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cochrane-simplification-train-100

cochrane-simplification-train-100

The search retrieved 126 trials; 10 fulfilled the inclusion criteria and we included them in the review (a total sample of 510 participants). Seven studies were considered to have low risk of bias, and three were considered as high risk of bias. A total of six trials compared Pilates to minimal intervention. There is low quality evidence that Pilates reduces pain compared with minimal intervention, with a medium effect size at short-term follow-up (less than three months after randomisation) (MD -14.05, 95% confidence interval (CI) -18.91 to -9.19). For intermediate-term follow-up (at least three months but less than 12 months after randomisation), two trials provided moderate quality evidence that Pilates reduces pain compared to minimal intervention, with a medium effect size (MD -10.54, 95% CI -18.46 to -2.62). Based on five trials, there is low quality evidence that Pilates improves disability compared with minimal intervention, with a small effect size at short-term follow-up (MD -7.95, 95% CI -13.23 to -2.67), and moderate quality evidence for an intermediate-term effect with a medium effect size (MD -11.17, 95% CI -18.41 to -3.92). Based on one trial and low quality evidence, a significant short-term effect with a small effect size was reported for function (MD 1.10, 95% CI 0.23 to 1.97) and global impression of recovery (MD 1.50, 95% CI 0.70 to 2.30), but not at intermediate-term follow-up for either outcome. Four trials compared Pilates to other exercises. For the outcome pain, we presented the results as a narrative synthesis due to the high level of heterogeneity. At short-term follow-up, based on low quality evidence, two trials demonstrated a significant effect in favour of Pilates and one trial did not find a significant difference. At intermediate-term follow-up, based on low quality evidence, one trial reported a significant effect in favour of Pilates, and one trial reported a non-significant difference for this comparison. For disability, there is moderate quality evidence that there is no significant difference between Pilates and other exercise either in the short term (MD -3.29, 95% CI -6.82 to 0.24) or in the intermediate term (MD -0.91, 95% CI -5.02 to 3.20) based on two studies for each comparison. Based on low quality evidence and one trial, there was no significant difference in function between Pilates and other exercises at short-term follow-up (MD 0.10, 95% CI -2.44 to 2.64), but there was a significant effect in favour of other exercises for intermediate-term function, with a small effect size (MD -3.60, 95% CI -7.00 to -0.20). Global impression of recovery was not assessed in this comparison and none of the trials included quality of life outcomes. Two trials assessed adverse events in this review, one did not find any adverse events, and another reported minor events. We did not find any high quality evidence for any of the treatment comparisons, outcomes or follow-up periods investigated. However, there is low to moderate quality evidence that Pilates is more effective than minimal intervention for pain and disability. When Pilates was compared with other exercises we found a small effect for function at intermediate-term follow-up. Thus, while there is some evidence for the effectiveness of Pilates for low back pain, there is no conclusive evidence that it is superior to other forms of exercises. The decision to use Pilates for low back pain may be based on the patient's or care provider's preferences, and costs.

This review included 10 studies and 510 patients. All studies included a similar population of people with non-specific low back pain. The studies only included participants with chronic low back pain. The duration of the treatment programmes in the included trials ranged from 10 days to 90 days. The duration of follow-up varied from four weeks to six months. None of the included studies measured follow-up beyond six months. The sample sizes ranged from 17 to 87 participants. The included studies demonstrated that Pilates is probably more effective than minimal intervention in the short and intermediate term for pain and disability outcomes, and more effective than minimal intervention for improvement in function and global impression of recovery in the short term. Pilates is probably not more effective than other exercises for pain and disability in the short and intermediate term. For function, other exercises were more effective than Pilates at intermediate-term follow-up, but not at short-term follow-up. Thus, while there is some evidence for the effectiveness of Pilates for low back pain, there is no conclusive evidence that it is superior to other forms of exercise. Minor or no adverse events were reported for the interventions in this review. The overall quality of the evidence in this review ranged from low to moderate.

10.1002/14651858.CD010265.pub2

cochrane-simplification-train-101

cochrane-simplification-train-101

We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes. Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm. There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo. All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events. There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.

In February 2017, we searched for clinical trials in which morphine was used to treat neuropathic pain in adults. Five studies satisfied the inclusion criteria, randomising 236 participants to treatment with morphine, placebo, or other drugs. Studies lasted four to seven weeks. Few studies reported beneficial outcomes that would be regarded as clinically relevant. Four small studies reported that pain was reduced by between a quarter and a third in some people. This level of pain reduction was experienced by 6 in 10 participants with morphine and 4 in 10 with placebo. Between 1 and 2 in 10 participants withdrew from treatment with both morphine and placebo, but the reasons were not given. Side effects were poorly reported, but were more common with morphine than with placebo, and included drowsiness, dizziness, constipation, feeling sick, dry mouth, and decreased appetite. The evidence was of very low quality. This means that the research did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different is very high. Small studies like those in this review tend to overestimate results of treatment compared to the effects found in larger, better designed studies. There were other problems that might lead to over-optimistic results. The very low quality evidence and the lack of any important benefit mean that we need new, longer-lasting, large trials before we will know if morphine is useful for the treatment of neuropathic pain.

10.1002/14651858.CD011669.pub2

cochrane-simplification-train-102

cochrane-simplification-train-102

This update of the systematic review includes a total of 91 trials with 20,102 participants. Use of ESAs significantly reduced the relative risk of red blood cell transfusions (risk ratio (RR) 0.65; 95% confidence interval (CI) 0.62 to 0.68, 70 trials, N = 16,093). On average, participants in the ESAs group received one unit of blood less than the control group (mean difference (MD) -0.98; 95% CI -1.17 to -0.78, 19 trials, N = 4,715). Haematological response was observed more often in participants receiving ESAs (RR 3.93; 95% CI 3.10 to 3.71, 31 trials, N = 6,413). There was suggestive evidence that ESAs may improve Quality of Life (QoL). There was strong evidence that ESAs increase mortality during active study period (hazard ratio (HR) 1.17; 95% CI 1.06 to 1.29, 70 trials, N = 15,935) and some evidence that ESAs decrease overall survival (HR 1.05; 95% CI 1.00 to 1.11, 78 trials, N = 19,003). The risk ratio for thromboembolic complications was increased in patients receiving ESAs compared to controls (RR 1.52, 95% CI 1.34 to 1.74; 57 trials, N = 15,498). ESAs may also increase the risk for hypertension (fixed-effect model: RR 1.30; 95% CI 1.08 to 1.56; random-effects model: RR 1.12; 95% CI 0.94 to 1.33, 31 trials, N = 7,228) and thrombocytopenia/haemorrhage (RR 1.21; 95% CI 1.04 to 1.42; 21 trials, N = 4,507). There was insufficient evidence to support an effect of ESA on tumour response (fixed-effect RR 1.02; 95% CI 0.98 to 1.06, 15 trials, N = 5,012). ESAs reduce the need for red blood cell transfusions but increase the risk for thromboembolic events and deaths. There is suggestive evidence that ESAs may improve QoL. Whether and how ESAs affects tumour control remains uncertain. The increased risk of death and thromboembolic events should be balanced against the potential benefits of ESA treatment taking into account each patient’s clinical circumstances and preferences. More data are needed for the effect of these drugs on quality of life and tumour progression. Further research is needed to clarify cellular and molecular mechanisms and pathways of the effects of ESAs on thrombogenesis and their potential effects on tumour growth.

- More people who received epoetin or darbepoetin died during and up to 30 days after the end of study compared with people who took placebo or underwent standard treatment. The increased risk for people taking epoetin or darbepoetin was 17%. One hundred and fourteen out of 1,000 persons receiving epoetin or darbepoetin died, compared with 98 out of 1,000 persons not receiving epoetin or darbepoetin. We could not identify particular characteristics of people or treatment strategies that increased or decreased the risk for dying. - Concerning long-term survival people taking epoetin or darbepoetin were 5% more at risk for dying than people taking placebo or receiving standard treatment. - People receiving epoetin or darbepoetin rated their fatigue symptoms to be an average of 2.08 points improved on a scale of 0-52 points after 3-4 months, compared with people taking placebo or having standard treatment. This improvement, however, is less than the 3.0 point increase which is considered to be the minimum required for the patient to feel a difference in his experience of fatigue-related symptoms using this scale. - People taking epoetin or darbepoetin rated their fatigue and anaemia symptoms had to be an average of 6.14 points improved after three to four months, on a scale of 0-80 points. This improvement is considered to reflect a positive change in the way patients experience their fatigue and anaemia related symptoms, as it is more than four to five points of increase which is the minimum required for this scale. - Seven people out of 100 who took epoetin or darbepoetin suffered a thromboembolic event such as stroke and myocardial infarction compared with five people out of 100 who did not receive epoetin or darbepoetin. - Six out of 100 people receiving epoetin or darbepoetin developed high blood pressure compared with four out of 100 people who took placebo or had standard care.

10.1002/14651858.CD003407.pub5

cochrane-simplification-train-103

cochrane-simplification-train-103

We included seven randomised and cluster-randomised controlled trials that together recruited 1614 participants. Four studies evaluated interventions delivered by specialised palliative care teams, and the remaining studies assessed models of co-ordinated care. Overall, risk of bias at the study level was mostly low, apart from possible selection bias in three studies and attrition bias in one study, along with insufficient information on blinding of participants and outcome assessment in six studies. Compared with usual/standard cancer care alone, early palliative care significantly improved health-related quality of life at a small effect size (SMD 0.27, 95% confidence interval (CI) 0.15 to 0.38; participants analysed at post treatment = 1028; evidence of low certainty). As re-expressed in natural units (absolute change in Functional Assessment of Cancer Therapy-General (FACT-G) score), health-related quality of life scores increased on average by 4.59 (95% CI 2.55 to 6.46) points more among participants given early palliative care than among control participants. Data on survival, available from four studies enrolling a total of 800 participants, did not indicate differences in efficacy (death hazard ratio 0.85, 95% CI 0.56 to 1.28; evidence of very low certainty). Levels of depressive symptoms among those receiving early palliative care did not differ significantly from levels among those receiving usual/standard cancer care (five studies; SMD -0.11, 95% CI -0.26 to 0.03; participants analysed at post treatment = 762; evidence of very low certainty). Results from seven studies that analysed 1054 participants post treatment suggest a small effect for significantly lower symptom intensity in early palliative care compared with the control condition (SMD -0.23, 95% CI -0.35 to -0.10; evidence of low certainty). The type of model used to provide early palliative care did not affect study results. One RCT reported potential adverse events of early palliative care, such as a higher percentage of participants with severe scores for pain and poor appetite; the remaining six studies did not report adverse events in study publications. For these six studies, principal investigators stated upon request that they had not observed any adverse events. This systematic review of a small number of trials indicates that early palliative care interventions may have more beneficial effects on quality of life and symptom intensity among patients with advanced cancer than among those given usual/standard cancer care alone. Although we found only small effect sizes, these may be clinically relevant at an advanced disease stage with limited prognosis, at which time further decline in quality of life is very common. At this point, effects on mortality and depression are uncertain. We have to interpret current results with caution owing to very low to low certainty of current evidence and between-study differences regarding participant populations, interventions, and methods. Additional research now under way will present a clearer picture of the effect and specific indication of early palliative care. Upcoming results from several ongoing studies (N = 20) and studies awaiting assessment (N = 10) may increase the certainty of study results and may lead to improved decision making. In perspective, early palliative care is a newly emerging field, and well-conducted studies are needed to explicitly describe the components of early palliative care and control treatments, after blinding of participants and outcome assessors, and to report on possible adverse events.

In October 2016, we searched for clinical trials on early palliative care in adults with advanced cancer. We included seven studies and found 20 ongoing studies. Most of the studies included participants older than 65 years of age on average, diagnosed with different tumour types and receiving treatment in tertiary care centres in North America. Most of these studies compared early palliative care with standard oncological (cancer) care. All studies were funded by government agencies. When evaluated together in a meta-analysis, studies showed that in patients with advanced cancer, early palliative care may slightly increase quality of life. It may also decrease symptom intensity to a small degree. Effects on survival and depression are uncertain. A single study reported side effects (adverse events), for example, more pain and reduced appetite. For the remaining six studies, information about side effects was not published, but trial authors told us they had not observed any. We rated the certainty of the evidence using four levels: very low, low, moderate, and high. Evidence of very low certainty means that we have little confidence in the results. Evidence of high certainty means that we are very confident in the results. We found that certainty of the evidence was low for health-related quality of life and symptom intensity, and was very low for depression and survival. We downgraded certainty of the evidence for various reasons, for example, problems in the way studies were carried out, differences between studies, and the small number of studies. We remain uncertain about the effects of early palliative care; therefore we have to interpret the results with caution. When published, ongoing studies may provide more evidence, and this may affect the certainty of the results.

10.1002/14651858.CD011129.pub2

cochrane-simplification-train-104

cochrane-simplification-train-104

Seven studies were found to be suitable for inclusion from 33 identified as relevant. None of the trials provided adequate evidence to support the use of hydroxyurea owing to small sample size, large numbers of post-randomisation exclusions and questionable rules for censoring, particularly a failure to include treatment-related deaths in the survival analysis. Details of statistical analysis were limited and often confusing, and we felt meta-analysis would lead to unreliable and invalid conclusions. Most studies appeared to be double blind placebo-controlled studies but none give details of power calculations or reasons for stopping recruitment. Only two studies had more than 50 patients. Patients were excluded from analysis in most trials for treatment-related reasons; in one, less than half those recruited were used in the analysis, the remainder having been excluded because of tumour progression or treatment-related conditions e.g. septicaemia, worsening renal/hepatic function. In another trial five out of 20 in the hydroxyurea group died of treatment-related complications but the five-year survival group was presented as 94%. We found no evidence to support the use of hydroxyurea in addition to radiotherapy in the routine treatment of cervix cancer.

The orally-administered cytotoxic, hydroxyurea, may be given alongside radiotherapy for treating cervix cancer. Eight trials comparing concomitant hydroxyurea and radiotherapy with radiotherapy alone were assessed. They were not of sufficient quality to be able to pool the data. Although several trials reported an improvement in survival for patients receiving hydroxyurea, this conclusion was unreliable owing to methodological problems associated with trials including small sample size, a large number of patients excluded from analysis and questionable methods of analysis such as exclusion of treatment related deaths.

10.1002/14651858.CD003918.pub2

cochrane-simplification-train-105

cochrane-simplification-train-105

A total of 13 trials with 9961 participants were included in the review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta2-agonist comparison. The comparator beta2-agonists were salmeterol, formoterol and eformoterol. One of these trials, with a total of 90 participants, provided no data that could be used in this review. Two trials included both indacaterol versus placebo and indacaterol versus twice-daily beta2-agonist comparisons. Trials were between 12 weeks and 52 weeks in duration. Overall the quality of the evidence was strong, and risk of significant bias was minimal in most of the included studies. Enrolled participants had stable COPD across a range of spirometric severities. Forced expiratory volume in 1 second (FEV1) was generally between 30% and 80% predicted, and a mean FEV1 of approximately 50% was predicted in most studies. Patients with concurrent respiratory disease, including asthma, were excluded. Concomitant use of inhaled corticosteroids was permitted. The primary objectives were to compare trough FEV1 at the end of dosing, exacerbation rates and quality of life. Significant adverse events, mortality and dyspnoea were included as secondary outcomes. Compared with placebo, a significant and clinically relevant improvement in trough FEV1 was noted with indacaterol (mean difference (MD) 149.11, 95% confidence interval (CI) 137.09 to 161.12). In addition, compared with placebo, a significant improvement in mean St George Respiratory Questionaire (SGRQ) score (MD -3.60, 95% CI -4.36 to -2.83) was reported, and the proportion of participants experiencing clinically relevant improvement in SGRQ score was significantly greater (odds ratio (OR) 1.64, 95% CI 1.46 to 1.845. Compared with twice-daily beta2-agonists, a small but statistically significant increase in trough FEV1 was seen with indacaterol (MD 61.71 mL, 95% CI 41.24 to 82.17). Differences between indacaterol and twice-daily beta2-agonists in mean SGRQ scores (MD -0.81, 95% CI -2.28 to 0.66) and in the proportions of participants achieving clinically relevant improvements in SGRQ scores (OR 1.07, 95% CI 0.87 to 1.32) were not statistically significant, but the confidence intervals are too wide to permit the conclusion that the treatments were equivalent. For patients with stable COPD, use of indacaterol versus placebo results in statistically significant and clinically meaningful improvements in lung function and quality of life. The clinical benefit for lung function is at least as good as that seen with twice-daily long-acting beta2-agonists, but the comparative effect on quality of life remains uncertain, as important differences cannot be excluded.

13 trials with a total of 9961 participants were included in this review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta2-agonist comparison. Two trials included both indacaterol versus placebo and indacaterol versus twice-daily beta2-agonist comparisons. Trials were between 12 and 52 weeks duration and compared doses between 75 mcg and 600 mcg. In most trials, mean forced expiratory volume in 1 second (FEV1) was approximately 50% predicted. 1. Indacaterol is an effective medication for the treatment of patients with stable COPD. It results in improved lung function and quality of life. 2. Indacaterol led to improvements in lung function that were clinically similar to those seen with twice-daily long-acting beta2-agonists. 3. No measurable difference was noted between indacaterol and twice-daily long-acting beta2-agonists with respect to quality of life, but important differences cannot be excluded. 4. No significant difference was observed in the number of participants suffering a serious adverse event or mortality, but the confidence intervals were too wide because very few events could be used to rule out important differences. Overall the quality of the evidence was judged to be high. Indacaterol is an effective treatment for patients with stable COPD; it offers benefits that are clinically similar to those of existing twice-daily preparations within the same class of medication but provides the possible advantage of once-daily dosing.

10.1002/14651858.CD010139.pub2

cochrane-simplification-train-106

cochrane-simplification-train-106

Nine RCTs of mixed duration (3 days-52 weeks), recruiting 1175 participants were included (NYHA functional classes II-IV). Intravenous prostacyclin versus usual care (four studies) : There were significant improvements in exercise capacity of around 90 metres, cardiopulmonary haemodynamics and NYHA functional class over 3 days-12 weeks. Effects were consistent in primary and secondary pulmonary hypertension. Oral prostacyclin versus placebo (two studies) : Short-term data (3-6 months) indicated that there was a significant improvement in exercise capacity, but data from one study of 52 weeks reported no significant difference at 12 months. No significant differences were observed for any other outcome. Subcutaneous treprostinil versus placebo (two studies, 8-12 weeks): One large study reported a significant median improvement in exercise capacity of around 16 metres. Cardiopulmonary haemodynamics and symptom scores favoured treprostinil. Infusion site pain and withdrawals due to adverse events were more frequent with treprostinil. Inhaled prostacyclin versus placebo (one study, 12 weeks): There was a significant increase in exercise capacity of approximately 36 metres. Treatment led to better symptom scores and functional class status than with placebo. Subgroup analyses reported by individual studies showed a better exercise capacity in participants with PPH, than those participants with PH secondary to other diseases. Side effects and adverse events were common in the studies. There is evidence that intravenous prostacyclin in addition to conventional therapy at tolerable doses optimised by titration, can confer some short-term benefits (up to 12 weeks of treatment) in exercise capacity, NYHA functional class and cardiopulmonary haemodynamics. There is also some evidence that patients with more severe disease based upon NYHA functional class showed a greater response to treatment.

Prostacyclin may benefit patients with pulmonary hypertension (raised blood pressure in the lungs) in the short term but studies longer in duration are required. Pulmonary hypertension occurs when blood is pumped through arteries in the lungs at an increased pressure. The condition can lead to heart failure and death. Once the diagnosis is made, life expectancy ranges from a few months to a few years. Most current treatments apart from lung transplantation do not improve survival. Over an 8-12 week period prostacyclin improved exercise capacity and some measures of blood flow when given intravenously or via injection to patients with pulmonary hypertension. However, with intravenous administration there can be serious side effects as the drug has to be given continuously via a pump into a catheter placed into a central vein. It is not clear how long the drug continues to confer benefit without serious side effects. Prostacyclin can also be given by mouth, under the skin or through an inhaler. These forms of administration may be safer than intravenous prostacyclin and there is evidence that these may be effective in the short term.

