled trials meeting the inclusion criteria were identified. Eight trials enrolled healthy participants, and one was of subjects with age-associated memory impairment (AAMI). Only five of the identified trials had extractable information and were included in the analysis. Four studies investigated the effects of ginseng extract and one assessed the efficacy of ginseng compound HT008-1. All of these trials investigated the effects of ginseng on healthy participants. Pooling the data was impossible owing to heterogeneity in outcome measures, trial duration, and ginseng dosage. Results of the analysis suggested improvement of some aspects of cognitive function, behavior and quality of life. No serious adverse events associated with ginseng were found. Currently, there is a lack of convincing evidence to show a cognitive enhancing effect of Panax ginseng in healthy participants and no high quality evidence about its efficacy in patients with dementia. Randomized, double-blind, placebo-controlled, parallel group trials with large sample sizes are needed to further investigate the effect of ginseng on cognition in different populations, including dementia patients.

This review aimed to identify all double-blind and single-blind randomized, placebo-controlled trials assessing the effects of ginseng on cognitive function. Five trials investigating the effects of ginseng on healthy participants had extractable information for efficacy and were included in the review. Ginseng appeared to have some beneficial effects on cognition, behavior and quality of life. More rigorously designed studies are needed on this important issue.

10.1002/14651858.CD007769.pub2

cochrane-simplification-train-2793

cochrane-simplification-train-2793

The review currently includes two short-term low-quality randomised trials (total n=508) both comparing sertindole with risperidone. One third of participants left the studies early (2 RCTs, n=504, RR 1.23 CI 0.94 to 1.60). There was no difference in efficacy (2 RCTs, n=493, WMD PANSS total change from baseline 1.98 CI -8.24 to 12.20). Compared with relatively high doses of risperidone (between 4 and 12 mg/day), sertindole produced significantly less akathisia and parkinsonism (1 RCT, n=321, RR 0.24 CI 0.09 to 0.69, NNT 14, CI 8 to 100). Sertindole produced more cardiac effects (2 RCTs, n=508, RR QTc prolongation 4.86 CI 1.94 to 12.18), weight change (2 RCTs, n=328, WMD 0.99 CI 0.12 to 1.86) and male sexual dysfunction (2 RCTs, n=437, RR 2.90 CI 1.32 to 6.35, NNH 13 CI 8 to 33). Sertindole may induce fewer movement disorders, but more cardiac effects, weight change and male sexual dysfunction than risperidone. However these data are based on only two studies and are too limited to allow firm conclusions. Nothing can be said about the effects of sertindole compared with second generation antipsychotics other than risperidone. There are several relevant trials underway or completed and about to report.

This review aims to compare sertindole to the other newer second generation (atypical) antipsychotics in people who have schizophrenia. Two studies were identified which included 508 people. Both compared sertindole to risperidone, were short (12 weeks) and the participants were either at least moderately ill or treatment resistant. There was no overall significant difference between these two medications in terms of improvement in people’s general well-being or their mental state. Also while people on risperidone showed more movement side-effects, those on sertindole were more likely to put on weight, have changes in their heart rhythm and the men were more likely to suffer from sexual dysfunction. The data from these trials are limited and a considerable number of the participants left the study early. In addition, sertindole has only been compared to one second generation antipsychotic and the trials are relatively short. A larger and longer trial comparing sertindole to other second generation antipsychotics, with the outcomes including mental state, general functioning, adverse effects and quality of life, would enhance our knowledge in this area considerably. (Plain language summary prepared for this review by Janey Antoniou of RETHINK, UK www.rethink.org).

10.1002/14651858.CD006752.pub2

cochrane-simplification-train-2794

cochrane-simplification-train-2794

This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I2 = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I2 = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I2 = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I2 = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I2 = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I2 = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I2 = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I2 = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose. Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.

In this updated review we included 38 controlled trials comparing LOD with medical ovulation induction or comparing different techniques of LOD. The evidence is current to October 2019 Our main analysis with low-quality evidence shows that LOD with and without medical ovulation induction may decrease the live birth rate slightly in women with anovulatory PCOS and CC-resistance compared with medical ovulation induction alone. Analysis including only the higher-quality RCTs shows uncertainty about any difference between the treatments. The evidence suggests that if the chance of live birth following medical ovulation induction alone is 44%, the chance following LOD would be between 32% and 52%. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancies. The evidence suggests that if we assume the chance of a multiple pregnancy following medical ovulation induction alone to be 5.0%, the chance following LOD would be between 0.9% and 3.4%. There may be little or no difference between the treatments for clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. Ovarian hyperstimulation syndrome (OHSS) may occur less often following LOD. The quality of the evidence is not sufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage for the analysis of unilateral LOD versus bilateral LOD. The results of the primary outcomes for the other interventions were insufficient to enable us to draw any conclusions. The evidence was of very low to moderate quality. The main limitations in the evidence were poor reporting of study methods, the presence of bias introduced by the selection of individuals and variability in the results.