10.1002/14651858.CD002994.pub2

cochrane-simplification-train-107

cochrane-simplification-train-107

The review now includes four trials (total 75 people, one additional trial since 2006, 21 people) randomising inpatients and outpatients in China and the USA. Risk of bias was mostly unclear as reporting was poor. We are uncertain about all the effects as all evidence was graded at very low quality. We found no significant difference between benzodiazepines and placebo for the outcome of 'no clinically important improvement in TD' (2 RCTs, 32 people, RR 1.12, 95% CI 0.60 to 2.09, very low quality evidence). Significantly fewer participants allocated to clonazepam compared with phenobarbital (as active placebo) experienced no clinically important improvement (RR 0.44, 95% CI 0.20 to 0.96, 1 RCT, 21 people, very low quality evidence). For the outcome 'deterioration of TD symptoms,' we found no clear difference between benzodiazepines and placebo (2 RCTs, 30 people, RR 1.48, 95% CI 0.22 to 9.82, very low quality evidence). All 10 participants allocated to benzodiazepines experienced any adverse event compared with 7/11 allocated to phenobarbital (RR 1.53, 95% CI 0.97 to 2.41, 1 RCT, 21 people, very low quality evidence). There was no clear difference in the incidence of participants leaving the study early for benzodiazepines compared with placebo (3 RCTs, 56 people, RR 2.73, 95% CI 0.15 to 48.04, very low quality evidence) or compared with phenobarbital (as active placebo) (no events, 1 RCT, 21 people, very low quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, which are outcomes designated important by patients. No trials comparing benzodiazepines with placebo or treatment as usual reported on adverse effects. There is only evidence of very low quality from a few small and poorly reported trials on the effect of benzodiazepines as an adjunctive treatment for antipsychotic-induced TD. These inconclusive results mean routine clinical use is not indicated and these treatments remain experimental. New and better trials are indicated in this under-researched area; however, as benzodiazepines are addictive, we feel that other techniques or medications should be adequately evaluated before benzodiazepines are chosen.

The review includes four clinical trials with 75 people who had tardive dyskinesia as a result of using antipsychotic medicines. The participants were randomised into groups that received either their usual antipsychotic medicine plus a benzodiazepine or their usual antipsychotic plus a placebo (dummy medicine). Improvement in TD symptoms was similar between the treatment groups. Participants were just as likely to leave the studies early from the placebo groups as the benzodiazepine groups. Data were not available for outcomes important to patients such as improvement in social confidence, social inclusion, social networks or quality of life. Evidence is limited because the trials are so few, small, and poorly reported. It is uncertain whether benzodiazepines are helpful in the treatment of tardive dyskinesia. The use of benzodiazepines for treating people with antipsychotic-induced TD therefore remains experimental, and because they are highly addictive, a last resort. The low number of studies in this review strongly indicates that this is not an active area of research. To fully investigate whether benzodiazepines have any positive effects for people with tardive dyskinesia, there would have to be more well-designed, conducted and reported 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.CD000205.pub3

cochrane-simplification-train-108

cochrane-simplification-train-108

Our literature search yielded 11,277 results. In total, we included 23 studies (99 references) with 7335 newly-diagnosed individuals with classic HL (all stages). Participants in 16 studies underwent (interim) PET combined with computed tomography (PET-CT), compared to PET only in the remaining seven studies. The standard chemotherapy regimen included ABVD (16) studies, compared to BEACOPP or other regimens (seven studies). Most studies (N = 21) conducted interim PET scans after two cycles (PET2) of chemotherapy, although PET1, PET3 and PET4 were also reported in some studies. In the meta-analyses, we used PET2 data if available as we wanted to ensure homogeneity between studies. In most studies interim PET scan results were evaluated according to the Deauville 5-point scale (N = 12). Eight studies were not included in meta-analyses due to missing information and/or data; results were reported narratively. For the remaining studies, we pooled the unadjusted hazard ratio (HR). The timing of the outcome measurement was after two or three years (the median follow-up time ranged from 22 to 65 months) in the pooled studies. Eight studies explored the independent prognostic ability of interim PET by adjusting for other established prognostic factors (e.g. disease stage, B symptoms). We did not pool the results because the multivariable analyses adjusted for a different set of factors in each study. Overall survival Twelve (out of 23) studies reported OS. Six of these were assessed as low risk of bias in all of the first four domains of QUIPS (study participation, study attrition, prognostic factor measurement and outcome measurement). The other six studies were assessed as unclear, moderate or high risk of bias in at least one of these four domains. Four studies were assessed as low risk, and eight studies as high risk of bias for the domain other prognostic factors (covariates). Nine studies were assessed as low risk, and three studies as high risk of bias for the domain 'statistical analysis and reporting'. We pooled nine studies with 1802 participants. Participants with HL who have a negative interim PET scan result probably have a large advantage in OS compared to those with a positive interim PET scan result (unadjusted HR 5.09, 95% confidence interval (CI) 2.64 to 9.81, I² = 44%, moderate-certainty evidence). In absolute values, this means that 900 out of 1000 participants with a negative interim PET scan result will probably survive longer than three years compared to 585 (95% CI 356 to 757) out of 1000 participants with a positive result. Adjusted results from two studies also indicate an independent prognostic value of interim PET scan results (moderate-certainty evidence). Progression-free survival Twenty-one studies reported PFS. Eleven out of 21 were assessed as low risk of bias in the first four domains. The remaining were assessed as unclear, moderate or high risk of bias in at least one of the four domains. Eleven studies were assessed as low risk, and ten studies as high risk of bias for the domain other prognostic factors (covariates). Eight studies were assessed as high risk, thirteen as low risk of bias for statistical analysis and reporting. We pooled 14 studies with 2079 participants. Participants who have a negative interim PET scan result may have an advantage in PFS compared to those with a positive interim PET scan result, but the evidence is very uncertain (unadjusted HR 4.90, 95% CI 3.47 to 6.90, I² = 45%, very low-certainty evidence). This means that 850 out of 1000 participants with a negative interim PET scan result may be progression-free longer than three years compared to 451 (95% CI 326 to 569) out of 1000 participants with a positive result. Adjusted results (not pooled) from eight studies also indicate that there may be an independent prognostic value of interim PET scan results (low-certainty evidence). PET-associated adverse events No study measured PET-associated AEs. This review provides moderate-certainty evidence that interim PET scan results predict OS, and very low-certainty evidence that interim PET scan results predict progression-free survival in treated individuals with HL. This evidence is primarily based on unadjusted data. More studies are needed to test the adjusted prognostic ability of interim PET against established prognostic factors.

We included 23 studies to explore the association between interim PET scan results after one to four cycles of chemotherapy and survival outcomes in adults with HL (all stages). We contacted 10 authors, and six provided us with relevant information and/or data. In 16 included studies, participants received either ABVD chemotherapy or BEACOPP chemotherapy (four studies) only, with or without radiotherapy. In 16 studies, participants underwent an interim PET scan in combination with a computed tomography (CT) (PET-CT), which have higher accuracy in detecting primary and secondary cancers than a PET scan alone. In the remaining seven studies, PET-only was conducted. Twenty-one studies conducted interim PET scans after two cycles (PET2) of chemotherapy. Eight studies did not report enough data on our outcomes or population of interest, so we reported the results from these studies narratively. We combined individual study results in meta-analyses to provide robust evidence for our outcomes of interest overall survival and progression-free survival. No study measured PET-associated adverse events (harms). For overall survival, combined results from nine studies (1802 participants) show that there is probably a large advantage in overall survival for people with a negative interim PET scan compared to people with a positive interim PET scan. For progression-free survival, combined results from 14 studies (2079 participants) show that interim PET-negative people may have an advantage for progression-free survival, compared to interim PET-positive people, but we are uncertain about this result. These are unadjusted results, where interim PET was tested as the only prognostic factor. Eight studies reported adjusted results, where the independent prognostic ability of interim PET was assessed against other established prognostic factors (e.g. disease stage, B symptoms). We could not combine individual study results because the studies did not include identical sets of covariates. Nevertheless, their results indicate a probable independent prognostic ability of interim PET to predict both outcomes. Regarding the unadjusted results, we rated our certainty of the evidence as 'moderate' for overall survival. This means that the true effect is likely to be close to the estimated effect, but there is a possibility that it is substantially different. For progression-free survival, we rated our certainty of the evidence as 'very low', meaning that we have little confidence in the effect estimate, and that the true effect is likely to be substantially different from the estimated effect. Regarding the adjusted results, we rated our certainty of the evidence as 'moderate' for overall survival, and 'low' for progression-free survival. We searched data bases up until 2 April 2019, and one trial registry on 25 January 2019.

10.1002/14651858.CD012643.pub3

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cochrane-simplification-train-109

Three trials with a total of 245 participants were included in this review. The three trials directly compared the use of normal saline and heparin, however, between studies, all used different protocols for the standard and experimental arms with different concentrations of heparin and different frequency of flushes reported. In addition, not all studies reported on all outcomes. The quality of the evidence ranged from low to very low because there was no blinding, heterogeneity and inconsistency between studies was high and the confidence intervals were wide. CVC occlusion was assessed in all three trials (243 participants). We were able to pool the results of two trials for the outcomes of CVC occlusion and CVC-associated blood stream infection. The estimated rate ratio for CVC occlusion per 1000 catheter days between the normal saline and heparin group was 0.75 (95% CI 0.10 to 5.51, two studies, 229 participants, very low quality evidence). The estimated rate ratio for CVC-associated blood stream infection was 1.48 (95% CI 0.24 to 9.37, two studies, 231 participants; low quality evidence). The duration of catheter placement was reported to be similar between the two study arms, in one study (203 participants). The review found that there was not enough evidence to determine the effects of intermittent flushing of heparin versus normal saline to prevent occlusion in long term central venous catheters in infants and children. Ultimately, if this evidence were available, the development of evidenced-based clinical practice guidelines and consistency of practice would be facilitated.

This review included randomised controlled trials, (clinical studies where people were randomly assigned into one of two or more treatment groups), that compared the use of saline and heparin to prevent blockage, and other complications related to long term catheters. The evidence is current to April 2015. Two review authors independently reviewed the studies. Three studies with a total of 245 participants were included in the review. The three trials directly compared the use of saline and heparin, however, between studies, all were very different in the way they compared saline and heparin, with different concentrations of heparin and different frequency of flushes reported. We were able to combine the results of two studies; the analysis showed imprecise results for the blocking of catheters and blood stream infections between normal saline and heparin. One study reported the duration of catheter placement to be similar between the two study arms. The overall quality of the evidence ranged from low to very low. There was high risk of bias for blinding, there were differences between the studies methods and interventions, inconsistent results between the studies, and not all studies reported all outcomes of interest. We found there was not enough evidence to determine which solution, heparin or saline, is more effective for reducing complications. Further research is required and is likely to have an important impact in this area.

10.1002/14651858.CD010996.pub2

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cochrane-simplification-train-110

We included six studies with a total of 438 participants. Five studies were conducted in the USA, and one in Iran. All studies evaluated a long-acting version of bupropion, with the dosage ranging from 150 mg up to 450 mg daily. Study intervention length varied from six to 10 weeks. Four studies explicitly excluded participants with psychiatric comorbidity and one study included only participants with opioid dependency. Four studies were funded by industry, but the impact of this on study results is unknown. Two studies were publicly funded and in one of these studies, the lead author was a consultant for several pharmaceutical companies and also received investigator-driven funding from two companies, however none of these companies manufacture bupropion. We judged none of the studies to be free of bias because for most risk of bias domains the study reports failed to provide sufficient details. Using the GRADE approach, we rated the overall quality of evidence as low. We downgraded the quality of the evidence because of serious risk of bias and serious imprecision due to small sample sizes. We found low-quality evidence that bupropion decreased the severity of ADHD symptoms (standardised mean difference -0.50, 95% confidence interval (CI) -0.86 to -0.15, 3 studies, 129 participants), and increased the proportion of participants achieving clinical improvement (risk ratio (RR) 1.50, 95% CI 1.13 to 1.99, 4 studies, 315 participants), and reporting an improvement on the Clinical Global Impression - Improvement scale (RR 1.78, 95% CI 1.27 to 2.50, 5 studies, 337 participants). There was low-quality evidence that the proportion of participants who withdrew due to any adverse effect was similar in the bupropion and placebo groups (RR 1.20, 95% CI 0.35 to 4.10, 3 studies, 253 participants). The results were very similar when using a random-effects model and when we analysed only studies that excluded participants with a psychiatric comorbidity. The findings of this review, which compared bupropion to placebo for adult ADHD, indicate a possible benefit of bupropion. We found low-quality evidence that bupropion decreased the severity of ADHD symptoms and moderately increased the proportion of participants achieving a significant clinical improvement in ADHD symptoms. Furthermore, we found low-quality evidence that the tolerability of bupropion is similar to that of placebo. In the pharmacological treatment of adults with ADHD, extended- or sustained-release bupropion may be an alternative to stimulants. The low-quality evidence indicates uncertainty with respect to the pooled effect estimates. Further research is very likely to change these estimates. More research is needed to reach more definite conclusions as well as clarifying the optimal target population for this medicine. Treatment response remains to be reported in a DSM5-diagnosed population. There is also a lack of knowledge on long-term outcomes.

We included six randomised controlled trials (RCTs), that is, studies in which participants are randomly allocated to one of two or more treatment groups. Five of the studies took place in the USA, and the sixth in Iran. The studies included 438 people with ADHD. All evaluated a long-acting version of bupropion, that is to say, a version of the drug is absorbed slowly, and can therefore be taken just once a day. This simple dosage suits people with ADHD, as the illness may make it difficult for them to remember to take their medication. The duration of the studies varied between six and 10 weeks. All participants were diagnosed with ADHD, and often had other mental health problems. In one study, all participants had ADHD and were addicted to opioids (a drug that relieves pain). Four studies were funded by industry and two studies were publicly funded. In one of the publicly-funded studies, the lead author was paid by industry (although not by the manufacturers of buproprion) for research activities. Bupropion may lead to a small improvement in ADHD and it may also decrease symptoms related to ADHD. The drug does not have more adverse effects than treatment with placebo. Bupropion may be an alternative treatment for adults with ADHD who cannot or will not take stimulant drugs. The quality of the evidence in this review is low, because we found very few studies; five of the six studies were small, and all were poorly conducted. The effect of bupropion on various aspects of daily functioning was not investigated. Also, no studies assessed the long-term effects of this drug. Further studies are needed, to assess whether bupropion is effective in specific ADHD subgroups or in people who have additional disorders.

10.1002/14651858.CD009504.pub2

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cochrane-simplification-train-111

In total, we identified 1298 publications through the search strategy. We included 28 publications reporting on 24 studies. COC users were at increased risk of myocardial infarction or ischemic stroke compared with non-users: relative risk (RR) 1.6 (95% CI 1.3-1.9).These RRs were similar for myocardial infarction (1.6, 95% CI 1.2 to 2.1) and ischemic stroke (1.7, 95% CI 1.5 to 1.9). The risks did not vary clearly according to the generation of progestagen or according to progestagen type. When we stratified preparations according to estrogen dose, the risk of myocardial infarction or ischemic stroke seemed to increase with higher doses of estrogen. This meta-analysis showed that the risk of myocardial infarction or ischemic stroke was 1.6-fold increased in women using COCs . The risk was highest for pills with > 50 microgram estrogen. When combined with the results of studies on the risk of venous thrombosis in COC users, it seems that the COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of combined oral hormonal contraception.

In total, 28 articles on 24 unique studies met the inclusion criteria. Our results showed that the overall risk of arterial thrombosis was was 1.6-fold increased in women using oral contraceptive pills compared with women who did not use oral contraceptive pills. The risk did not vary clearly according to progestagen type. However, we found that the risk of arterial thrombosis seemed to be twice as high in women taking pills with higher doses of estrogen. Also, the risk of other side effects of oral contraceptive pills (such as a blood clot in a vein-venous thrombosis) should be considered before any type of oral contraceptive pill is prescribed. It is likely that the COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of combined oral hormonal contraception. The overall quality of evidence in this review was moderate. Most studies (22 out of 28) correctly confirmed that patients had been diagnosed with arterial thrombosis. However, only four studies also checked that the type of pill a patient had been using was reported correctly. In addition, only half of the studies ensured that the correct comparisons were made between patients with and patients without arterial thrombosis. Also of importance is the fact that the analysis on progestagen type was based on few studies only.

10.1002/14651858.CD011054.pub2

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cochrane-simplification-train-112

Nine trials were identified and seven (with a total of 237 adult participants) were included. Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates. In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02). Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.

The evidence available was limited to six trials with participants who had not undergone lung transplants (total of 203 adults) and one trial with 34 adults who had undergone lung transplantation. Bisphosphonates consistently increased bone mineral density at the lumbar spine and hip regions. The rates of fractures (vertebral and non-vertebral) or deaths were not reduced by bisphosphonate therapy. However, this may be related to the small numbers of participants involved and the short duration of the trials. Severe bone pain and flu-like symptoms were commonly linked to intravenous bisphosphonates, especially in people not using corticosteroids. More research is needed to assess the effect of pre-treatment with corticosteroids. Additional trials are needed to determine if bone pain is more common or severe (or both) with the stronger drug zoledronate and if corticosteroids lessen or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.

10.1002/14651858.CD002010.pub4

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cochrane-simplification-train-113

We included seventeen studies with a total of 1655 randomised participants in this review. Risk of bias was variable among studies. Blinding of participants, personnel and outcome assessment was not possible in most trials because of obvious differences between the treatments. The lack of a blinded outcome assessor may have caused detection bias when ulcer healing was assessed. However, possible detection bias is hard to prevent due to the nature of the skin replacement products we assessed, and the fact that they are easily recognisable. Strikingly, nearly all studies (15/17) reported industry involvement; at least one of the authors was connected to a commercial organisation or the study was funded by a commercial organisation. In addition, the funnel plot for assessing risk of bias appeared to be asymmetrical; suggesting that small studies with 'negative' results are less likely to be published. Thirteen of the studies included in this review compared a skin graft or tissue replacement with standard care. Four studies compared two grafts or tissue replacements with each other. When we pooled the results of all the individual studies, the skin grafts and tissue replacement products that were used in the trials increased the healing rate of foot ulcers in patients with diabetes compared to standard care (risk ratio (RR) 1.55, 95% confidence interval (CI) 1.30 to 1.85, low quality of evidence). However, the strength of effect was variable depending on the specific product that was used (e.g. EpiFix® RR 11.08, 95% CI 1.69 to 72.82 and OrCel® RR 1.75, 95% CI 0.61 to 5.05). Based on the four included studies that directly compared two products, no specific type of skin graft or tissue replacement showed a superior effect on ulcer healing over another type of skin graft or tissue replacement. Sixteen of the included studies reported on adverse events in various ways. No study reported a statistically significant difference in the occurrence of adverse events between the intervention and the control group. Only two of the included studies reported on total incidence of lower limb amputations. We found fewer amputations in the experimental group compared with the standard care group when we pooled the results of these two studies, although the absolute risk reduction for amputation was small (RR 0.43, 95% CI 0.23 to 0.81; risk difference (RD) -0.06, 95% CI -0.10 to -0.01, very low quality of evidence). Based on the studies included in this review, the overall therapeutic effect of skin grafts and tissue replacements used in conjunction with standard care shows an increase in the healing rate of foot ulcers and slightly fewer amputations in people with diabetes compared with standard care alone. However, the data available to us was insufficient for us to draw conclusions on the effectiveness of different types of skin grafts or tissue replacement therapies. In addition, evidence of long term effectiveness is lacking and cost-effectiveness is uncertain.

We included thirteen randomised studies that compared two types of skin grafts or tissue replacements with standard care and four randomised studies that compared two grafts or tissue replacements with each other. In total 1655 patients were randomised in these seventeen trials. Risk of bias was variable among studies. The biggest drawbacks were the lack of blinding (i.e. patients and investigators were aware who was receiving the experimental therapy and who was receiving the standard therapy), industry involvement and the possibility that small studies were less likely to be published if they reported 'negative' results. Adverse advent rates (harm due to the treatment) varied widely. Based on the seventeen studies included in this review, skin grafts and tissue replacements, used in conjunction with standard care, increase the healing rate of foot ulcers and lead to slightly fewer amputations in people with diabetes compared with standard care alone. However, evidence of long term effectiveness is lacking and cost-effectiveness is uncertain. There was not enough evidence for us to be able to recommend a specific type of skin graft or tissue replacement. This plain language summary is up-to-date as of 9 April 2015.

10.1002/14651858.CD011255.pub2

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cochrane-simplification-train-114

Twenty-five trials (43 references) of varying methodological quality were eligible; they included 2907 randomised patients (2777 patients completed). Nine of the 25 included studies involved adults; four included adult and paediatric patients; eight studies enrolled paediatric patients; and in the remaining four studies the age of participants was not stated. The design, definitions, intervention and outcomes were different in all 25 studies; this heterogeneity made direct comparisons difficult. The quality of the evidence presented ranged from high to very low, with most outcomes graded as low or very low. This was largely due to concerns about the methodological quality of the included studies and imprecision in the pooled effect estimates. Inhaled magnesium sulfate in addition to inhaled β₂-agonist and ipratropium We included seven studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, results were inconsistent overall and the largest study reporting this outcome found no between-group difference at 60 minutes (MD −0.3 % predicted peak expiratory flow rate (PEFR), 95% CI −2.71% to 2.11%). Admissions to hospital at initial presentation may be reduced by the addition of inhaled magnesium sulfate (RR 0.95, 95% CI 0.91 to 1.00; participants = 1308; studies = 4; I² = 52%) but no difference was detected for re-admissions or escalation of care to ITU/HDU. Serious adverse events during admission were rare. There was no difference between groups for all adverse events during admission (RD 0.01, 95% CI −0.03 to 0.05; participants = 1197; studies = 2). Inhaled magnesium sulfate in addition to inhaled β₂-agonist We included 13 studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, none of the pooled results showed a conclusive benefit as measured by FEV1 or PEFR. Pooled results for hospital admission showed a point estimate that favoured the combination of MgSO₄ and β₂-agonist, but the confidence interval includes the possibility of admissions increasing in the intervention group (RR 0.78, 95% CI 0.52 to 1.15; participants = 375; studies = 6; I² = 0%). There were no serious adverse events reported by any of the included studies and no between-group difference for all adverse events (RD −0.01, 95% CI −0.05 to 0.03; participants = 694; studies = 5). Inhaled magnesium sulfate versus inhaled β₂-agonist We included four studies in this comparison. The evidence for the efficacy of β₂-agonists in acute asthma is well-established and therefore this could be considered a historical comparison. Two studies reported a benefit of β₂-agonist over MgSO₄ alone for PEFR and two studies reported no difference; we did not pool these results. Admissions to hospital were only reported by one small study and events were rare, leading to an uncertain result. No serious adverse events were reported in any of the studies in this comparison; one small study reported mild to moderate adverse events but the result is imprecise. Treatment with nebulised MgSO₄ may result in modest additional benefits for lung function and hospital admission when added to inhaled β₂-agonists and ipratropium bromide, but our confidence in the evidence is low and there remains substantial uncertainty. The recent large, well-designed trials have generally not demonstrated clinically important benefits. Nebulised MgSO₄ does not appear to be associated with an increase in serious adverse events. Individual studies suggest that those with more severe attacks and attacks of shorter duration may experience a greater benefit but further research into subgroups is warranted. Despite including 24 trials in this review update we were unable to pool data for all outcomes of interest and this has limited the strength of the conclusions reached. A core outcomes set for studies in acute asthma is needed. This is particularly important in paediatric studies where measuring lung function at the time of an exacerbation may not be possible. Placebo-controlled trials in patients not responding to standard maximal treatment, including inhaled β₂-agonists and ipratropium bromide and systemic steroids, may help establish if nebulised MgSO₄ has a role in acute asthma. However, the accumulating evidence suggests that a substantial benefit may be unlikely.

We looked for studies in adults and children attending the emergency department with an asthma attack. We included studies which compared giving inhaled magnesium sulfate, plus standard treatment, with standard treatment alone. We also included studies that compared inhaled magnesium sulfate directly with standard treatment. We included studies carried out anywhere in the world, at any time and written in any language. We found 25 studies in total, which included nearly 3000 people with asthma attacks. This latest update of the review includes several large trials that were carried out to a very high standard. We found that adding inhaled magnesium sulfate to standard treatments may result in small benefits in terms of lung function, hospital admission and severity scores, but we are uncertain about these findings. This is because many of the studies were carried out in different ways and measured different outcomes at different times so it was quite hard to combine the results from individual studies. Inhaled magnesium sulfate did not seem to cause any serious side effects in the studies we found. We did not find evidence that using inhaled magnesium sulfate instead of standard treatment is beneficial. We used a scoring system to rate how confident we are in the findings presented. Our scores ranged from high confidence to very low confidence, but most outcomes we rated as low or very low. This is because we had concerns about the way in which some of the studies were carried out: for example, it was perhaps not clear how people were chosen for the two different treatment groups in the study; or it was unclear whether the patients or people running the trial knew who was getting which treatment. Another factor that reduced our confidence was uncertainty about the combined results: for example in some cases we could not tell whether magnesium sulfate was better, worse or the same. There is some limited evidence that inhaled magnesium sulfate may have a small benefit for people having asthma attacks when added to standard treatment. However, the most recent, high-quality trials did not generally show important benefits. Also, we cannot be sure if some groups may benefit more than other, for example those having more severe attacks.

10.1002/14651858.CD003898.pub6

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cochrane-simplification-train-115

Authors identified 19 studies, of which nine studies with 202 participants met the review's inclusion criteria. There was wide variation in the methodological and written quality of the included studies. Four of the nine included studies were published as abstracts only and lacking concise details, thus limiting the information available. Seven studies were parallel studies and two of a cross-over design. Respiratory muscle training interventions varied dramatically, with frequency, intensity and duration ranging from thrice weekly to twice daily, 20% to 80% of maximal effort, and 10 to 30 minutes, respectively. Participant numbers ranged from 11 to 39 participants in the included studies; five studies were in adults only and four in a combination of children and adults. No significant improvement was reported in the primary outcome of pulmonary function (forced expiratory volume in one second and forced vital capacity) (very low-quality evidence). Although no change was reported in exercise capacity as assessed by the maximum rate of oxygen use, a 10% improvement in exercise duration was found when working at 60% of maximal effort in one study (n = 20) (very low-quality evidence). In a further study (n = 18), when working at 80% of maximal effort, health-related quality of life improved in the mastery and emotion domains (very low-quality evidence). With regards to the review's secondary outcomes, one study (n = 11) found a significant change in intramural pressure, functional residual capacity and maximal inspiratory pressure following training (low-quality evidence). A further study (n = 22) reported that respiratory muscle endurance was significantly longer in the training group (P < 0.01). No studies reported on any other secondary outcomes. Meta-analyses could not be performed due to a lack of consistency and insufficient detail in reported outcome measures. There is insufficient evidence to suggest whether this intervention is beneficial or not. Healthcare practitioners should consider the use of respiratory muscle training on a case-by-case basis. Further research of reputable methodological quality is needed to determine the effectiveness of respiratory muscle training in people with cystic fibrosis. Researchers should consider the following clinical outcomes in future studies; respiratory muscle function, pulmonary function, exercise capacity, hospital admissions, and health-related quality of life. Sensory-perceptual changes, such as respiratory effort sensation (e.g. rating of perceived breathlessness) and peripheral effort sensation (e.g. rating of perceived exertion) may also help to elucidate mechanisms underpinning the effectiveness of respiratory muscle training.

We searched for studies where people with cystic fibrosis were put into either a group for respiratory muscle training or a control group at random. We included nine studies with 202 people which used a wide variety of training methods and levels. In seven of the studies, the treatment group and the control group each only received either respiratory muscle training or a control treatment (one study had three groups in total: one receiving control treatment and two receiving different levels of training). In one study the participants received both types of treatment, but in a random order. Lastly, one study compared training with usual care. The studies lasted for a maximum of 12 weeks and all were quite small; the largest only had 29 people taking part. The studies included people with a range of ages over six years old, but most seemed to be adults. The studies reported a variety of outcomes. All reported some measure of respiratory muscle strength, and most reported at least one measure of lung function, however only three studies reported on quality of life. Results could not be combined to answer the review question, because the studies either did not publish enough details or did not use the same standard measurements. No study found any difference in lung function after training, but one of the studies reported an improvement in exercise duration when training at 60% of maximal effort and a further study which trained participants at 80% of maximal effort reported some improvements in quality of life judgements. There was some evidence of an improvement in respiratory muscle function in one study. Given this lack of information, a recommendation for or against respiratory muscle training cannot be made. Future studies should look to improve upon the methods of those previously conducted, and should report using standardised measurements. It was generally unclear how people were split into groups for treatment and whether this would have affected the results. Two studies stated that the people assessing the outcomes did not know which treatment those taking part had received, but this was unclear in other studies. Individuals dropped out of three of the studies for reasons which may be directly related to the treatment and therefore may introduce a risk of bias to the results. Other studies did not state how many people dropped out of them. We assessed the quality of the evidence and judged the evidence for lung function, exercise capacity and health-related quality of life to be very low quality, but the evidence for respiratory muscle function to be low quality.

10.1002/14651858.CD006112.pub4

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cochrane-simplification-train-116

We found two studies involving 162 adults that met our inclusion criteria. Neither of the two studies included children. The duration of treatment and length of sessions varied between studies from four sessions delivered weekly, to four sessions over two months. Similarly, length of sessions varied slightly from one 60-minute session and three 45-minute sessions to four 30-minute sessions. The control interventions were healthy lifestyle advice in both studies. One study contributed HRQoL data, using the Leicester Cough Questionnaire (LCQ), and we judged the quality of the evidence to be low using the GRADE approach. Data were reported as between-group difference from baseline to four weeks (MD 1.53, 95% confidence interval (CI) 0.21 to 2.85; participants = 71), revealing a statistically significant benefit for people receiving a physiotherapy and speech and language therapy intervention (PSALTI) versus control. However, the difference between PSALTI and control was not observed between week four and three months. The same study provided information on SAEs, and there were no SAEs in either the PSALTI or control arms. Using the GRADE approach we judged the quality of evidence for this outcome to be low. Data were also available for our prespecified secondary outcomes. In each case data were provided by only one study, therefore there were no opportunities for aggregation; we judged the quality of this evidence to be low for each outcome. A significant difference favouring therapy was demonstrated for: objective cough counts (ratio for mean coughs per hour on treatment was 59% (95% CI 37% to 95%) relative to control; participants = 71); symptom score (MD 9.80, 95% CI 4.50 to 15.10; participants = 87); and clinical improvement as defined by trialists (OR 48.13, 95% CI 13.53 to 171.25; participants = 87). There was no significant difference between therapy and control regarding subjective measures of cough (MD on visual analogue scale of cough severity: −9.72, 95% CI −20.80 to 1.36; participants = 71) and cough reflex sensitivity (capsaicin concentration to induce five coughs: 1.11 (95% CI 0.80 to 1.54; participants = 49) times higher on treatment than on control). One study reported data on adverse events, and there were no adverse events reported in either the therapy or control arms of the study. The paucity of data in this review highlights the need for more controlled trial data examining the efficacy of SLT interventions in the management of UCC. Although a large number of studies were found in the initial search as per protocol, we could include only two studies in the review. In addition, this review highlights that endpoints vary between published studies. The improvements in HRQoL (LCQ) and reduction in 24-hour cough frequency seen with the PSALTI intervention were statistically significant but short-lived, with the between-group difference lasting up to four weeks only. Further studies are required to replicate these findings and to investigate the effects of SLT interventions over time. It is clear that SLT interventions vary between studies. Further research is needed to understand which aspects of SLT interventions are most effective in reducing cough (both objective cough frequency and subjective measures of cough) and improving HRQoL. We consider these endpoints to be clinically important. It is also important for future studies to report information on adverse events. Because of the paucity of data, we can draw no robust conclusions regarding the efficacy of SLT interventions for improving outcomes in unexplained chronic cough. Our review identifies the need for further high-quality research, with comparable endpoints to inform robust conclusions.

We found two relevant studies to include in the review. Both studies were randomised controlled trials (a type of study in which participants are assigned to one of two or more treatment groups using a random method) in which participants had a diagnosis of UCC. Participants received either an intervention including SLT techniques or 'healthy lifestyle advice' as a control group. We chose to use health-related quality of life and serious adverse events to judge whether SLT is a useful intervention. Only one of the studies comparing SLT to usual care reported data about quality of life (using a questionnaire). After four weeks, participants in the study who were receiving the SLT treatment, physiotherapy and speech and language therapy intervention (PSALTI), had on average an improvement in their quality of life compared to people in the control group. However, this benefit compared to control was short-lived and disappeared after four weeks. This means that although the treatment appeared to work in the shorter term, it may not improve quality of life in the longer term compared to usual care. We also looked for information about side effects or harms of the treatment. The same study reported that no one experienced serious side effects or harms during the study. Other ways of measuring the impact of SLT were also considered, and in each case relevant data were only provided by one study. An improvement in objective cough counts (using a cough monitor), symptoms (using symptom scores), and clinical improvement was shown with SLT compared to controls. The included trials reported no difference for other secondary outcomes such as subjective measures of cough or cough reflex sensitivity (measured in the laboratory using airway irritants). The small number of high-quality, relevant studies found in this review means that we cannot be sure of the overall benefits of SLT in the management of UCC. Improvements in health-related quality of life were associated with the PSALTI intervention over a short period in one study, but further research is required to replicate this finding. Overall, more controlled trials are required to fully examine the potential of SLT for the management of UCC.

10.1002/14651858.CD013067.pub2

cochrane-simplification-train-117

cochrane-simplification-train-117

Six RCTs (434 participants) appraised four types of chest physiotherapy (conventional chest physiotherapy; osteopathic manipulative treatment (which includes paraspinal inhibition, rib raising and myofascial release); active cycle of breathing techniques (which include active breathing control, thoracic expansion exercises and forced expiration techniques); and positive expiratory pressure). None of the physiotherapies (versus no physiotherapy or placebo) improved mortality rates of adults with pneumonia. Conventional chest physiotherapy (versus no physiotherapy), active cycle of breathing techniques (versus no physiotherapy) and osteopathic manipulative treatment (versus placebo) did not increase the cure rate or chest X-ray improvement rate. Osteopathic manipulative treatment (versus placebo) and positive expiratory pressure (versus no physiotherapy) reduced the mean duration of hospital stay by 2.0 days (mean difference (MD) -2.0 days, 95% CI -3.5 to -0.6) and 1.4 days (MD -1.4 days, 95% CI -2.8 to -0.0), respectively. Conventional chest physiotherapy and active cycle of breathing techniques did not. Positive expiratory pressure (versus no physiotherapy) reduced fever duration (MD -0.7 day, 95% CI -1.4 to -0.0). Osteopathic manipulative treatment did not. Osteopathic manipulative treatment (versus placebo) reduced the duration of intravenous (MD -2.1 days, 95% CI -3.4 to -0.9) and total antibiotic treatment (MD -1.9 days, 95% CI -3.1 to -0.7). Limitations of this review are that the studies addressing osteopathic manipulative treatment were small, and that six published studies which appear to meet the inclusion criteria are awaiting classification. Based on current limited evidence, chest physiotherapy might not be recommended as routine additional treatment for pneumonia in adults.

Six randomised controlled trials assessing 434 participants were included. The studies appraised four types of chest physiotherapy, namely conventional chest physiotherapy, osteopathic manipulative treatment (including paraspinal inhibition, rib raising, and diaphragmatic or soft myofascial release), active cycle of breathing techniques (including active breathing control, thoracic expansion exercises and forced expiration technique) and positive expiratory pressure. None of these techniques (versus no physiotherapy or placebo therapy) reduce mortality. Among three of the techniques (conventional chest physiotherapy, active cycle of breathing techniques and osteopathic manipulative treatment) there is no evidence to support a better cure rate in comparison with no physiotherapy or placebo therapy. Limited evidence indicates that positive expiratory pressure (versus no physiotherapy) and osteopathic manipulative treatment (versus placebo therapy) can slightly reduce the duration of hospital stay (by 2.02 and 1.4 days, respectively). In addition, positive expiratory pressure (versus no physiotherapy) can slightly reduce the duration of fever by 0.7 day, and osteopathic manipulative treatment (versus placebo therapy) might reduce the duration of antibiotic use by 1.93 days. No severe adverse events were found. In summary, chest physiotherapy should not be recommended as routine additional treatment for pneumonia in adults. The limitation of our review is that six published studies which appear to meet the inclusion criteria are awaiting classification (five of which are published in Russian).

10.1002/14651858.CD006338.pub3

cochrane-simplification-train-118

cochrane-simplification-train-118

This review included four RCTs with 442 participants. The evidence was very low-quality with the main limitations being due to serious imprecision, inconsistency and indirectness. Myomectomy versus no intervention One study examined the effect of myomectomy compared to no intervention on reproductive outcomes. We are uncertain whether myomectomy improves clinical pregnancy rate for intramural (odds ratio (OR) 1.88, 95% confidence interval (CI) 0.57 to 6.14; 45 participants; one study; very low-quality evidence), submucous (OR 2.04, 95% CI 0.62 to 6.66; 52 participants; one study; very low-quality evidence), intramural/subserous (OR 2.00, 95% CI 0.40 to 10.09; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 3.24, 95% CI 0.72 to 14.57; 42 participants; one study; very low-quality evidence). Similarly, we are uncertain whether myomectomy reduces miscarriage rate for intramural fibroids (OR 1.33, 95% CI 0.26 to 6.78; 45 participants; one study; very low-quality evidence), submucous fibroids (OR 1.27, 95% CI 0.27 to 5.97; 52 participants; one study; very low-quality evidence), intramural/subserous fibroids (OR 0.80, 95% CI 0.10 to 6.54; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 2.00, 95% CI 0.32 to 12.33; 42 participants; one study; very low-quality evidence). This study did not report on live birth, preterm delivery, ongoing pregnancy or caesarean section rate. Laparoscopic myomectomy versus myomectomy by laparotomy or mini-laparotomy Two studies compared laparoscopic myomectomy to myomectomy at laparotomy or mini-laparotomy. We are uncertain whether laparoscopic myomectomy compared to laparotomy or mini-laparotomy improves live birth rate (OR 0.80, 95% CI 0.42 to 1.50; 177 participants; two studies; I2 = 0%; very low-quality evidence), preterm delivery rate (OR 0.70, 95% CI 0.11 to 4.29; participants = 177; two studies; I2 = 0%, very low-quality evidence), clinical pregnancy rate (OR 0.96, 95% CI 0.52 to 1.78; 177 participants; two studies; I2 = 0%, very low-quality evidence), ongoing pregnancy rate (OR 1.61, 95% CI 0.26 to 10.04; 115 participants; one study; very low-quality evidence), miscarriage rate (OR 1.25, 95% CI 0.40 to 3.89; participants = 177; two studies; I2 = 0%, very low-quality evidence), or caesarean section rate (OR 0.69, 95% CI 0.34 to 1.39; participants = 177; two studies; I2 = 21%, very low-quality evidence). Monopolar resectoscope versus bipolar resectoscope One study evaluated the use of two electrosurgical systems during hysteroscopic myomectomy. We are uncertain whether bipolar resectoscope use compared to monopolar resectoscope use improves live birth/ongoing pregnancy rate (OR 0.86, 95% CI 0.30 to 2.50; 68 participants; one study, very low-quality evidence), clinical pregnancy rate (OR 0.88, 95% CI 0.33 to 2.36; 68 participants; one study; very low-quality evidence), or miscarriage rate (OR 1.00, 95% CI 0.19 to 5.34; participants = 68; one study; very low-quality evidence). This study did not report on preterm delivery or caesarean section rate. There is limited evidence to determine the role of myomectomy for infertility in women with fibroids as only one trial compared myomectomy with no myomectomy. If the decision is made to have a myomectomy, the current evidence does not indicate a superior method (laparoscopy, laparotomy or different electrosurgical systems) to improve rates of live birth, preterm delivery, clinical pregnancy, ongoing pregnancy, miscarriage, or caesarean section. Furthermore, the existing evidence needs to be viewed with caution due to the small number of events, minimal number of studies and very low-quality evidence.