10.1002/14651858.CD001122.pub5

cochrane-simplification-train-2795

cochrane-simplification-train-2795

We identified four studies that met the inclusion criteria: three randomized controlled trials and a pilot study for one of the included trials. The interventions differed markedly: computer-delivered, individually tailored sessions; phone counseling added to clinic counseling; and case management plus a peer-leadership program. The latter study, which addressed multiple risks, showed an effect on contraceptive use. Compared to the control group, the intervention group was more likely to report consistent dual-method use, i.e., oral contraceptives and condoms. The reported relative risk was 1.58 at 12 months (95% CI 1.03 to 2.43) and 1.36 at 24 months (95% CI 1.01 to 1.85). The related pilot study showed more reporting of consistent dual-method use for the intervention group compared to the control group (reported P value = 0.06); the investigators used a higher alpha (P < 0.10) for this pilot study. The other two trials did not show any significant difference between the study groups in reported dual-method use or in test results for pregnancy or STIs at 12 or 24 months. We found few behavioral interventions for improving dual-method contraceptive use and little evidence of effectiveness. A multifaceted program showed some effect but only had self-reported outcomes. Two trials were more applicable to clinical settings and had objective outcomes measures, but neither showed any effect. The included studies had adequate information on intervention fidelity and sufficient follow-up periods for change to occur. However, the overall quality of evidence was considered low. Two trials had design limitations and two had high losses to follow up, as often occurs in contraceptive trials. Good quality studies are still needed of carefully designed and implemented programs or services.

Through January 2014, we did computer searches for studies of programs to improve use of dual-methods. We wrote to researchers to find missing data. Studies examined a behavioral intervention for improving dual-method use. The educational program had to address preventing pregnancy and HIV/STI by using condoms plus another modern contraceptive. The intervention was compared with a different program, usual care, or no intervention. We only found four studies to include. Three were randomized trials and the fourth was a pilot study for one of the included trials. The programs differed from one another. They included computer-delivered sessions tailored for each person; phone counseling added to clinic counseling; and case management plus a peer-leadership program. In the latter study, more women in the intervention group reported regular use of dual methods, namely birth control pills plus condoms, than the control group. The pilot study reported a trend toward more regular dual-method use for the intervention group compared to the control group. The other two trials did not show any major difference between the study groups in reported use of dual methods or in test results for pregnancy or STIs. We found few programs to improve use of dual methods, and only one showed an effect. The reports gave enough information on how the interventions were conducted. The studies had adequate follow-up periods of 12 to 24 months. However, the overall quality of results was low, mainly due to study design and losing many women to follow up.

10.1002/14651858.CD010915.pub2

cochrane-simplification-train-2796

cochrane-simplification-train-2796

Six RCTs involving 439 participants with dementia were included in the review, but no studies of participants with MCI were identified. The studies included people with dementia living in the community or in nursing home care and were carried out in several countries. Only one of the studies was classified as low risk of bias. Five studies were at unclear or high risk of bias due to uncertainties around randomisation, blinding and selective reporting of results. The studies used the different psychological approaches of cognitive behavioural therapy (CBT), interpersonal therapy and counselling. Two studies were of multimodal interventions including a specific psychological therapy. The comparison groups received either usual care, attention-control educational programs, diagnostic feedback or services slightly above usual care. Meta-analysis showed a positive effect of psychological treatments on depression (6 trials, 439 participants, standardised mean difference (SMD) -0.22; 95% confidence interval (CI) -0.41 to -0.03, moderate quality evidence) and on clinician-rated anxiety (2 trials, 65 participants, mean difference (MD) -4.57; 95% CI -7.81 to -1.32, low quality evidence), but not on self-rated anxiety (2 trials, SMD 0.05; 95% CI -0.44 to 0.54) or carer-rated anxiety (1 trial, MD -2.40; 95% CI -4.96 to 0.16). Results were compatible with both benefit and harm on the secondary outcomes of patient quality of life, activities of daily living (ADLs), neuropsychiatric symptoms and cognition, or on carers' self-rated depressive symptoms, but most of the studies did not measure these outcomes. There were no reports of adverse events. We found evidence that psychological interventions added to usual care can reduce symptoms of depression and clinician-rated anxiety for people with dementia. We conclude that psychological interventions have the potential to improve patient well-being. Further high quality studies are needed to investigate which treatments are most effective and to evaluate the effect of psychological interventions in people with MCI.