This review included four studies with 442 participants. One study compared myomectomy to no treatment. The remaining three studies compared different surgical methods of performing a myomectomy. The evidence is current to February 2019. One study examined the effect of myomectomy compared to no treatment. Results found insufficient evidence to determine a difference between treatment options for clinical pregnancy rate or miscarriage rate. This study did not report on live birth, preterm delivery, ongoing pregnancy or caesarean section rate. Regarding the best surgical approach, three studies were identified. Two studies compared myomectomy by mini-laparotomy or laparotomy to laparoscopic myomectomy and found insufficient evidence to determine a difference for live birth, preterm delivery, clinical pregnancy, miscarriage, caesarean section and ongoing pregnancy rate. The third study compared use of different surgical equipment during hysteroscopic myomectomy and found insufficient evidence to determine a difference for live birth/ongoing pregnancy rate, clinical pregnancy rate and miscarriage rate. This study did not report on caesarean section or preterm delivery rate. It is clear that more studies are needed before a consensus can be reached on the role of myomectomy for infertility. The evidence was very low quality. There are some concerns regarding how the data were analysed and therefore the evidence cannot be considered to be conclusive until further studies are available.

10.1002/14651858.CD003857.pub4

cochrane-simplification-train-119

cochrane-simplification-train-119

We included 10 studies (1354 women). The risk of bias was unclear or high in most of the included studies. All of the included trials involved women undergoing caesarean section whether elective or non-elective. Intravenous antibiotics versus antibiotic irrigation (nine studies, 1274 women) Nine studies (1274 women) compared the administration of intravenous antibiotics with antibiotic irrigation. There were no clear differences between groups in terms of this review's maternal primary outcomes: endometritis (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.29; eight studies (966 women) (low-quality evidence)); wound infection (RR 0.49, 95% CI 0.17 to 1.43; seven studies (859 women) (very low-quality evidence)). The outcome of infant sepsis was not reported in the included studies. In terms of this review's maternal secondary outcomes, there were no clear differences between intravenous antibiotic or irrigation antibiotic groups in terms of postpartum febrile morbidity (RR 0.87, 95% CI 0.48 to 1.60; three studies (264 women) (very low-quality evidence)); or urinary tract infection (RR 0.74, 95% CI 0.25 to 2.15; five studies (660 women) (very low-quality evidence)). In terms of adverse effects of the treatment on the women, no drug allergic reactions were reported in three studies (284 women) (very low-quality evidence), and there were no cases of serious infectious complications reported (very low-quality evidence). There was no clear difference between groups in terms of maternal length of hospital stay (mean difference (MD) 0.28 days, 95% CI -0.22 to 0.79 days, (random-effects analysis), four studies (512 women). No data were reported for the number of women readmitted to hospital. For the baby, there were no data reported in relation to oral thrush, infant length of hospital stay or immediate adverse effects of the antibiotics on the infant. Intravenous antibiotic prophylaxis versus oral antibiotic prophylaxis (one study, 80 women) One study (80 women) compared an intravenous versus an oral route of administration of prophylactic antibiotics, but did not report any of this review's primary or secondary outcomes. There was no clear difference between irrigation and intravenous antibiotic prophylaxis in reducing the risk of post-caesarean endometritis. For other outcomes, there is insufficient evidence regarding which route of administration of prophylactic antibiotics is most effective at preventing post-caesarean infections. The quality of evidence was very low to low, mainly due to limitations in study design and imprecision. Furthermore, most of the included studies were underpowered (small sample sizes with few events). Therefore, we advise caution in the interpretation and generalisability of the results. For future research, there is a need for well-designed, properly-conducted, and clearly-reported RCTs. Such studies should evaluate the more recently available antibiotics, elaborating on the various available routes of administration, and exploring potential neonatal side effects of such interventions.

We searched for evidence from randomised controlled trials on 6 January 2016 and found 10 studies (involving a total of 1354 women). Nine studies (1274 women) compared intravenous antibiotic administration with antibiotic irrigation (washing with a saline solution containing antibiotics). The two routes gave similar results on important outcomes including infection of the uterus/womb (low-quality evidence) and wound infection (very low-quality evidence). The studies did not report on blood infections in the newborn infant (sepsis). The numbers of women who had urinary tract infection (very low-quality evidence), serious infectious complications (very low-quality evidence) or fever after birth (very low-quality evidence) also did not clearly differ between groups. There was no clear difference between groups in terms of how long women spent in hospital and no data reported on the number of women who were readmitted to hospital. No women had allergic reactions to the antibiotics (very low-quality evidence) in the three studies that reported this outcome. None of the studies reported information about whether the babies had any immediate adverse reactions to the antibiotics. One study (involving 80 women) compared intravenous antibiotics with taking antibiotics orally but it did not report on any of this review's outcomes. The studies included in this review did not clearly report how they were carried out and outcome data were incomplete. Too few women were included in each study for sufficient numbers of events to see a clear difference in outcomes between the two groups of women. This meant the evidence was of low quality. Therefore, we need to exercise caution in the interpretation and generalisability of the results. High-quality studies are needed to determine the safest, most effective way of giving preventive antibiotics. Such studies should evaluate more recently available antibiotics and consider potential side effects that the intervention may have for the baby.

10.1002/14651858.CD011876.pub2

cochrane-simplification-train-120

cochrane-simplification-train-120

We found 19 RCTs that met our eligibility criteria. Eleven trials compared different combined oral contraceptives (COCs) or regimens of COCs; five examined an injectable versus another injectable, implant, or IUD; two studied implants, and one compared the transdermal patch versus the vaginal ring. No trial had fracture as an outcome. BMD was measured in 17 studies and 12 trials assessed biochemical markers of bone turnover. Depot medroxyprogesterone acetate (DMPA) was associated with decreased bone mineral density (BMD). The placebo-controlled trials showed BMD increases for DMPA plus estrogen supplement and decreases for DMPA plus placebo supplement. COCs did not appear to negatively affect BMD, and some formulations had more positive effects than others. However, no COC trial was placebo-controlled. Where studies showed differences between groups in bone turnover markers, the results were generally consistent with those for BMD. For implants, the single-rod etonogestrel group showed a greater BMD decrease versus the two-rod levonorgestrel group but results were not consistent across all implant comparisons. The sensitivity analysis included 11 trials providing evidence of moderate or high quality. Four trials involving DMPA showed some positive effects of an estrogen supplement on BMD, a negative effect of DMPA-subcutaneous on lumbar spine BMD, and a negative effect of DMPA on a bone formation marker. Of the three COC trials, one had a BMD decrease for the group with gestodene plus EE 15 μg. Another indicated less bone resorption in the group with gestodene plus EE 30 μg versus EE 20 μg. Whether steroidal contraceptives influence fracture risk cannot be determined from existing information. The evidence quality was considered moderate overall, largely due to the trials of DMPA, implants, and the patch versus ring. The COC evidence varied in quality but was low overall. Many trials had small numbers of participants and some had large losses. Health care providers and women should consider the costs and benefits of these effective contraceptives. For example, injectable contraceptives and implants provide effective, long-term birth control yet do not involve a daily regimen. Progestin-only contraceptives are considered appropriate for women who should avoid estrogen due to medical conditions.

Through April 2014, we did computer searches for studies of birth control methods containing hormones and risk of fractures. Outcomes could also be bone mineral density or markers of bone changes. Birth control pills included types with both estrogen and progestin. Also included were implants and injectables with only progestin. We wrote to researchers to find other trials. We included randomized trials in any language that had at least three treatment cycles. The studies had to compare two types of birth control or one type of birth control or a supplement with a placebo or 'dummy' method. We found 19 trials. Fifteen studies compared one birth control method with another hormone method. Two trials used a placebo or 'dummy.' One compared a hormone method to a method without hormones. None had fractures as an outcome and most looked at bone density. Birth control methods with both estrogen and progestin did not appear to affect bone health. However, 'depo,' which is injected and has only progestin, was related to lower bone density. The two depo trials with placebos showed increased bone density when some estrogen was given to women on depo. Bone density decreased in women who got a 'dummy' with the depo. Whether this decrease is important to the woman's health is not known. For implants, an etonogestrel implant with one rod showed a greater decrease in bone density than a two-rod levonorgestrel implant. However, other implants studied did not show the same pattern. The studies had data of moderate quality. Whether hormonal contraceptives affect fracture risk cannot be judged from current information. These contraceptive methods work well for birth control. Health-care providers and women should think about the costs and benefits. For instance, injectable use can occur without a partner's knowledge, and is simpler than taking pills every day. Also, progestin-only methods are suggested for some women with health problems who should avoid estrogen.

10.1002/14651858.CD006033.pub5

cochrane-simplification-train-121

cochrane-simplification-train-121

The search identified 13 studies in addition to the two studies in the previous version of our systematic review. Overall, we included data from 15 trials with 33,970 people. We completed a 'Risk of bias' assessment for all studies. The risk of bias was low in four trials because they were at low risk of bias for all key domains (random sequence generation, allocation concealment, blinding, selective outcome reporting and incomplete outcome data), even if some of them were funded by the pharmaceutical industry. Analysis showed no difference in the effectiveness of aspirin plus clopidogrel in preventing cardiovascular mortality (RR 0.98, 95% CI 0.88 to 1.10; participants = 31,903; studies = 7; moderate quality evidence), and no evidence of a difference in all-cause mortality (RR 1.05, 95% CI 0.87 to 1.25; participants = 32,908; studies = 9; low quality evidence). There was a lower risk of fatal and non-fatal myocardial infarction with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 0.78, 95% CI 0.69 to 0.90; participants = 16,175; studies = 6; moderate quality evidence). There was a reduction in the risk of fatal and non-fatal ischaemic stroke (RR 0.73, 95% CI 0.59 to 0.91; participants = 4006; studies = 5; moderate quality evidence). However, there was a higher risk of major bleeding with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 1.44, 95% CI 1.25 to 1.64; participants = 33,300; studies = 10; moderate quality evidence) and of minor bleeding (RR 2.03, 95% CI 1.75 to 2.36; participants = 14,731; studies = 8; moderate quality evidence). Overall, we would expect 13 myocardial infarctions and 23 ischaemic strokes be prevented for every 1000 patients treated with the combination in a median follow-up period of 12 months, but 9 major bleeds and 33 minor bleeds would be caused during a median follow-up period of 10.5 and 6 months, respectively. The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infarction and ischaemic stroke, and an increased risk of major and minor bleeding compared with aspirin alone. According to GRADE criteria, the quality of evidence was moderate for all outcomes except all-cause mortality (low quality evidence) and adverse events (very low quality evidence).

This review contains evidence up to July 2017. We found 15 studies which together included more than 30,000 people at high risk of heart disease who are taking aspirin. All studies randomly assigned participants to the intervention group (taking aspirin and clopidogrel) or the control group (taking aspirin and placebo (a pretend treatment that has no effect). Participants took clopidogrel between six weeks and 3.4 years, depending on the study they took part in. The results do not apply to people with recent placement of coronary stents (tubes inserted in the blood vessel to keep it open), who were excluded from this review. The results showed that there is a benefit of adding clopidogrel to aspirin in terms of reducing the risk of heart attack or stroke. However, there is a higher risk of major and minor bleeding associated with this. There was no effect on death due to heart problems or death from any cause. Using Cochrane criteria, four trials were at low risk of bias. Using GRADE standards, the quality of published evidence was moderate for most results, but low for death from any cause and very low for side effects.

10.1002/14651858.CD005158.pub4

cochrane-simplification-train-122

cochrane-simplification-train-122

Twenty-eight study comparisons drawn from 27 trials (22 adult; five paediatric) met the review entry criteria (8050 participants). Baseline data from the studies indicated that trial populations had moderate or mild airway obstruction (FEV1≥65% predicted), and that they were symptomatic prior to randomisation. In comparison 1, the combination of ICS and LABA was not associated with a significantly lower risk of patients with exacerbations requiring oral corticosteroids (RR 1.04; 95% confidence interval (CI) 0.73 to 1.47) or requiring hospital admissions (RR 0.38; 95% CI 0.09 to 1.65) compared to a similar dose of ICS alone. The combination of LABA and ICS led to a significantly greater improvement from baseline in FEV1 (0.12 L/sec; 95% CI 0.07 to 0.17), in symptoms (SMD -0.26; 95% CI -0.37 to -0.14) and in rescue ß2-agonist use (-0.41 puffs/day; 95% CI -0.73 to -0.09) compared with a similar dose of ICS alone. There was no significant group difference in the risk of serious adverse events (RR 1.15; 95% CI 0.64 to 2.09), any adverse events (RR 1.02; 95% CI 0.96 to 1.09), study withdrawals (RR 0.95; 95% CI 0.82 to 1.11), or withdrawals due to poor asthma control (RR 0.94; 95% CI 0.63 to 1.41). In comparison 2, the combination of LABA and ICS was associated with a higher risk of patients requiring oral corticosteroids (RR 1.24; 95% CI 1 to 1.53) and study withdrawal (RR 1.31; 95% CI 1.07 to 1.59) than a higher dose of ICS alone. For every 100 patients treated over 43 weeks, nine patients using a higher dose ICS compared to 11 (95% CI 9 to 14) on LABA and ICS suffered one or more exacerbations requiring rescue oral corticosteroids. There was a high level of statistical heterogeneity for FEV1 and morning peak flow. There was no statistically significant group difference in the risk of serious adverse events. Due to insufficient data we could not aggregate results for hospital admission, symptoms and other outcomes. In steroid-naive patients with mild to moderate airway obstruction, the combination of ICS and LABA does not significantly reduce the risk of patients with exacerbations requiring rescue oral corticosteroids over that achieved with a similar dose of ICS alone. However, it significantly improves lung function, reduces symptoms and marginally decreases rescue ß2-agonist use. Initiation of a higher dose of ICS is more effective at reducing the risk of exacerbations requiring rescue systemic corticosteroids, and of withdrawals, than combination therapy. Although children appeared to respond similarly to adults, no firm conclusions can be drawn regarding combination therapy in steroid-naive children, given the small number of children contributing data.

Yet, many physicians initiate combination therapy in patients with asthma, without a prior trial of inhaled corticosteroids alone. The purpose of this review was to compare the benefit and safety profile of initiating treatment with the combination of ICS and LABA as compared to a (1) similar and (2) higher dose of ICS alone in asthmatic patients who had not received ICS previously. This review identified 28 randomised controlled trials. The combination of ICS and LABA did not reduce the risk of patients with exacerbations requiring rescue oral corticosteroids but improved lung function, symptoms and minimally reduced the use of rescue ß2-agonists as compared to a similar dose of ICS alone. Initiating ICS at a higher dose than that used with LABA in the control group significantly reduced the risk of exacerbations and study withdrawals over that observed with the combination of LABA and a lower dose of ICS; there is insufficient evidence to comment on the impact on lung function, symptoms and use of rescue ß2-agonists. The current evidence does not support use of combination therapy with LABA and ICS as first line treatment in adults and children with asthma, without a prior trial of inhaled corticosteroids.

10.1002/14651858.CD005307.pub2

cochrane-simplification-train-123

cochrane-simplification-train-123

We found three relevant small, short trials (total n=126). Clinical Global Impression data were equivocal (n=27, 1 RCT, WMD -0.43 CI -0.9 to 0.1). Average total PANSS scores were not significantly different between the DHEA plus antipsychotic group and those given antipsychotic drugs and placebo (n=82, 2 RCTs, WMD -4.16 CI -13.8 to 5.5). PANSS positive scores were equivocal (n=55, 1 RCT, WMD -1.00 CI -3.8 to 1.8). For negative symptoms binary SANS scale data favoured the DHEA plus antipsychotic group (n=30, 1 RCT, RR 0.23 CI 0.1 to 0.6, NNT 2 CI 2 to 3) but PANSS negative scores were not significantly different between comparison groups (n=55, 1 RCT, WMD -2.30 CI -6.4 to 1.8). About 17% of people left both groups early (n=64, 2 RCTs, RR 0.80 CI 0.3 to 2.4). St Hans Rating Scale data for extrapyramidal symptoms favoured the DHEA plus antipsychotic group (n=30, 1 RCT, WMD -5.00 CI -8.8 to -1.2) but akathisia ratings were equivocal (n=34, 1 RCT, RR 2.67 CI 0.3 to 23.1). Ratings of parkinsonian movement disorder differed within the same trial depending of the outcome scale used. Quality of life seemed unaffected by use of DHEA (n=55, 1 RCT, WMD 6.20 CI -1.4 to 13.8). Results are inconclusive with most outcomes being either non-significant or producing contradictory findings. Currently, adjunctive DHEA should remain an experimental treatment for people with schizophrenia.

We reviewed the effects of dehydroepiandrosterone (DHEA)/testosterone as an adjunctive therapy to standard antipsychotic drugs for people with schizophrenia and found three relevant small, short studies. All trials compared antipsychotic drugs plus DHEA with antipsychotic drugs and placebo. Results are inconclusive, with most outcomes being either non-significant or contradictory and a much larger, conclusive study should be undertaken. Currently however, people with schizophrenia should only agree to take this experimental treatment within the context of a well designed experimental study. We found nothing in these studies to suggest that it should be used in routine care.

10.1002/14651858.CD006197.pub2

cochrane-simplification-train-124

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Six studies met the inclusion criteria; two were randomised studies and four were observational comparative studies evaluating different methods for obtaining missing data. Methods to obtain missing data Five studies, two randomised studies and three observational comparative studies, assessed methods for obtaining missing data (i.e. data available to the original researchers but not reported in the published study). Two studies found that correspondence with study authors by e-mail resulted in the greatest response rate with the fewest attempts and shortest time to respond. The difference between the effect of a single request for missing information (by e-mail or surface mail) versus a multistage approach (pre-notification, request for missing information and active follow-up) was not significant for response rate and completeness of information retrieved (one study). Requests for clarification of methods (one study) resulted in a greater response than requests for missing data. A well-known signatory had no significant effect on the likelihood of authors responding to a request for unpublished information (one study). One study assessed the number of attempts made to obtain missing data and found that the number of items requested did not influence the probability of response. In addition, multiple attempts using the same methods did not increase the likelihood of response. Methods to obtain unpublished studies One observational comparative study assessed methods to obtain unpublished studies (i.e. data for studies that have never been published). Identifying unpublished studies ahead of time and then asking the drug industry to provide further specific detail proved to be more fruitful than sending of a non-specific request. Those carrying out systematic reviews should continue to contact authors for missing data, recognising that this might not always be successful, particularly for older studies. Contacting authors by e-mail results in the greatest response rate with the fewest number of attempts and the shortest time to respond.

This methodology review was conducted to assess the effects of different methods for obtaining unpublished studies (data) and missing data from studies to be included in systematic reviews. Six studies met the inclusion criteria, two were randomised studies and four were observational comparative studies evaluating different methods for obtaining missing data. Five studies assessed methods for obtaining missing data (i.e. data available to the original researchers but not reported in the published study). Two studies found that correspondence with study authors by e-mail resulted in the greatest response rate with the fewest attempts and shortest time to respond. The difference between the effect of a single request for missing information (by e-mail or surface mail) versus a multistage approach (pre-notification, request for missing information and active follow-up) was not significant for response rate and completeness of information retrieved (one study). Requests for clarification of methods (one study) resulted in a greater response than requests for missing data. A well-known signatory had no significant effect on the likelihood of authors responding to a request for unpublished information (one study). One study assessed the number of attempts made to obtain missing data and found that the number of items requested did not influence the probability of response. In addition, multiple attempts using the same methods did not increase the likelihood of response. One study assessed methods to obtain unpublished studies (i.e. data for studies that have never been published). Identifying unpublished studies ahead of time and then asking the drug industry to provide further specific detail proved to be more fruitful than sending of a non-specific request. Those carrying out systematic reviews should continue to contact authors for missing data, recognising that this might not always be successful, particularly for older studies. Contacting authors by e-mail results in the greatest response rate with the fewest number of attempts and the shortest time to respond.

10.1002/14651858.MR000027.pub2

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Two randomized controlled trials enrolling a total of 268 patients satisfied the inclusion criteria. The risk of bias for Drewry 1994 was unclear as this study was presented as an abstract, while Bennett 2003 was rated as at low risk. Pooling of data was not possible. In one study there was no evidence of improved effectiveness with the addition of a non-steroidal anti-inflammatory drug (tenoxicam) to routine recompression therapy (at six weeks: relative risk (RR) 1.04, 95% confidence interval (CI) 0.90 to 1.20, P = 0.58) but there was a reduction in the number of compressions required when tenoxicam was added from three to two (P = 0.01, 95% CI 0 to 1). In the other study, the odds of multiple recompressions were lower with a helium and oxygen (heliox) table compared to an oxygen treatment table (RR 0.56, 95% CI 0.31 to 1.00, P = 0.05). Recompression therapy is standard for the treatment of DCI, but there is no randomized controlled trial evidence for its use. Both the addition of a non-steroidal anti-inflammatory drug (NSAID) and the use of heliox may reduce the number of recompressions required, but neither improve the odds of recovery. The application of either of these strategies may be justified. The modest number of patients studied demands a cautious interpretation. Benefits may be largely economic and an economic analysis should be undertaken. There is a case for large randomized trials of high methodological rigour in order to define any benefit from the use of different breathing gases and pressure profiles during recompression therapy.

This review found only two randomized trials enrolling a total of 268 patients. One trial compared standard oxygen recompression to helium and oxygen recompression, while the other compared oxygen recompression alone to recompression and an adjunctive non-steroidal anti-inflammatory drug (NSAID). Both trials suggested that these additional interventions may shorten the course of recompression required. For example, the use of an NSAID reduced the median number of recompression sessions required from three to two. We conclude that there is little evidence for using one recompression strategy over another in the treatment of decompression illness and that the addition of an anti-inflammatory drug may shorten the course of recompression required. More research is needed.

10.1002/14651858.CD005277.pub3

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We included one trial with 226 participants: A Randomized trial of Unruptured Brain Arteriovenous Malformations (ARUBA), comparing intervention versus conservative management for unruptured brain AVMs (that had never bled). The quality of evidence was moderate because we found just one trial that was at low risk of bias other than a high risk of performance bias due to participants and treating physicians not being blinded to allocated treatment. Data on functional outcome and death at a follow-up of 12 months were provided for 218 (96%) of the participants in ARUBA. In this randomized controlled trial (RCT), intervention compared to conservative management increased death or dependency (modified Rankin Scale score ≥ 2, risk ratio (RR) 2.53, 95% confidence interval (CI) 1.28 to 4.98; 1 trial, 226 participants; moderate-quality evidence) and the proportion of participants with symptomatic intracranial haemorrhage (RR 6.75, 95% CI 2.07 to 21.96; 1 trial, 226 participants; moderate-quality evidence), but there was no difference in the frequency of epileptic seizures (RR 1.14, 95% CI 0.63 to 2.06; 1 trial, 226 participants; moderate-quality evidence). Three RCTs are ongoing. We found moderate-quality evidence from one RCT including adults with unruptured brain AVMs that conservative management was superior to intervention with respect to functional outcome and symptomatic intracranial haemorrhage over one year after randomization. More RCTs will help to confirm or refute these findings.

We found one published randomized controlled trial, including 226 adults. We found moderate-quality evidence of harm (stroke due to bleeding in the brain, and death or dependency) over one year of follow-up from interventional treatments compared to conservative management for adults who had a brain AVM that had never bled. The long-term risks are unknown. Overall, the quality of the evidence was moderate because there was just one trial and it did not use blinding. More information will become available from the three trials that are ongoing.

10.1002/14651858.CD003436.pub4

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Ten trials, with a total of 2345 participants, met the inclusion criteria. The trials were conducted in four geographical regions and were often small, but they included comparisons across eight drugs. Nine trials were funded by a pharmaceutical company, only three carried out an intention-to-treat analysis, and allocation concealment was unclear in seven. Atovaquone-proguanil had fewer treatment failures by day 28 than chloroquine (RR 0.04, 95% CI 0.00 to 0.57; 27 participants, 1 trial), amodiaquine (RR 0.22, 95% CI 0.13 to 0.36; 342 participants, 2 trials), and mefloquine (RR 0.04, 95% CI 0.00 to 0.73; 158 participants, 1 trial). There were insufficient data to draw a conclusion for this outcome from comparisons with sulfadoxine-pyrimethamine (172 participants, 2 trials), halofantrine (205 participants, 1 trial), artesunate plus mefloquine (1063 participants, 1 trial), quinine plus tetracycline (154 participants, 1 trial), and dihydroartemisinin-piperaquine-trimethoprim-primaquine (161 participants, 1 trial). Adverse events were mainly common symptoms of malaria and did not differ in frequency between groups. Data are limited but appear to suggest that atovaquone-proguanil is more effective than chloroquine, amodiaquine, and mefloquine. There are insufficient data for comparisons against sulfadoxine-pyrimethamine, halofantrine, artesunate plus mefloquine, quinine plus tetracycline, and dihydroartemisinin-piperaquine-trimethoprim-primaquine in treating malaria. There are not enough data to assess safety, but a number of adverse events were identified with all drugs. Large trials comparing atovaquone-proguanil with other new combination therapies are needed.

The review found 10 trials, most of low methodological quality and most funded by a single pharmaceutical company. In addition, trials were small and had few participants thus evidence suggesting atovaquone-proguanil as more effective than a number of single drug treatments at eliminating the Plasmodium falciparum malaria parasite from the blood was limited. There were few good quality data comparing atovaquone-proguanil with other new combination therapies. There were not enough data to assess adverse events, but all trials recorded some adverse events.

10.1002/14651858.CD004529.pub2

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We included seven RCTs and studied 7586 women of the 8955 enrolled. Local recurrence-free survival appeared worse for women receiving PBI/APBI compared to WBRT (hazard ratio (HR) 1.62, 95% confidence interval (CI) 1.11 to 2.35; six studies, 6820 participants, low-quality evidence). Cosmesis (physician-reported) appeared worse with PBI/APBI (odds ratio (OR) 1.51, 95% CI 1.17 to 1.95, five studies, 1720 participants, low-quality evidence). Overall survival did not differ with PBI/APBI (HR 0.90, 95% CI 0.74 to 1.09, five studies, 6718 participants, high-quality evidence). Late radiation toxicity (subcutaneous fibrosis) appeared worse with PBI/APBI (OR 6.58, 95% CI 3.08 to 14.06, one study, 766 participants, moderate-quality evidence). Acute skin toxicity appeared reduced with PBI/APBI (OR 0.04, 95% CI 0.02 to 0.09, two studies, 608 participants). Telangiectasia (OR 26.56, 95% CI 3.59 to 196.51, 1 study, 766 participants) and radiological fat necrosis (OR 1.58, 95% CI 1.02 to 2.43, three studies, 1319 participants) appeared worse with PBI/APBI. Late skin toxicity (OR 0.21, 95% CI 0.01 to 4.39, two studies, 608 participants) and breast pain (OR 2.17, 95% CI 0.56 to 8.44, one study, 766 participants) appeared not to differ with PBI/APBI. 'Elsewhere primaries' (new primaries in the ipsilateral breast) appeared more frequent with PBI/APBI (OR 3.97, 95% CI 1.51 to 10.41, three studies, 3009 participants). We found no clear evidence of a difference for the comparison of PBI/APBI with WBRT for the outcomes of: cause-specific survival (HR 1.08, 95% CI 0.73 to 1.58, five studies, 6718 participants, moderate-quality evidence), distant metastasis-free survival (HR 0.94, 95% CI 0.65 to 1.37, four studies, 3267 participants, moderate-quality evidence), relapse-free survival (HR 1.36, 95% CI 0.88 to 2.09, three studies, 3811 participants), loco-regional recurrence-free survival (HR 1.80, 95% CI 1.00 to 3.25, two studies, 3553 participants) or mastectomy rates (OR 1.20, 95% CI 0.77 to 1.87, three studies, 4817 participants, low-quality evidence). Compliance was met: more than 90% of the women in all studies received the RT they were assigned to receive. We found no data for the outcomes of costs, quality of life or consumer preference. It appeared that local recurrence and 'elsewhere primaries' (new primaries in the ipsilateral breast) are increased with PBI/APBI (the difference was small), but we found no evidence of detriment to other oncological outcomes. It appeared that cosmetic outcomes and some late effects were worse with PBI/APBI but its use was associated with less acute skin toxicity. The limitations of the data currently available mean that we cannot make definitive conclusions about the efficacy and safety or ways to deliver of PBI/APBI. We await completion of ongoing trials.

seven studies, which involved 7586 women. Our evidence is current to May 2015. Local recurrence was rare, but more common with PBI (low-quality evidence) and the breast appearance (scored by doctors) was worse with PBI (low-quality evidence). Survival did not differ (high-quality evidence). Scarring in the breast was worse with PBI (moderate-quality evidence). The same number of women died of breast cancer with either treatment (moderate-quality evidence). The same number of women developed spread of breast cancer around their body with either treatment (moderate-quality evidence). There appeared to be the same number of women who eventually needed the breast removed (mastectomy) after both treatments. Mastectomy could happen because of cancer regrowth in the breast or bad side effects (low-quality evidence). that at the moment, PBI does not give the same cancer control in the breast as treating the whole breast, but the difference was small. It may cause worse side effects. There are five big ongoing studies that will be important to answer this question. We hope to have a clearer answer in the next update of this review.

10.1002/14651858.CD007077.pub3

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Four studies with a total of 141 participants were included in the review, two of these were in children (aged six months to 14.5 years), and the other two did not specify participants’ age. All studies used different formulations and doses of vitamin E for various durations of treatment (10 days to six months). Two studies compared the supplementation of fat-soluble as well as water-soluble formulations to no supplementation in different arms of the same study. A third study compared a water-soluble formulation to a placebo; and in the fourth study a fat-soluble formulation of vitamin E was assessed against placebo. At one month, three months and six months, water-soluble vitamin E significantly improved serum vitamin E levels compared with control: at one month, two studies, mean difference 17.66 (95% confidence interval 10.59 to 24.74); at three months, one study, mean difference 11.61 (95% confidence interval 4.77 to 18.45); and at six months, one study, mean difference 19.74 (95% confidence interval 13.48 to 26.00). At one month fat-soluble vitamin E significantly improved serum vitamin E levels compared with control: one month, two studies, mean difference 13.59 (95% CI 9.52 to 17.66). The findings at three months were imprecise; one study; mean difference 6.40 (95% confidence interval -1.45 to 14.25). None of the studies report the review's primary outcomes of vitamin E total lipid ratio or the incidence of vitamin E-specific deficiency disorders, or the secondary outcomes lung function or quality of life. Only one study, comparing water-soluble vitamin E with placebo, reported the secondary outcome of growth and nutritional status (weight), but the results are uncertain due to imprecision around the effect estimate. There was limited detail about randomisation and blinding in the included studies which compromises the quality of the evidence base for the review. The heterogeneous mix of the formulations with differing biovailabilities among these studies also limits the generalisability of the data to the wider cystic fibrosis population. Vitamin E supplementation led to an improvement in vitamin E levels in people with cystic fibrosis, although the studies may have been at risk of bias. No data on other outcomes of interest were available to allow conclusions about any other benefits of this therapy. In future, larger studies are needed, especially in people already being treated with enteric-coated pancreatic enzymes and supplemented with vitamin E, to look at more specific outcome measures such as vitamin E status, lung function and nutritional status. Future studies could also look at the optimal dose of vitamin E required to achieve maximal clinical effectiveness.

The review identified four studies including 141 participants; two of these were in children (aged six months to 14.5 years) and the other two did not specify the age of the participants. The people taking part in the studies received different forms of vitamin E supplements (either water-soluble or fat-soluble), placebo (a substance containing no medication) or no supplements. Three studies stated that the treatment for each person was chosen at random, but one study only said the people were split into different groups. Three of the studies showed an improvement in vitamin E levels after supplementation, but result should be interpreted with caution due to potential risks of bias. No studies reported any disorders related to vitamin E deficiency. As the studies used different forms of supplements and different doses, it was difficult to combine the results and apply them to the wider cystic fibrosis population, but the results did show that vitamin E supplementation can lead to an improvement in vitamin E levels in people with cystic fibrosis and may help avoid problems caused by vitamin E deficiency. Future trials, especially in people already receiving treatment with pancreatic enzymes and vitamin E supplements, should look at more specific outcomes such as vitamin E status, lung function and nutritional status. They could also look at the best level of vitamin E supplements needed to be most clinically effective. We do not think that any of the people taking part in the studies could tell whether they received the supplements or the placebo, so that would not have affected the results; although they would have known if they were taking supplements or not taking anything. We could not tell from the information we have whether most of the studies were designed so all people had an equal chance of being in any of the groups. We also could not tell if anyone would have been able to guess in advance which group they would be in. It was also not clear if there were results reported for everyone taking part in the studies and the reasons why anyone might have dropped out of the studies. We do not know if these facts will affect our confidence in the results.

10.1002/14651858.CD009422.pub3

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Two RCTs from Kenya were included in the review. One trial compared short weekly text messages against standard care. The other trial compared short daily, long daily, short weekly and long weekly messages against standard care. Both trials were with adult patients. In the trial comparing only short weekly messages to standard care, text messaging was associated with a lower risk of non-adherence at 12 months (RR 0.77, 95% CI 0.63 to 0.93) and with the non-occurrence of virologic failure at 12 months (RR 0.83, 95% CI 0.69 to 0.99). In the trial that compared different intervals and lengths for text-messaging to standard care, long weekly text-messaging was not significantly associated with a lower risk of non-adherence compared to standard care (RR 0.79, 95% CI 0.60 to 1.04). Patients receiving weekly text-messages of any length were at lower risk of non-adherence at 48 weeks than were patients receiving daily messages of any length (RR 0.79, 95% CI 0.64 to 0.99). There were no significant differences between weekly text-messaging of any length (RR 1.01, 95% CI 0.75 to 1.37) and between short or long messaging at either interval (RR 0.99, 95% CI 0.78 to 1.27). Compared to standard care, any daily text-messaging, whether short or long, did not reduce the risk for non-adherence (RR 0.99, 95% CI 0.82 to 1.20). In meta-analysis of both trials, any weekly text-messaging (i.e. whether short or long messages) was associated with a lower risk of non-adherence at 48-52 weeks (RR 0.78, 95% CI 0.68 to 0.89). The effect of short weekly text-messaging was also significant (RR 0.77, 95% CI 0.67 to 0.89). There is high-quality evidence from the two RCTs that mobile phone text-messaging at weekly intervals is efficacious in enhancing adherence to ART, compared to standard care. There is high quality evidence from one trial that weekly mobile phone text-messaging is efficacious in improving HIV viral load suppression. Policy-makers should consider funding programs proposing to provide weekly mobile phone text-messaging as a means for promoting adherence to antiretroviral therapy. Clinics and hospitals should consider implementing such programs. There is a need for large RCTs of this intervention in adolescent populations, as well as in high-income countries.

Two randomised controlled trials from Kenya were included in the review. One trial compared short weekly text messages against standard care. The other trial compared short daily, long daily, short weekly and long weekly messages against standard care. In the trial comparing only short weekly messages to standard care, text messaging was associated with lower risk of non-adherence at 12 months, and with the non-occurrence of virologic failure at 12 months. Combining the data from both trials, weekly mobile phone text-messaging was associated with greater ART adherence at 48-52 weeks. The effect of short weekly text-messaging was also significant. In the trial that compared different intervals and lengths for text-messaging to standard care, long weekly text-messaging was not significantly associated with a lower risk of non-adherence compared to standard care. Patients receiving weekly text-messages of any length were at lower risk of non-adherence at 48 weeks than were patients receiving daily messages of any length. There were no significant differences between weekly text-messaging of any length and between short or long messaging at either interval. Compared to standard care, any daily text-messaging, whether short or long, did not reduce the risk for non-adherence. Weekly mobile phone text messages to patients on ART can help them to take their medication every day. It can also help to reduce the amount of HIV in their bloodstream. Because the two included trials were with adult patients only, there is a need for trials of this intervention with adolescents. Also, as the two trials were conducted in Kenya, a low-income country, there is a need for trials of this intervention in high-income countries.

10.1002/14651858.CD009756

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When the described search method was used and the eligibility criteria of the search results were applied, 653 records were found. Only two of these were randomised clinical trials that were considered eligible for inclusion. We assessed both trials as trials with high risk of bias. One of the trials was a pilot trial in which 16 participants with biopsy-proven NASH were randomised to receive simvastatin 40 mg (n = 10) or placebo (n = 6) once daily for 12 months. No statistically significant improvement in the aminotransferase level was seen in the simvastatin group compared with the placebo group. Liver histology was not significantly affected by simvastatin. The other trial had three arms. The trial compared atorvastatin 20 mg daily (n = 63) versus fenofibrate 200 mg daily (n = 62) versus a group treated with a combination of the two interventions (n = 61). There were no statistically significant differences between any of the three intervention groups regarding the week 54 mean activity levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. The triglyceride levels seemed higher in the fenofibrate group compared with the atorvastatin group. Liver histology was not assessed in this trial. The presence of biochemical and ultrasonographic evidence of NAFLD seemed to be higher in the fenofibrate group compared with the atorvastatin group (58% versus 33%). Three patients discontinued treatment due to myalgia and elevated serum creatine kinase activity; one from the atorvastatin group and two from the combination group. Another patient from the atorvastatin group discontinued treatment due to alanine aminotransferase activity that was over three times the upper normal limit. No data for all-cause mortality and hepatic-related mortality were reported in the included trials. Based on the findings of this review, which included two trials with high risk of bias and a small numbers of participants, it seems possible that statins may improve serum aminotransferase levels as well as ultrasound findings. Neither of the trials reported on possible histological changes, liver-related morbidity or mortality. Trials with larger sample sizes and low risk of bias are necessary before we may suggest statins as an effective treatment for patients with NASH. However, as statins can improve the adverse outcomes of other conditions commonly associated with NASH (for example, hyperlipidaemia, diabetes mellitus, metabolic syndrome), their use in patients with non-alcoholic steatohepatitis may be justified.

This systematic review identified two randomised clinical trials with very small numbers of participants. One of the trials was a pilot trial and compared simvastatin with placebo, and the other trial assessed atorvastatin versus fenofibrate versus a combination of the two. The small pilot trial (n = 16 patients) assessing simvastatin versus placebo in NASH patients did not show significant effects on liver enzyme activities or liver histology. No adverse events were reported. The other trial compared atorvastatin versus fenofibrate versus a group receiving both interventions in 186 patients with NAFLD. There were no statistically significant differences between any of the three intervention groups regarding the 54 week mean activities of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, or alkaline phosphatases (liver enzymes) in the blood. The triglyceride levels seemed higher in the fenofibrate group compared with the atorvastatin group. Liver histology was not assessed in this trial. The presence of biochemical and ultrasonographic evidence of NAFLD seemed higher in the fenofibrate group compared with the other two intervention groups. Three patients discontinued treatment due to myalgia and elevated serum creatine kinase activity, one from the atorvastatin group and two from the combination group. Another patient from the atorvastatin group discontinued treatment due to raised alanine aminotransferase activity, over three times the upper normal limit. Both trials were at high risk of bias (that is, overestimation of benefits and underestimation of harms). Furthermore, the groups were small raising the risks of random errors (that is, play of chance). Accordingly, we did not find evidence to support or refute the use of statins for patients with NAFLD or NASH. Further unbiased trials with larger numbers of patients looking explicitly at patient-related outcomes of interest (for example, quality of life, development of cirrhosis, and mortality) are needed to assess the effects of statins on NAFLD or NASH.