This review identified six randomised controlled trials, including 439 participants, in which a psychological treatment for people with dementia was compared to usual care. Most participants had mild dementia, but one trial was conducted with nursing home residents who had more severe dementia. We found no trials of participants with MCI. The psychological interventions used were based on established psychological models such as cognitive behavioural therapy (CBT), counselling, and interpersonal psychodynamic therapy. In two trials, the psychological treatment was combined with other interventions. We found evidence that psychological treatments can reduce depressive symptoms in people with dementia. There was also some evidence from two trials that CBT may reduce clinician-rated anxiety symptoms in people with mild dementia. Due to the imprecision of our results, we could not tell whether psychological treatments had an effect on patients' quality of life, ability to perform daily activities, overall psychiatric symptoms, or cognition, or on carers' self-rated depressive symptoms, but most studies did not measure these outcomes. Although these results are promising, the small number of studies and the variation between them in the type and duration of treatment make it difficult to draw conclusions about the best way to provide psychological treatment for people with dementia who have symptoms of depression or anxiety. More high quality trials in this area would be beneficial, including trials involving participants with MCI.

10.1002/14651858.CD009125.pub2

cochrane-simplification-train-2797

cochrane-simplification-train-2797

We included one study involving 15 participants from the UK. The included participants were diagnosed with delirium based on the Confusion Assessment Method (CAM) criteria. Eight males and seven females were included, with a mean age of 82.5 years. Seven of the 15 participants had comorbid dementia at baseline. The risk of bias was low in all domains. The study compared rivastigmine with placebo. We did not find any clear differences between the two groups in terms of duration of delirium (MD -3.6, 95% CI -15.6 to 8.4), adverse events (nausea, RR 0.30, 95% CI 0.01 to 6.29), use of rescue medications (RR 0.13, 95% CI 0.01 to 2.1), mortality (RR 0.10, 95% CI 0.01 to 1.56), and leaving the study early (RR 0.88, 95% CI 0.07 to 11.54). Evidence was not available regarding the severity of delirium, persistent cognitive impairment, length of hospitalisation, cost of intervention, or other predefined secondary outcomes. The quality of evidence is low due to the very small sample size. There is insufficient evidence to support or refute the use of cholinesterase inhibitors for the treatment of delirium in non-ICU settings. No clear benefits or harms associated with cholinesterase inhibitors were observed when compared with placebo due to the lack of data. More trials are required.

We found one trial from the UK, which included 15 participants with delirium. The average age of the participants was 82.5 years; eight participants were male and seven were female. Seven participants also had a history of dementia. This trial compared rivastigmine (a type of cholinesterase inhibitor used in the treatment of dementia) with an inactive treatment (placebo). The trial did not show any difference in effect between those participants given rivastigmine and those given placebo. The study was conducted and reported appropriately, but the small number of participants limits any conclusions that could be made about rivastigmine as a treatment for delirium.

10.1002/14651858.CD012494.pub2

cochrane-simplification-train-2798

cochrane-simplification-train-2798

Four trials including a total of 1447 young offenders were included in the review. Results failed to find a significant effect for restorative justice conferencing over normal court procedures for any of the main analyses, including number re-arrested (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.59 to 1.71; P = 0.99), monthly rate of reoffending (standardised mean difference (SMD) -0.06, 95% CI -0.28 to 0.16; P = 0.61), young person’s remorse following conference (OR 1.73, 95% CI 0.97 to 3.10; P = 0.06), young person's recognition of wrongdoing following conference (OR 1.97, 95% CI 0.81 to 4.80; P = 0.14), young person's self-perception following conference (OR 0.95, 95% CI 0.55 to 1.63; P = 0.85), young person's satisfaction following conference (OR 0.42, 95% CI 0.04 to 4.07; P = 0.45) and victim's satisfaction following conference (OR 4.05, 95% CI 0.56 to 29.04; P = 0.16). A small number of sensitivity analyses did indicate significant effects, although all are to be interpreted with caution. There is currently a lack of high quality evidence regarding the effectiveness of restorative justice conferencing for young offenders. Caution is urged in interpreting the results of this review considering the small number of included studies, subsequent low power and high risk of bias. The effects may potentially be more evident for victims than offenders. The need for further research in this area is highlighted.

The purpose of this review was to look at whether young people who are part of a restorative justice conference are less likely to reoffend than those who go through normal court proceedings. Four randomised controlled trials were included in this review. Findings indicate that there was no difference between those who are part of restorative justice conferences and those in normal court proceedings in terms of the rate of reoffending after the intervention. There was also no difference between these two groups in terms of a change in their self-esteem or their satisfaction with the process. Results may indicate that victims who are part of a restorative conference are more satisfied than those who are part of court proceedings. The quality of the included studies was low. More high quality research using a design where participants are randomly allocated to an intervention or control group is needed.

10.1002/14651858.CD008898.pub2

cochrane-simplification-train-2799

cochrane-simplification-train-2799

We included a total of 20 heterogeneous studies (2012 participants with acute ankle sprains); three of which included more than one comparison. Seventeen trials were conducted in China. All of the studies had a high risk of bias due to lack of blinding. The results may also have been affected by selection bias, particularly as five studies were quasi-randomised controlled trials and 12 studies gave no information on their method of randomisation. Of our three prespecified primary outcomes, only cure rate was reported by the majority of studies. No study reported on patient-reported assessment of function and only one reported on adverse events (in which three participants receiving a control intervention experienced skin problems from over-the-counter Chinese herbal patches). The other 19 studies did not record or report on adverse events. We assessed the quality of evidence for cure rates as very low for all comparisons, which means we are very uncertain about the reliability of any of the estimates. The single study comparing acupuncture treatment with no treatment found acupuncture to be more effective with regard to cure rate at five days (31/31 versus 1/30; RR 20.34, 95% CI 4.27 to 96.68). Acupuncture plus another standard treatment versus that standard treatment alone was tested in eight studies; with cure rate data available for seven. Most of these studies reported higher cure rates in the acupuncture plus another standard treatment group than in the standard treatment alone group. However, while the results of an exploratory meta-analysis of cure rate data from eight trials testing acupuncture versus no acupuncture tended to favour acupuncture, the results were very inconsistent across the studies and the estimated effect was very imprecise (383/396 versus 272/355; RR 1.32, 95% CI 0.95 to 1.84; P value = 0.1; I2 = 98%). Fourteen studies compared acupuncture with a variety of other non-surgical treatments, such as Chinese drug patches, hot and cold water, ice packs, oral Chinese herbal medicine and elastic bandage. Some studies found in favour of acupuncture, some in favour of the other treatment and some found a lack of evidence for a difference between the two interventions under test. The results of an exploratory meta-analysis of cure rate data from 11 trials testing acupuncture versus another non-surgical intervention tended to slightly favour acupuncture, but these were not statistically significant and the data were very heterogeneous (404/509 versus 416/497; RR 1.07, 95% CI 0.94 to 1.22; P value = 0.30; I2 = 92%). The currently available evidence from a very heterogeneous group of randomised and quasi-randomised controlled trials evaluating the effects of acupuncture for the treatment of acute ankle sprains does not provide reliable support for either the effectiveness or safety of acupuncture treatments, alone or in combination with other non-surgical interventions; or in comparison with other non-surgical interventions. Future rigorous randomised clinical trials with larger sample sizes will be necessary to establish robust clinical evidence concerning the effectiveness and safety of acupuncture treatment for acute ankle sprains.

Our review includes 20 studies involving 2012 people with ankle sprains. These studies differed from each other in many ways and compared various types of acupuncture with a variety of standard control interventions. Most studies reported only the 'cure rate' - the number of participants who had recovered at a set time. No study reported on patient-reported assessment of function. Only one study reported on adverse events and found skin problems in individuals receiving over-the-counter traditional Chinese herbal patches as a control intervention. Most trials had flaws in the way they were conducted, which makes their results less reliable; for example, most studies failed to ensure participants did not know which intervention they were receiving. One study, which compared acupuncture with no treatment, found more people were cured with acupuncture. Most of the eight studies comparing acupuncture plus another standard treatment versus that standard treatment alone found higher cure rates in the acupuncture group. However, we found that pooling these results did not provide conclusive evidence that acupuncture resulted in a better cure rate. Fourteen studies compared acupuncture with a variety of other non-surgical treatments, such as Chinese herbal patches, hot and cold water, ice packs, Chinese oral herbal medicine and elastic bandages. Some studies found in favour of acupuncture, some in favour of the other treatment and some found a lack of evidence for a difference between the two interventions under test. The pooled results from 11 studies comparing acupuncture versus another non-surgical intervention tended to favour acupuncture, but this evidence was not conclusive. Currently, we are unable to conclude whether or not acupuncture is more effective than other standard methods for the treatment of ankle sprains in adults because of the very low quality of the available evidence. Because the adverse effects of acupuncture treatment were not described in most of the studies, we are also unable to draw any conclusions about the safety of acupuncture. Large, high quality studies of acupuncture for sudden-onset ankle sprains in adults are needed.

10.1002/14651858.CD009065.pub2