10.1002/14651858.CD008623.pub2

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We included one RCT with 184 participants comparing Aquablation to TURP. The mean age and International Prostate Symptom Score were 65.9 years and 22.6, respectively. The mean prostate volume was 53.2 mL. We only found short-term data for all outcomes based on a single randomised trial. Primary outcomes Up to 12 months, Aquablation likely results in a similar improvement in urologic symptom scores to TURP (mean difference (MD) −0.06, 95% confidence interval (CI) −2.51 to 2.39; participants = 174; moderate-certainty evidence). We downgraded the evidence certainty by one level due to study limitations. Aquablation may also result in similar quality of life when compared to TURP (MD 0.27, 95% CI −0.24 to 0.78; participants = 174, low-certainty evidence). We downgraded the evidence certainty by two levels due to study limitations and imprecision. Aquablation may result in little to no difference in major adverse events (risk ratio (RR) 0.84, 95% CI 0.31 to 2.26; participants = 181, very low-certainty evidence) but we are very uncertain of this finding. This would correspond to 15 fewer major adverse events per 1000 participants (95% CI 64 fewer to 116 more). We downgraded the evidence certainty by one level for study limitations and two levels for imprecision. Secondary outcomes Up to 12 months, Aquablation may result in little to no difference in retreatments (RR 1.68, 95% CI 0.18 to 15.83; participants = 181, very low-certainty evidence) but we are very uncertain of this finding. This would correspond to 10 more retreatments per 1000 participants (95% CI 13 fewer to 228 more). We downgraded the evidence certainty by one level due to study limitations and two levels for imprecision. Aquablation may result in little to no difference in erectile function as measured by International Index of Erectile Function questionnaire Erectile Function domain compared to TURP (MD 2.31, 95% CI −0.63 to 5.25; participants = 64, very low-certainty evidence), and may cause slightly less ejaculatory dysfunction than TURP, as measured by Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MD 2.57, 95% CI 0.60 to 4.53; participants = 121, very low-certainty evidence). However, we are very uncertain of both findings. We downgraded the evidence certainty by two levels due to study limitations and one level for imprecision for both outcomes. We did not find other prospective, comparative studies comparing Aquablation to TURP or other procedures such as laser ablation, enucleation, or other minimally invasive therapies. Based on short-term (up to 12 months) follow-up, the effect of Aquablation on urological symptoms is probably similar to that of TURP (moderate-certainty evidence). The effect on quality of life may also be similar (low-certainty evidence). We are very uncertain whether patients undergoing Aquablation are at higher or lower risk for major adverse events (very low-certainty evidence). We are very uncertain whether Aquablation may result in little to no difference in erectile function but offer a small improvement in preservation of ejaculatory function (both very low-certainty evidence). These conclusions are based on a single study of men with a prostate volume up to 80 mL in size. Longer-term data and comparisons with other modalities appear critical to a more thorough assessment of the role of Aquablation for the treatment of LUTS in men with BPH.

We looked for all studies that compared Aquablation to transurethral resection of the prostate. We included both studies in chance decided how men were treated and studies in which men and their urologist decided. We searched for studies up to 11 February 2019. We found only one study in which chance decided how men were treated. The study compared Aquablation to transurethral resection of the prostate. On average, men were about 66 years old. We did not find any other studies. We found that Aquablation likely improves urinary symptoms similarly to transurethral resection of the prostate and may also lead to similar quality of life. Rates of unwanted serious effects may also be similar but we are very uncertain about this. Men who have Aquablation may have a similar risk of needing a repeat procedure as those having transurethral resection of the prostate but we are very uncertain of this finding. Aquablation may make little to no difference to erectile function but may have fewer issues with ejaculation, but we are very uncertain of both findings. These findings are based on a single study funded by the company that makes the device used for Aquablation. All data were limited to 12 months' follow-up or less and prostate size was less than or equal to 80 mL. Our certainty about the evidence we found ranged from moderate to very low due to shortcomings in how the study was done and small study size. This means that we have either moderate, limited or very little confidence in the results, depending on the outcome.

10.1002/14651858.CD013143.pub2

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Two new trials were included in this update. Baker 2003 was an expanded study of Baker 2001 reported in the previous version. Both Baker 2003 and van Weert 2005 examined the short-term and longer-term effects of snoezelen on behaviour, mood, and communication of people with moderate to severe dementia. The format of implementation was different in the two trials: one was session-based snoezelen programme (Baker 2003), whilst the other was a 24-hour integrated snoezelen care (van Weert 2005). Owing to the differences in study methodology, the results of the two trials were not pooled for analysis. The session-based snoezelen programme (Baker 2003) did not show any effects on behaviour, mood, cognition and communication / interaction in the short term (during or immediately after sessions) or longer term (at post-intervention or 1-month post-intervention follow-up). Likewise, the 24-hour integrated snoezelen care (van Weert 2005) failed to demonstrate any significant short-term and longer term effects on behaviour, mood and interaction. A more vigorous review methodology was adopted in this update. The study of Kragt 1997, reported in the previous version, was excluded because the snoezelen programme only consisted of three sessions, which was considered too brief for a therapeutic intervention. Two new trials were reviewed. Meta-analyses could not be performed because of the limited number of trials and different study methods of the available trials. Overall, there is no evidence showing the efficacy of snoezelen for dementia. There is a need for more reliable and sound research-based evidence to inform and justify the use of snoezelen in dementia care.

Originally, two randomised clinical trials were available for this review. Some short-term benefits were documented in promoting adaptive behaviours in people with dementia during and immediately after their participation in the sessions. In this update, two new trials were included and revealed two different forms of applying snoezelen to dementia care. One is a session-based snoezelen programme while the other is a 24-hour integrated snoezelen care programme. Both trials did not show any significant effects on behaviour, interaction, and mood of people with dementia.

10.1002/14651858.CD003152

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Twenty-one trials with 2570 participants met the inclusion criteria; 18 trials with 2376 participants for the prevention of dry socket and three studies with 194 participants for the treatment of dry socket. The risk of bias assessment identified six studies at high risk of bias, 14 studies at unclear risk of bias and one studies at low risk of bias. When compared to placebo, rinsing with chlorhexidine mouthrinses (0.12% and 0.2% concentrations) both before and after extraction(s) prevented approximately 42% of dry socket(s) with a RR of 0.58 (95% CI 0.43 to 0.78; P < 0.001) (four trials, 750 participants, moderate quality of evidence). The prevalence of dry socket varied from 1% to 5% in routine dental extractions to upwards of 30% in surgically extracted third molars. The number of patients needed to be treated with (0.12% and 0.2%) chlorhexidine rinse to prevent one patient having dry socket (NNT) was 232 (95% CI 176 to 417), 47 (95% CI 35 to 84) and 8 (95% CI 6 to 14) for control prevalences of dry socket of 1%, 5% and 30% respectively. Compared to placebo, placing chlorhexidine gel (0.2%) after extractions prevented approximately 58% of dry socket(s) with a RR of 0.42 (95% CI 0.21 to 0.87; P = 0.02) (two trials, in 133 participants, moderate quality of evidence). The number of patients needed to be treated with chlorhexidine gel to prevent one patient having dry socket (NNT) was 173 (95% CI 127 to 770), 35 (95% CI 25 to 154) and 6 (95% CI 5 to 26) for control prevalences of dry socket of 1%, 5% and 30% respectively. A further 10 intrasocket interventions to prevent dry socket were each evaluated in single studies, and therefore there is insufficient evidence to determine their effects. Five interventions for the treatment of dry socket were evaluated in a total of three studies providing insufficient evidence to determine their effects. Most tooth extractions are undertaken by dentists for a variety of reasons, however, all but three studies included in the present review included participants undergoing extraction of third molars, most of which were undertaken by oral surgeons. There is some evidence that rinsing with chlorhexidine (0.12% and 0.2%) or placing chlorhexidine gel (0.2%) in the sockets of extracted teeth, provides a benefit in preventing dry socket. There was insufficient evidence to determine the effects of the other 10 preventative interventions each evaluated in single studies. There was insufficient evidence to determine the effects of any of the interventions to treat dry socket. The present review found some evidence for the association of minor adverse reactions with use of 0.12%, 0.2% and 2% chlorhexidine mouthrinses, though most studies were not designed to detect the presence of hypersensitivity reactions to mouthwash as part of the study protocol. No adverse events were reported in relation to the use of 0.2% chlorhexidine gel placed directly into a socket (though previous allergy to chlorhexidine was an exclusion criterion in these trials). In view of recent reports in the UK of two cases of serious adverse events associated with irrigation of dry socket with chlorhexidine mouthrinse, it is recommended that all members of the dental team prescribing chlorhexidine products are aware of the potential for both minor and serious adverse side effects.

The studies looked at adults over 18 years of age and included (amongst others) people who smoked and took oral contraceptives (both possible risk factors). However, studies involving people who were extremely ill or who had compromised immune systems were not included. Studies which looked at the use of antibiotics to manage dry socket were also not included. Prevention It was found that there is some evidence to show that rinsing both before and after tooth extraction with chlorhexidine gluconate rinse (at 0.12% and 0.2% strength) reduced the risk of having a dry socket. Placing chlorhexidine gel (0.2% strength) in the socket of an extracted tooth also reduced the risk of having dry socket. The risk of developing dry socket depends on many factors, some of which are unknown. Your dentist or dental care professional (DCP) should be able to advise you of your own risk status. To illustrate the effectiveness of chlorhexidine treatment as a preventive measure: if the risk of contracting alveolar osteitis (dry socket) was 1% (one in a hundred) then 232 people undergoing tooth extractions would need to be treated to prevent one case of dry socket; if the risk was 5%, then the number needed to be treated to prevent one case of dry socket would be 47; if the risk rises to 30%, the number needed to be treated to prevent one case of dry socket would be 8. In these trials no serious side effects or reactions by patients due to chlorhexidine were reported. However, two serious events associated with the use of chlorhexidine mouthwash for irrigation of dry socket have been reported in the UK. If people have a history of allergies or have had adverse reactions previously to the use of chlorhexidine mouthwashes they should tell their dentist or DCP before using chlorhexidine. They should also tell their dentist or DCP if they experience any unusual symptoms such as rashes, itching or swelling of the lips whilst using chlorhexidine. It is recommended that all members of the dental team prescribing chlorhexidine products are aware of the potential for both minor and serious side effects, are competent to manage a medical emergency associated with anaphylaxis (toxic shock) and warn patients of the potential for adverse events. Treatment There was insufficient evidence to conclude whether any treatments relieved established dry socket or not.

10.1002/14651858.CD006968.pub2

cochrane-simplification-train-135

cochrane-simplification-train-135

A total of 43 trials (35 RCTs and eight qRCTs) with 7465 participants were identified. Twenty-two trials with 5546 participants were involved in prevention of Aloe vera for phlebitis, and a further 21 trials with 1919 participants were involved in the treatment of phlebitis. The included studies compared external application of Aloe vera alone or plus non-Aloe vera interventions with no treatment or the same non-Aloe vera interventions. The duration of the intervention lasted from one day to 15 days. Most of the included studies were of low methodological quality with concerns for selection bias, attrition bias, reporting bias and publication bias. The effects of external application of fresh Aloe vera on preventing total incidence of phlebitis varied across the studies and we did not combine the data. Aloe vera reduced the occurrence of third degree phlebitis (RR 0.06, 95% CI 0.03 to 0.11, P < 0.00001) and second degree phlebitis (RR 0.18, 95% CI 0.10 to 0.31, P < 0.00001) compared with no treatment. Compared with external application of 75% alcohol, or 33% MgSO4 alone, Aloe vera reduced the total incidence of phlebitis (RR 0.02, 95% CI 0.00 to 0.28, P = 0.004 and RR 0.43, 95% CI 0.24 to 0.78, P = 0.005 respectively) but there was no clear evidence of an effect when compared with 50% or 75% MgSO4 (total incidence of phlebitis RR 0.41, 95% CI 0.16 to 1.07, P = 0.07 and RR 1.10 95% CI 0.54 to 2.25, P = 0.79 respectively; third degree phlebitis (RR 0.28, 95% CI 0.07 to 1.02, P = 0.051 and RR 1.19, 95% CI 0.08 to 18.73, P = 0.9 respectively; second degree phlebitis RR 0.68, 95% CI 0.21 to 2.23, P = 0.53 compared to 75% MgSO4) except for a reduction in second degree phlebitis when Aloe vera was compared with 50% MgSO4 (RR 0.26, 95% CI 0.14 to 0.50, P < 0.0001). For the treatment of phlebitis, Aloe vera was more effective than 33% or 50% MgSO4 in terms of both any improvement (RR 1.16, 95% CI 1.09 to 1.24, P < 0.0001 and RR 1.22, 95% CI 1.16 to 1.28, P < 0.0001 respectively) and marked improvement of phlebitis (RR 1.97, 95% CI 1.44 to 2.70, P < 0.001 and RR 1.56, 95% CI 1.29 to 1.87, P = 0.0002 respectively). Compared with 50% MgSO4, Aloe vera also improved recovery rates from phlebitis (RR 1.42, 95% CI 1.24 to 1.61, P < 0.0001). Compared with routine treatments such as external application of hirudoid, sulphonic acid mucopolysaccharide and dexamethasone used alone, addition of Aloe vera improved recovery from phlebitis (RR 1.75, 95% CI 1.24 to 2.46, P = 0.001) and had a positive effect on overall improvement (marked improvement RR 1.26, 95% CI 1.09 to 1.47, P = 0.0003; any improvement RR 1.23, 95% CI 1.13 to 1.35, P < 0.0001). Aloe vera, either alone or in combination with routine treatment, was more effective than routine treatment alone for improving the symptoms of phlebitis including shortening the time of elimination of red swelling symptoms, time of pain relief at the location of the infusion vein and time of resolution of phlebitis. Other secondary outcomes including health-related quality of life and adverse effects were not reported in the included studies. There is no strong evidence for preventing or treating infusion phlebitis with external application of Aloe vera. The current available evidence is limited by the poor methodological quality and risk of selective outcome reporting of the included studies, and by variation in the size of effect across the studies. The positive effects observed with external application of Aloe vera in preventing or treating infusion phlebitis compared with no intervention or external application of 33% or 50% MgSO4 should therefore be viewed with caution.

This review examined 35 randomised controlled trials and eight quasi-randomised controlled trials with 7465 participants. Twenty-two trials with 5546 participants were involved in looking at prevention of phlebitis with Aloe vera, and a further 21 trials with 1919 participants were involved in looking at Aloe vera for the treatment of phlebitis. The included trials mainly compared external application of fresh Aloe vera alone or with another non-Aloe vera treatment such as a wet compress of 75% alcohol or 33%, 50% or 75% MgSO4 with no treatment or the same non-Aloe vera treatment. The duration of intervention lasted from one day to 15 days. Most of the included studies were of low methodological quality with concerns for selection bias, attrition bias, reporting bias and publication bias. The incidence of phlebitis at varying degrees of severity as well as the resolution rate and level of improvement of phlebitis were investigated. The available evidence suggests that external application of fresh Aloe vera alone or combined with other non-Aloe vera treatment may be effective for the prevention and treatment of infusion phlebitis resulting from the intravenous therapy. The conclusions should be cautiously interpreted due to the low methodological quality of the included trials.

10.1002/14651858.CD009162.pub2

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cochrane-simplification-train-136

We included 14 studies that evaluated the effect of training and education on RPE use, which involved 2052 participants. The included studies had been conducted with farm, healthcare, production line, office and coke oven workers as well as nursing students and people with mixed occupations. All included studies reported the effects of interventions as use of RPE, as correct use of RPE or as indirect measures of RPE use. We did not find any studies where the intervention was delivered and assessed at the whole organization level or in which the main focus was on positive or negative incentives. We rated the quality of the evidence for all comparisons as low to very low. Training versus no training One CBA study in healthcare workers compared training with and without a fit test to no intervention. The study found that the rate of properly fitting respirators was not considerably different in the workers who had received training with a fit test (RR 1.17, 95% Confidence Interval (CI) 0.97 to 1.10) or training without a fit test (RR 1.16, 95% CI 0.95 to 1.42) compared to those who had no training. Two RCTs that evaluated training did not contribute to the analyses because of lack of data. Conventional training plus additions versus conventional training alone One cluster-randomised trial compared conventional training plus RPE demonstration versus training alone and reported no significant difference in appropriate use of RPE between the two groups (RR 1.41, 95% CI 0.96 to 2.07). One RCT compared interactive training with passive training, with an information screen, and an information book. The mean RPE performance score for the active group was not different from that of the passive group (MD 2.10, 95% CI -0.76 to 4.96). However, the active group scored significantly higher than the book group (MD 4.20, 95% CI 0.89 to 7.51) and the screen group (MD 7.00, 95% CI 4.06 to 9.94). One RCT compared computer-simulation training with conventional personal protective equipment (PPE) training but reported only results for donning and doffing full-body PPE. Education versus no education One RCT found that a multifaceted educational intervention increased the use of RPE (risk ratio (RR) 1.69, 95% CI 1.10 to 2.58) at three years' follow-up when compared to no intervention. However, there was no difference between intervention and control at one year's, two years' or four years' follow-up. Two RCTs did not report enough data to be included in the analysis. Four CBA studies evaluated the effectiveness of education interventions and found no effect on the frequency or correctness of RPE use, except in one study for the use of an N95 mask (RR 4.56, 95% CI 1.84 to 11.33, 1 CBA) in workers. Motivational interviewing versus traditional lectures One CBA study found that participants given motivational group interviewing-based safety education scored higher on a checklist measuring PPE use (MD 2.95, 95% CI 1.93 to 3.97) than control workers given traditional educational sessions. There is very low quality evidence that behavioural interventions, namely education and training, do not have a considerable effect on the frequency or correctness of RPE use in workers. There were no studies on incentives or organisation level interventions. The included studies had methodological limitations and we therefore need further large RCTs with clearer methodology in terms of randomised sequence generation, allocation concealment and assessor blinding, in order to evaluate the effectiveness of behavioural interventions for improving the use of RPE at both organisational and individual levels. In addition, further studies should consider some of the barriers to the successful use of RPE, such as experience of health risk, types of RPE and the employer's attitude to RPE use.

We searched for relevant research studies up to 20 August 2016. We found 14 studies that analysed the effectiveness of behavioural interventions to promote RPE use. We also located one ongoing study. Studies had been conducted with 2052 farm, healthcare, production line, office and coke oven workers as well as nursing students and people with mixed occupations. We did not find any studies where the researchers conducted and assessed an intervention at the level of a whole organization. What the research says All included studies compared different education and training interventions to encourage workers to use RPE correctly or more often. We found very low quality evidence that behavioural interventions such as education and training do not increase the number of workers that use RPE or that use RPE correctly. What is the bottom line We conclude that there is low to very low quality evidence that behavioural interventions do not encourage workers to use RPE correctly or more often. It is likely that our conclusions will change when new studies are published. We need better quality studies that look at the effectiveness of different types of interventions. These interventions should be targeted at both individuals and organisations, to improve effective RPE use. In addition, further studies should consider some of the barriers to the successful use of RPE, such as experience of health risk, types of RPE and the employer's attitude to RPE use.

10.1002/14651858.CD010157.pub2

cochrane-simplification-train-137

cochrane-simplification-train-137

We included three trials (four interventions) involving 196 participants with stroke and co-morbid anxiety. One trial (described as a 'pilot study') randomised 21 community-dwelling stroke survivors to four-week use of a relaxation CD or to wait list control. This trial assessed anxiety using the Hospital Anxiety and Depression Scale and reported a reduction in anxiety at three months among participants who had used the relaxation CD (mean (standard deviation (SD) 6.9 (± 4.9) and 11.0 (± 3.9)), Cohen's d = 0.926, P value = 0.001; 19 participants analysed). The second trial randomised 81 participants with co-morbid anxiety and depression to paroxetine, paroxetine plus psychotherapy, or standard care. Mean levels of anxiety severity scores based on the Hamilton Anxiety Scale (HAM-A) at follow-up were 5.4 (SD ± 1.7), 3.8 (SD ± 1.8), and 12.8 (SD ± 1.9), respectively (P value < 0.01). The third trial randomised 94 stroke patients, also with co-morbid anxiety and depression, to receive buspirone hydrochloride or standard care. At follow-up, the mean levels of anxiety based on the HAM-A were 6.5 (SD ± 3.1) and 12.6 (SD ± 3.4) in the two groups, respectively, which represents a significant difference (P value < 0.01). Half of the participants receiving paroxetine experienced adverse events that included nausea, vomiting, or dizziness; however, only 14% of those receiving buspirone experienced nausea or palpitations. Trial authors provided no information about the duration of symptoms associated with adverse events. The trial of relaxation therapy reported no adverse events. The quality of the evidence was very low. Each study included a small number of participants, particularly the study of relaxation therapy. Studies of pharmacological agents presented details too limited to allow judgement of selection, performance, and detection bias and lack of placebo treatment in control groups. Although the study of relaxation therapy had allocated participants to treatment using an adequate method of randomisation, study recruitment methods might have introduced bias, and drop-outs in the intervention group may have influenced results. Evidence is insufficient to guide the treatment of anxiety after stroke. Further well-conducted randomised controlled trials (using placebo or attention controls) are required to assess pharmacological agents and psychological therapies.

Evidence is current to January 2017. We found three studies with 196 stroke survivors who had received a diagnosis of anxiety. One study assessed the effect of a relaxation CD used five times a week for one month for participants with a diagnosis of anxiety. Two studies assessed the use of antidepressants in participants who had both anxiety and depression. One study found that participants were less anxious three months after using a relaxation CD when compared with those who were given no therapy. One study reported that participants were less anxious when treated with an antidepressant medicine (paroxetine), or with paroxetine and psychotherapy, than with standard care. This study reported that half of the participants receiving paroxetine experienced side effects that included nausea, vomiting, or dizziness. The third study also reported that participants were less anxious when treated with an antidepressant (buspirone hydrochloride) than with standard care, and only 14% of those receiving buspirone hydrocholoride reported nausea or palpitations. We judged that the quality of this evidence was very low. Studies were few and each included a small number of participants. Studies assessing antidepressants did not include comparison with a placebo drug, and information in both study reports was insufficient to permit assessment of whether other biases had been introduced. The study of relaxation therapy was very small, with loss of two participants who used the CD, and the study recruitment process may have attracted participants who had a positive bias towards psychological therapies. Current evidence is insufficient to guide the treatment of anxiety after stroke. Additional well-conducted randomised trials are needed.

10.1002/14651858.CD008860.pub3

cochrane-simplification-train-138

cochrane-simplification-train-138

We identified five RCTs involving 167 participants (mean age ranged from 54 to 72.5 years; sample size ranged from 19 to 60 participants). Overall, we found that the risk of bias in the included studies was high, and the quality of evidence for all outcomes was low. Pooled data from four studies demonstrated that preoperative exercise training reduced the risk of developing a postoperative pulmonary complication by 67% (risk ratio (RR) 0.33, 95% CI 0.17 to 0.61). The number of days patients in the exercise group needed an intercostal catheter was lower than in the non-exercise group (mean difference (MD) -3.33 days, 95% CI -5.35 to -1.30 days; two studies); postoperative length of hospital stay was also lower in the exercise group (MD -4.24 days, 95% CI -5.43 to -3.06 days; four studies). Pooled data from two studies demonstrated that compared to the non-exercise group, post-intervention 6-minute walk distance (MD 18.23 m, 95% CI 8.50 to 27.96 m), and post-intervention FVC (MD 2.97% predicted, 95% CI 1.78 to 4.16% predicted) were higher in the exercise group. Preoperative exercise training may reduce the risk of developing a postoperative pulmonary complication, the duration of intercostal catheter use, postoperative length of hospital stay, and improve both exercise capacity and FVC in people undergoing lung resection for NSCLC. The findings of this review should be interpreted with caution due to disparities between the studies, risk of bias, and small sample sizes. This review emphasises the need for larger RCTs.

The evidence is current to November 2016. This review included data from 167 participants (mean age ranged from 54 to 72.5 years) in five studies (sample size of the included studies ranged from 19 to 60 participants). Results from our review showed that compared to a control group that did not exercise before lung surgery, people with NSCLC who exercised before lung surgery had 67% less risk of developing a postoperative lung complication. Based on this result, we would expect that out of 100 people with NSCLC who exercise before lung surgery, seven will experience a postoperative lung complication, compared with 22 people with NSCLC who will experience a postoperative lung complication if they do not exercise before lung surgery. Also, compared to the control group, people with NSCLC who exercised before lung surgery had a chest drain for fewer days (three days less), had a shorter length of hospital stay (four days less), and better 6-minute walk distance (18 metres more), and lung function before surgery (3% better). The overall quality of evidence was low for all of the outcomes, mainly because of the small number of studies found, the small number of participants in the included studies, and limitations in the studies' methods.

10.1002/14651858.CD012020.pub2

cochrane-simplification-train-139

cochrane-simplification-train-139

We identified 1036 records, scrutinized 52 full-text articles and included 19 completed RCTs (one trial is awaiting assessment). A total of 2216 participants entered the trials, 1280 participants were randomly assigned to fluoxetine (60 mg/d, 40 mg/d, 20 mg/d and 10 mg/d) and 936 participants were randomly assigned to various comparison groups (placebo; the anti-obesity agents diethylpropion, fenproporex, mazindol, sibutramine, metformin, fenfluramine, dexfenfluramine, fluvoxamine, 5-hydroxy-tryptophan; no treatment; and omega-3 gel). Within the 19 RCTs there were 56 trial arms. Fifteen trials were parallel RCTs and four were cross-over RCTs. The participants in the included trials were followed up for periods between three weeks and one year. The certainty of the evidence was low or very low: the majority of trials had a high risk of bias in one or more of the risk of bias domains. For our main comparison group — fluoxetine versus placebo — and across all fluoxetine dosages and durations of treatment, the MD was −2.7 kg (95% CI −4 to −1.4; P < 0.001; 10 trials, 956 participants; low-certainty evidence). The 95% prediction interval ranged between −7.1 kg and 1.7 kg. The MD in body mass index (BMI) reduction across all fluoxetine dosages compared with placebo was −1.1 kg/m² (95% CI −3.7 to 1.4; 3 trials, 97 participants; very low certainty evidence). Only nine placebo-controlled trials reported adverse events. A total of 399 out of 627 participants (63.6%) receiving fluoxetine compared with 352 out of 626 participants (56.2%) receiving placebo experienced an adverse event. Random-effects meta-analysis showed an increase in the risk of having at least one adverse event of any type in the fluoxetine groups compared with placebo (RR 1.18, 95% CI 0.99 to 1.42; P = 0.07; 9 trials, 1253 participants; low-certainty evidence). The 95% prediction interval ranged between 0.74 and 1.88. Following fluoxetine treatment the adverse events of dizziness, drowsiness, fatigue, insomnia and nausea were observed approximately twice as often compared to placebo. A total of 15 out of 197 participants (7.6%) receiving fluoxetine compared with 12 out of 196 participants (6.1%) receiving placebo experienced depression. The RR across all fluoxetine doses compared with placebo was 1.20 (95% CI 0.57 to 2.52; P = 0.62; 3 trials, 393 participants; very low certainty evidence). All-cause mortality, health-related quality of life and socioeconomic effects were not reported. The comparisons of fluoxetine with other anti-obesity agents (3 trials, 234 participants), omega-3 gel (1 trial, 48 participants) and no treatment (1 trial, 60 participants) showed inconclusive results (very low certainty evidence). Low-certainty evidence suggests that off-label fluoxetine may decrease weight compared with placebo. However, low-certainty evidence suggests an increase in the risk for dizziness, drowsiness, fatigue, insomnia and nausea following fluoxetine treatment.

We found 19 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) evaluating mainly women receiving different doses of fluoxetine. A total of 1280 overweight or obese participants received fluoxetine and 936 participants received mainly placebo or another anti-obesity medication. The participants in the included studies were followed up for periods varying between three weeks and one year. For our main comparison group — fluoxetine compared with placebo — and for all fluoxetine doses there was a 2.7 kg weight loss in favour of fluoxetine. We are uncertain, however, if an additional study would again show a benefit for fluoxetine. A total of 399 out of 627 participants (63.6%) receiving fluoxetine compared with 352 out of 626 participants (56.2%) receiving placebo experienced a side effect. Dizziness, drowsiness, fatigue, insomnia and nausea were observed approximately twice as often after fluoxetine compared to placebo. A total of 15 out of 197 participants (7.6%) receiving fluoxetine compared with 12 out of 196 participants (6.1%) receiving placebo experienced depression. The studies did not report on death from any cause, health-related quality of life and socioeconomic effects. This evidence is up to date as of December 2018. The overall certainty of the evidence was low or very low, mainly because of the small number of studies per outcome measurement and the small number of participants.

10.1002/14651858.CD011688.pub2

cochrane-simplification-train-140

cochrane-simplification-train-140

We included 20 RCTs and two quasi-RCTs with 7711 participants, all of which compared antibiotic prophylaxis with placebo or no treatment control. We found no studies comparing antibiotic prophylaxis with non-antibiotic prophylaxis. Primary outcomes Systemic UTI: antibiotic prophylaxis may have little or no effect on the risk of systemic UTI compared with placebo or no treatment (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.38 to 3.32; 5 RCTs; 504 participants; low-quality evidence); this corresponds to two more people (95% CI 12 fewer to 46 more) per 1000 people developing a systemic UTI. We downgraded the quality of the evidence for study limitations and imprecision. Symptomatic UTI: antibiotic prophylaxis may reduce the risk of symptomatic UTI (RR 0.49, 95% CI 0.28 to 0.86; 11 RCTs; 5441 participants; low-quality evidence); this corresponds to 30 fewer people (95% CI 42 fewer to 8 fewer) per 1000 people developing a symptomatic UTI when provided with antibiotic prophylaxis. We downgraded the quality of the evidence for study limitations and potential publication bias. Serious adverse events: the studies reported no serious adverse events in either the intervention group or control group and no effect size could be calculated. Antibiotic prophylaxis may have little or no effect on serious adverse events (4 RCTs, 630 participants; very low-quality evidence), but we are very uncertain of this finding. We downgraded the quality of the evidence for study limitations and very serious imprecision. Secondary outcomes Minor adverse events: prophylactic antibiotics may have little or no effect on minor adverse events when compared with placebo or no treatment (RR 2.82, 95% CI 0.54 to 14.80; 4 RCTs; 630 participants; low-quality evidence). We downgraded the quality of the evidence for study limitations and imprecision. Localized UTI: prophylactic antibiotics may have little or no effect on the risk of localized UTI (RR 1.0, 95% CI 0.06 to 15.77; 1 RCT; 200 participants; very low-quality evidence), but we were very uncertain of this finding. We downgraded the quality of the evidence for study limitations and very serious imprecision. Bacterial resistance: prophylactic antibiotics may increase bacterial resistance (RR 1.73, 95% CI 1.04 to 2.87; 38 participants; 2 RCTs; very low-quality evidence), but we were uncertain of this finding. We downgraded the quality of the evidence for study limitations, indirectness, and imprecision. We were able to perform few secondary analyses; these did not suggest any subgroup effects. Antibiotic prophylaxis may reduce the risk of symptomatic UTI but not systemic UTIs. Serious and minor adverse events may not be increased with the use of antibiotic prophylaxis. The findings are informed by low- and very low-quality evidence ratings for all outcomes.

We found 22 studies with 7711 participants. These studies were published from 1971 to 2017. In these studies, chance decided whether people received an antibiotic or a placebo/no treatment. The evidence is current to 4 February 2019. Antibiotics given for UTI prevention before cystoscopy may have had little or no effect on the risk of developing a more serious infection that went into the bloodstream. They may have reduced the risk of infection when both serious infection that went into the bloodstream and infections limited to the bladder were taken together. None of the people included in the trials had serious unwanted effects. Therefore, we concluded that antibiotics given for prevention of UTIs may not cause serious unwanted effects but we are very uncertain of this finding. Antibiotics may also have had little or no effect on minor unwanted effects. They may also have had little or no effect on infections limited to the bladder taken alone, but we were very uncertain of this finding. People treated with antibiotics may have been more likely to have bacteria that were more resistant to antibiotics, but we are very uncertain of this finding. We rated the quality of the evidence as low or very low meaning that our confidence in the results was limited or very limited. The true effect of antibiotics for prevention of UTIs before cystoscopy may be quite different from what this review found.

10.1002/14651858.CD012305.pub2

cochrane-simplification-train-141

cochrane-simplification-train-141

Analyses included 18 trials including 9017 participants, of whom 6924 were NHW and 2093 NHB participants. Data were available for the following biomarkers: nine SNPs (rs1051730 (CHRNA3); rs16969968, rs588765, and rs2036527 (CHRNA5); rs3733829 and rs7937 (in EGLN2, near CYP2A6); rs1329650 and rs1028936 (LOC100188947); and rs215605 (PDE1C)), two variable number tandem repeats (VNTRs; DRD4 and SLC6A4), and the NMR. Included data produced a total of 40 active versus placebo comparisons, 16 active versus active comparisons, and 64 between-genotype comparisons within treatment arms. For those meta-analyses showing statistically significant heterogeneity between genotype groups, we found the quality of evidence (GRADE) to be generally moderate. We downgraded quality most often because of imprecision or risk of bias due to potential selection bias in genotyping trial participants. Comparisons of relative treatment effects by genotype For six-month abstinence, we found statistically significant heterogeneity between genotypes (rs16969968) for nicotine replacement therapy (NRT) versus placebo at six months for NHB participants (P = 0.03; n = 2 trials), but not for other biomarkers or treatment comparisons. Six-month abstinence was increased in the active NRT group as compared to placebo among participants with a GG genotype (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.07 to 2.03), but not in the combined group of participants with a GA or AA genotype (RR 0.43, 95% CI 0.15 to 1.26; ratio of risk ratios (RRR) GG vs GA or AA of 3.51, 95% CI 1.19 to 10.3). Comparisons of treatment effects between genotype groups within pharmacotherapy randomisation arms For those receiving active NRT, treatment was more effective in achieving six-month abstinence among individuals with a slow NMR than among those with a normal NMR among NHW and NHB combined participants (normal NMR vs slow NMR: RR 0.54, 95% CI 0.37 to 0.78; n = 2 trials). We found no such differences in treatment effects between genotypes at six months for any of the other biomarkers among individuals who received pharmacotherapy or placebo. We did not identify widespread differential treatment effects of pharmacotherapy based on genotype. Some genotype groups within certain ethnic groups may benefit more from NRT or may benefit less from the combination of bupropion with NRT. The reader should interpret these results with caution because none of the statistically significant meta-analyses included more than two trials per genotype comparison, many confidence intervals were wide, and the quality of this evidence (GRADE) was generally moderate. Although we found evidence of superior NRT efficacy for NMR slow versus normal metabolisers, because of the lack of heterogeneity between NMR groups, we cannot conclude that NRT is more effective for slow metabolisers. Access to additional data from multiple trials is needed, particularly for comparisons of different pharmacotherapies.

We searched for studies of smokers treated with medicine to help them quit. We looked at people's genes and at how well their bodies could process nicotine, as this might help us to identify people more likely to quit successfully. We found 33 studies relevant to our review, and we were able to get enough information for 18 clinical trials, including over 9000 smokers, that looked at different medicines used to help people to stop smoking. The results suggest that smokers with specific genotypes may be more likely to be successful quitting smoking with the use of nicotine replacement therapies compared with smokers who do not have those specific genotypes. Smokers whose bodies process nicotine more slowly may also benefit more from nicotine replacement therapy. We did not see effects of genes on the effectiveness of medicines other than nicotine replacement therapy. These results should be interpreted with caution because the included studies did not assign treatments to smokers on the basis of genotype or the rate at which they process nicotine, and because a small number of clinical trials were included in some comparisons.

10.1002/14651858.CD011823.pub2

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cochrane-simplification-train-142

Three completed randomised-controlled studies examined the role of alendronate in patients with HIV and osteopenia or osteoporosis. When all three studies were combined, much heterogeneity was seen (p<0.0001), most likely due to different populations and interventions. A sensitivity analysis showed that in two studies without heterogeneity (p=0.11), alendronate, calcium and vitamin D improved lumbar BMD after one year when compared with calcium and vitamin D (weighted mean difference +2.65 95% confidence interval (CI) 0.80, 4.51 percent). However the alendronate group did not have less fragility fractures, relative risk (RR) 1.28 (95% CI 0.20, 8.21), or osteoporosis, RR 0.50 (95% CI 0.24, 1.01). Adverse events were not significantly different between groups, RR 1.28 (95% 0.20, 8.21). One randomised-controlled study done in patients with AIDS wasting found that after three months, testosterone enanthane improved lumbar BMD compared to placebo by +3.70 (95% CI 0.48, 6.92) percent, but progressive resistance training did not improve lumbar BMD (+0.40 95% CI -2.81, 3.61 percent). No group in this study had any adverse effects. The very limited data reviewed showed that bisphosphonate therapy andin those with AIDS wasting syndrome, testosteronemay be safe and possibly effective methods to improve bone mineral density in HIV patients. The available studies are small, of short duration, and not powered to detect changes in WHO categories and fracture rates. Larger studies using bisphosphonates are currently underway. The role of colecalciferol, androgen replacement in women, and growth hormone are also under investigation.

Three trials examined the use of the drug alendronate to improve BMD in patients with HIV. These three studies were quite different from each other in terms of the populations studied and the interventions used, but even similar studies did not always have heterogeneity. A fourth study examined the use of testosterone in male patients with HIV and AIDS wasting syndrome. The four studies in this review were limited by the fact they were all very small and lasted a short amount of time, and thus they were unable to detect prevention of fractures or changes in number of patients with osteoporosis. There were also further compromises in study design. However, the limited available data show that there may be safe and perhaps effective treatments in the form of alendronate for patients with HIV who have decreased bone mineral density and, in those with AIDS wasting syndrome, testosterone. Larger studies further examining the issue of decreased BMD are currently underway.

10.1002/14651858.CD005645.pub2

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cochrane-simplification-train-143

We included three trials involving 538 participants. We found low quality of evidence indicating uncertainty whether pre-hopsital thrombolysis reduces all-cause mortality in individuals with STEMI compared to in-hospital thrombolysis (risk ratio 0.73, 95% confidence interval 0.37 to 1.41). We found high-quality evidence (two trials, 438 participants) that pre-hospital thrombolysis reduced the time to receipt of thrombolytic treatment compared with in-hospital thrombolysis. For adverse events, we found moderate-quality evidence that the occurrence of bleeding events was similar between participants receiving in-hospital or pre-hospital thrombolysis (two trials, 438 participants), and low-quality evidence that the occurrence of ventricular fibrillation (two trials, 178 participants), stroke (one trial, 78 participants) and allergic reactions (one trial, 100 participants) was also similar between participants receiving in-hospital or pre-hospital thrombolysis. We considered the included studies to have an overall unclear/high risk of bias. Pre-hospital thrombolysis reduces time to treatment, based on studies conducted in higher income countries. In settings where it can be safely and correctly administered by trained staff, pre-hospital thrombolysis may be an appropriate intervention. Pre-hospital thrombolysis has the potential to reduce the burden of STEMI in lower- and middle-income countries, especially in individuals who have limited access to in-hospital thrombolysis or percutaneous coronary interventions. We found no randomised controlled trials evaluating the efficacy of pre-hospital thrombolysis for STEMI in lower- and middle-income countries. Large high-quality multicentre randomised controlled trials implemented in resource-constrained countries will provide additional evidence for the efficacy and safety of this intervention. Local policy makers should consider their local health infrastructure and population distribution needs. These considerations should be taken into account when developing clinical guidelines for pre-hospital thrombolysis.

The aim of this review was to compare the effect of pre-hospital and in-hospital administration of thrombolytic therapy on all-cause death and disability in individuals having a heart attack. We carried out a comprehensive search for all trials that have investigated this outcome. Two authors worked independently to ensure we found all of the trials and obtained the relevant information from them. Overall, we found three trials with 538 participants which could be included in this review. We found low-quality evidence indicating uncertainty whether the numbers of people dying were different when therapy was given before hospital compared to in hospital (3 trials). We found high-quality evidence that giving therapy before hospital reduced the time taken for an individual to receive thrombolytic therapy by more than 30 minutes (two studies) and generally low-quality evidence that side effects, such as allergic reactions and bleeding, were similar whether therapy was given pre-hospital or in hospital. The main limitations of the evidence were the unclear/high risk of bias in the studies and the low numbers of people recruited. We conclude that clot-busting therapy given before arriving at a hospital reduces the time taken for an individual to receive thrombolytic treatment. The limitations of the evidence we have found should be considered carefully, especially in settings where thrombolysis can be safely and correctly administered by trained staff. We found that there were no trials evaluating pre-hospital thrombolytic therapy in poorer countries, and therefore further research in such settings will provide more information to advise on whether giving this therapy for heart attacks is safe and effective.

10.1002/14651858.CD010191.pub2

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cochrane-simplification-train-144

A total of 1912 children were enrolled from seven studies. Data interpretation was limited by the inability to extract data that referred to children with M. pneumoniae. In most studies, clinical response did not differ between children randomised to a macrolide antibiotic and children randomised to a non-macrolide antibiotic. In one controlled study (of children with recurrent respiratory infections, whose acute LRTI was associated with Mycoplasma, Chlamydia or both, by polymerase chain reaction and/or paired sera) 100% of children treated with azithromycin had clinical resolution of their illness compared to 77% not treated with azithromycin at one month. There is insufficient evidence to draw any specific conclusions about the efficacy of antibiotics for this condition in children (although one trial suggests macrolides may be efficacious in some children with LRTI secondary to Mycoplasma). The use of antibiotics has to be balanced with possible adverse events. There is still a need for high quality, double-blinded RCTs to assess the efficacy and safety of antibiotics for LRTI secondary to M. pneumoniae in children.

Randomised controlled trials (RCTs) comparing either two types of antibiotic therapy or an antibiotic versus a placebo in children with pneumonia. We identified seven studies (1912 children). Within each study, there were some children who hadM. pneumoniaebut we could not extract relevant data relating to efficacy or adverse events relating only to children withM. pneumoniae. Overall the quality of the evidence for each of the main outcomes is very low as there are insufficient data for any outcome. Hence, currently, there is insufficient evidence to show conclusively that antibiotics are effective in children with LRTI caused byM. pneumoniae.

10.1002/14651858.CD004875.pub5

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cochrane-simplification-train-145

Six heterogeneous trials were identified with 442 participants. Methodological flaws of the included trials included incomplete follow-up and inadequate reporting of outcomes. Three trials compared ACI versus mosaicplasty. One reported statistically significant results in favour of ACI at one year in the numbers of people with 'good' or 'excellent' functional results. Conversely, another trial found significant improvement for the mosaicplasty group when assessed using one functional scoring system at two years, but no statistically significant differences based on two other scoring systems. A third trial found no difference between ACI and mosaicplasty, 10 months on average after the surgery. There was no statistically significant difference in functional outcomes at two years in a single trial comparing ACI with microfracture nor in the functional results at 18 months of a single trial comparing characterised chondrocyte implantation versus microfracture. However, the results at 36 months for this trial seemed to indicate better functional results for characterised chondrocyte implantation compared with those for microfracture. The sixth trial comparing matrix-guided ACI versus microfracture found significantly better results for functional outcomes at two year follow-up in the MACI group. There is insufficient evidence to draw conclusions on the use of ACI for treating full thickness articular cartilage defects in the knee. Further good quality randomised controlled trials with long-term functional outcomes are required.

This review includes six small randomised controlled trials that compared ACI with either mosaicplasty or microfracture. Although there are some promising results for ACI compared with microfracture from one trial, the evidence from two other trials testing the same comparison did not confirm these. None of the other three trials testing different comparisons provided conclusive evidence in favour of ACI, although the longer-term results suggest that the results for some types of ACI may improve over time. The review identified several ongoing trials that should help to provide evidence to inform on the use of ACI in the future. Meanwhile, there is insufficient evidence to draw conclusions on the use of ACI.

10.1002/14651858.CD003323.pub3

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cochrane-simplification-train-146

We identified 10 randomised clinical trials with 488 randomised participants that met our inclusion criteria. All the trials were at high risk of bias in one or more domains. Overall, the evidence for all the outcomes was very low quality evidence. Nine trials (467 participants) provided information for one or more outcomes. Three trials (99 participants) compared interferon-alpha versus no intervention. Three trials (90 participants) compared interferon-beta versus no intervention. One trial (21 participants) compared pegylated interferon-alpha versus no intervention, but it did not provide any data for analysis. One trial (41 participants) compared MTH-68/B vaccine versus no intervention. Two trials (237 participants) compared pegylated interferon-alpha versus pegylated interferon-alpha plus ribavirin. None of the trials compared direct-acting antivirals versus placebo or other interventions. The mean or median follow-up period in the trials ranged from six to 36 months. There was no short-term mortality (less than one year) in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials that reported follow-up beyond one year, there were no further deaths. The number of serious adverse events was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha (rate ratio 2.74, 95% CI 1.40 to 5.33; participants = 237; trials = 2; I2 = 0%). The proportion of people with any adverse events was higher with interferon-alpha and interferon-beta compared with no intervention (OR 203.00, 95% CI 9.01 to 4574.81; participants = 33; trials = 1 and OR 27.88, 95% CI 1.48 to 526.12; participants = 40; trials = 1). None of the trials reported health-related quality of life, liver transplantation, decompensated liver disease, cirrhosis, or hepatocellular carcinoma. The proportion of people with chronic HCV infection as indicated by the lack of sustained virological response was lower in the interferon-alpha group versus no intervention (OR 0.27, 95% CI 0.09 to 0.76; participants = 99; trials = 3; I2 = 0%). The differences between the groups were imprecise or not estimable (because neither group had any events) for all the remaining comparisons. Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. Very low quality evidence suggests that interferon-alpha may decrease the incidence of chronic HCV infection as measured by sustained virological response. However, the clinical impact such as improvement in health-related quality of life, reduction in cirrhosis, decompensated liver disease, and liver transplantation has not been reported. It is also not clear whether this finding is applicable in the current clinical setting dominated by the use of pegylated interferons and direct-acting antivirals, although we found no evidence to support that pegylated interferons or ribavirin or both are effective in people with acute HCV infection. We could find no randomised trials comparing direct-acting antivirals with placebo or other interventions for acute HCV infection. There is significant uncertainty in the benefits and harms of the interventions, and high-quality randomised clinical trials are required.

We identified 10 randomised clinical trials which were eligible for our review. Nine randomised clinical trials (467 participants) provided information for one or more measures (outcomes). The main interventions compared included different forms of interferon (protein secreted in response to viral infection), namely, interferon-alpha alone, interferon-beta alone, pegylated interferon-alpha alone, pegylated interferon-alpha plus ribavirin (another antiviral drug), a vaccine called MTH-68/B made from a different virus, versus no intervention. None of the trials compared direct-acting antivirals (the latest option for treating HCV infection) versus placebo or other interventions. The average follow-up period in the trials ranged from six months to three years. Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. All the trials were at high risk of bias, and the overall quality of the evidence was very low. This means that there is a possibility of making wrong conclusions overestimating benefits or underestimating harms of one intervention or the other because of the way that the trials were conducted. No deaths occurred less than one year after treatment in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials in which participants were followed up beyond one year, there were no further deaths. The number of serious complications was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha. The percentage of people with any complications was higher with interferon-alpha and interferon-beta than with no intervention. None of the trials reported health-related quality of life, liver transplantation, liver failure, severe liver damage, or liver cancer. The percentage of people in whom the virus remained in the blood six months after the end of treatment was lower in the interferon-alpha than in the no intervention groups. There was no evidence of differences between the groups for all the remaining comparisons. There is significant uncertainty about the size and direction of the results and high quality randomised clinical trials are required.

10.1002/14651858.CD011644.pub3

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cochrane-simplification-train-147

We identified three randomised controlled trials with 84 participants. Forty-one participants underwent surgical palliation and 43 participants underwent duodenal stent placement. There may have been little or no difference in the technical success of the procedure (RR 0.98, 95% CI 0.88 to 1.09; low-quality evidence), or whether the time to resumption of oral intake was quicker for participants who had undergone duodenal stent placement (MD -3.07 days, 95% CI -4.76 to -1.39; low-quality evidence). Due to very low-quality evidence, we were uncertain whether surgical palliation improved all-cause mortality and median survival postintervention. The time to recurrence of obstructive symptoms may have increased slightly following duodenal stenting (RR 5.08, 95% CI 0.96 to 26.74; moderate-quality evidence). Due to very low-quality evidence, we were uncertain whether surgical palliation improved serious and minor adverse events. The heterogeneity for adverse events was moderately high (serious adverse events: Chi² = 1.71; minor adverse events: Chi² = 3.08), reflecting the differences in definitions used and therefore, may have impacted the outcomes. The need for reintervention may have increased following duodenal stenting (RR 4.71, 95% CI 1.36 to 16.30; very low-quality evidence). The length of hospital stay may have been shorter (by approximately 4 to 10 days) following stenting (MD -6.70 days, 95% CI -9.41 to -3.98; moderate-quality evidence). The use of duodenal stent placement in malignant gastric outlet obstruction has the benefits of a quicker resumption of oral intake and a reduced inpatient hospital stay; however, this is balanced by an increase in the recurrence of symptoms and the need for further intervention. It is impossible to draw further conclusions on these and the other measured outcomes, primarily due to the low number of eligible studies and small number of participants which resulted in low-quality evidence. It was not possible to analyse the impact on quality of life each intervention had for these participants.

Three studies with 84 participants compared a surgical operation to bypass the blockage with the placement of a duodenal stent to bridge the blockage. The evidence is current to May 2018. All studies found that people were able to eat and drink sooner following the placement of a duodenal stent and were subsequently discharged from hospital quicker. The return of symptoms was more likely after a stent and people required further treatment to again restore the ability to eat and drink. There was a higher number of immediate problems in the participants undergoing gastrojejunostomy, including wound and chest infections. In some of the participants who had a stent, subsequent blockage of the stent occurred that required a repeat procedure. The studies included only a small number of participants and all studies were used slightly different methods, making it difficult to be certain of the key results.

10.1002/14651858.CD012506.pub2

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cochrane-simplification-train-148

Fifty-eight studies met the inclusion criteria, nine of which are new for this update. Pooling 44 studies (over 20,000 participants) comparing a nursing intervention to a control or to usual care, we found the intervention increased the likelihood of quitting (RR 1.29, 95% CI 1.21 to 1.38); however, statistical heterogeneity was moderate (I2 = 50%) and not explained by subgroup analysis. Because of this, we judged the quality of evidence to be moderate. Despite most studies being at unclear risk of bias in at least one domain, we did not downgrade the quality of evidence further, as restricting the main analysis to only those studies at low risk of bias did not significantly alter the effect estimate. Subgroup analyses found no evidence that high-intensity interventions, interventions with additional follow-up or interventions including aids that demonstrate the pathophysiological effect of smoking are more effective than lower intensity interventions, or interventions without additional follow-up or aids. There was no evidence that the effect of support differed by patient group or across healthcare settings. There is moderate quality evidence that behavioural support to motivate and sustain smoking cessation delivered by nurses can lead to a modest increase in the number of people who achieve prolonged abstinence. There is insufficient evidence to assess whether more intensive interventions, those incorporating additional follow-up, or those incorporating pathophysiological feedback are more effective than one-off support. There was no evidence that the effect of support differed by patient group or across healthcare settings.

This review of clinical trials covered 58 studies in which nurses delivered a stop-smoking intervention to smokers. More than 20,000 participants were included in the main analysis, including hospitalized adults and adults in the general community. The most recent search was conducted in January 2017. All studies reported whether or not participants had quit smoking at six months or longer. This review found moderate-quality evidence that advice and support from nurses could increase people's success in quitting smoking, whether in hospitals or in community settings. Eleven studies compared different nurse-delivered interventions and did not find that adding more components changed the effect. The quality of evidence was moderate, meaning that further research may change our confidence in the result. This is because results were not consistent across all of the studies, and in some cases there were not very many studies contributing to comparisons.

10.1002/14651858.CD001188.pub5

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cochrane-simplification-train-149

We included 15 trials (5540 participants). Tramadol was examined in five trials (1378 participants); it was found to be better than placebo for pain (SMD -0.55, 95% CI -0.66 to -0.44; low quality evidence) and function (SMD -0.18, 95% CI -0.29 to -0.07; moderate quality evidence). Transdermal buprenorphine (two trials, 653 participants) may make little difference for pain (SMD -2.47, 95%CI -2.69 to -2.25; very low quality evidence), but no difference compared to placebo for function (SMD -0.14, 95%CI -0.53 to 0.25; very low quality evidence). Strong opioids (morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol), examined in six trials (1887 participants), were better than placebo for pain (SMD -0.43, 95%CI -0.52 to -0.33; moderate quality evidence) and function (SMD -0.26, 95% CI -0.37 to -0.15; moderate quality evidence). One trial (1583 participants) demonstrated that tramadol may make little difference compared to celecoxib (RR 0.82, 95% CI 0.76 to 0.90; very low quality evidence) for pain relief. Two trials (272 participants) found no difference between opioids and antidepressants for either pain (SMD 0.21, 95% CI -0.03 to 0.45; very low quality evidence), or function (SMD -0.11, 95% -0.63 to 0.42; very low quality evidence). The included trials in this review had high drop-out rates, were of short duration, and had limited interpretability of functional improvement. They did not report any serious adverse effects, risks (addiction or overdose), or complications (sleep apnea, opioid-induced hyperalgesia, hypogonadism). In general, the effect sizes were medium for pain and small for function. There is some evidence (very low to moderate quality) for short-term efficacy (for both pain and function) of opioids to treat CLBP compared to placebo. The very few trials that compared opioids to non-steroidal anti-inflammatory drugs (NSAIDs) or antidepressants did not show any differences regarding pain and function. The initiation of a trial of opioids for long-term management should be done with extreme caution, especially after a comprehensive assessment of potential risks. There are no placebo-RCTs supporting the effectiveness and safety of long-term opioid therapy for treatment of CLBP.

We searched for trials, both published and unpublished, up to October 2012. We included fifteen trials which included 5540 participants and compared opioids against a placebo (fake medication) or other drugs that have been used for LBP. Most people included in the trials were aged 40 to 50 years and all reported at least moderate pain across the low-back area. The trials included a slightly higher proportion of women. Most of the trials followed the patients during three months and were supported by the pharmaceutical industry. In general, people that received opioids reported more pain relief and had less difficulty performing their daily activities in the short-term than those who received a placebo. However, there is little data about the benefits of opioids based on objective measures of physical functioning. We have no information from randomized controlled trials supporting the efficacy and safety of opioids used for more than four months. Furthermore, the current literature does not support that opioids are more effective than other groups of analgesics for LBP such as anti-inflammatories or antidepressants. This review partially supports the effectiveness of several opioids for CLBP relief and function in the short-term. However, the effectiveness of prescribing of these medications for long-term use is unknown and should take into consideration the potential for serious adverse effects, complications, and increased risk of misuse, abuse, addiction, overdose, and deaths. As expected, side effects are more common with opioids but non-life-threatening with short-term use. Insufficient data prevented making conclusions about the side-effect profile of opioids versus other type of analgesics (for example, antidepressants or anti-inflammatories). The quality of evidence in this review ranged between "very low" and "moderate". The review results should be interpreted with caution and may not be appropriate in all clinical settings. High quality randomized trials are needed to address the long-term (months to years) risks and benefits of opioid use in CLBP, their relative effectiveness compared with other treatments, and to better understand which people may benefit most from this type of intervention.

10.1002/14651858.CD004959.pub4

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cochrane-simplification-train-150

We identified 1332 records as a result of the search (excluding duplicates). Of the 26 studies that potentially met the review criteria, we included four studies involving 205 women; most of the trials had unclear risks of bias. We identified one ongoing trial. The analysis of overall survival was not feasible, as there were no deaths reported among women allocated to standard radical hysterectomy. However, there were two deaths in among women allocated to the nerve-sparing technique. None of the included studies reported rates of intermittent self-catheterisation over one month following surgery. We could not analyse the relative effect of the two surgical techniques on quality of life due to inconsistent data reported. Nerve-sparing radical hysterectomy reduced postoperative bladder dysfunctions in terms of a shorter time to postvoid residual volume of urine ≤ 50 mL (mean difference (MD) -13.21 days; 95% confidence interval (CI) -24.02 to -2.41; 111 women; 2 studies; low-certainty evidence) and lower volume of postvoid residual urine measured one month following operation (MD -9.59 days; 95% CI -16.28 to -2.90; 58 women; 2 study; low-certainty evidence). There were no clear differences in terms of perioperative complications (RR 0.55; 95% CI 0.24 to 1.26; 180 women; 3 studies; low-certainty evidence) and disease-free survival (HR 0.63; 95% CI 0.00 to 106.95; 86 women; one study; very low-certainty evidence) between the comparison groups. Nerve-sparing radical hysterectomy may lessen the risk of postoperative bladder dysfunction compared to the standard technique, but the certainty of this evidence is low. The very low-certainty evidence for disease-free survival and lack of information for overall survival indicate that the oncological safety of nerve-sparing radical hysterectomy for women with early stage cervical cancer remains unclear. Further large, high-quality RCTs are required to determine, if clinically meaningful differences of survival exist between these two surgical treatments.

We found four small studies that compared nerve-sparing radical hysterectomy versus standard radical hysterectomy. None of the included studies reported data on overall survival and rate of intermittent self-catheterisation (procedure in which patient periodically inserts a small tube (catheter) through the urethra into the bladder to empty it of urine) over one month following surgery. We could not assess the relative effect of these two operations on quality of life due to inconsistent data reported. Women undergoing nerve-sparing radical hysterectomy had better voiding (a technique of bladder training in which the woman is instructed to urinate according to pre-determined schedules) functions following surgery than those undergoing standard radical hysterectomy. We found no evidence that women undergoing nerve-sparing radical hysterectomy were more likely to have adverse consequences of surgery or relapse of their cancer. The certainty of the evidence is therefore low or very low. Nerve-sparing radical hysterectomy may reduce the chance of bladder dysfunction compared to standard radical hysterectomy. However, the certainty of this evidence is low and further studies have the potential to better inform this outcome. We are very uncertain as to whether nerve-sparing radical hysterectomy is safe in terms of cancer survival outcomes. The evidence of cancer recurrence was of very low-certainty, there were no long term data available regarding risk of death from cancer or other causes. High-quality international studies involving many women would be needed to tell us whether nerve-sparing radical hysterectomy is beneficial in terms of survival for women with early stage cervical cancer, since risk of recurrence in this group are low.

10.1002/14651858.CD012828.pub2

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We included five trials (1799 participants) rated at low risk of bias apart from a high risk of attrition bias; all studies were funded by BIAL. The overall risk ratio (RR) with 95% confidence interval (CI) for 50% or greater reduction in seizure frequency was 1.71 (95% CI 1.42 to 2.05). Dose regression analysis showed evidence that ESL reduced seizure frequency with an increase in efficacy with increasing doses of ESL. ESL was significantly associated with seizure freedom (RR 2.90, 95% CI 1.49 to 5.68). Participants were more likely to have ESL withdrawn for adverse effects (RR 2.66, 95% CI 1.42 to 4.96) but not for any reason (RR 1.19, 95% CI 0.86 to 1.64). The following adverse effects were significantly associated with ESL: dizziness (RR 2.81, 99% CI 1.86 to 4.27); nausea (RR 2.61, 99% CI 1.36 to 5.01); diplopia (RR 4.14, 99% CI 1.74 to 9.84); somnolence (RR 1.71, 99% CI 1.11 to 2.63) and vomiting (RR 3.30, 99% CI 1.34 to 8.13). Overall the quality of the evidence was rated as moderate due to a high discontinuation rate. ESL reduces seizure frequency when used as an add-on treatment for people with drug-resistant focal epilepsy. The trials included in this review were of short-term duration and focused on adults. One new trial has been included in this update, but the conclusions are unchanged.

The evidence is current to December 2016. We included five clinical trials with 1799 participants aged 16 to 77 years. The included studies had different treatment periods of 12 to 14 weeks. All five trials were randomized controlled trials, which means that people were randomly divided into groups and compared. This review found that eslicarbazepine acetate was effective when used in combination with other medicines to reduce the number of seizures in drug-resistant focal epilepsy. People who took eslicarbazepine acetate were more likely to have no seizures than people who took the placebo (a pretend tablet), but they were more likely to withdraw from eslicarbazepine acetate treatment because of side effects. Side effects associated with eslicarbazepine acetate were dizziness, nausea (feeling sick), somnolence (feeling sleepy), vomiting (being sick) and diplopia (having double vision). Altogether the five trials used good methods, but information was missing from the trials for between 10% and 45% of people taking each medicine in each trial. This missing information may have introduced uncertainty into results so the evidence in this review is of moderate quality. More research is needed to look at the long-term effects of eslicarbazepine acetate and to explore how well it works in children with epilepsy.

10.1002/14651858.CD008907.pub3

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cochrane-simplification-train-152

Four RCTs were identified, each using a different image guided technique: 1. iMRI (58 patients), 2. 5-aminolevulinic acid (5-ALA) fluorescence guided surgery (322 patients), 3. neuronavigation (45 patients) and 4. DTI-neuronavigation (238 patients). Meta-analysis was not appropriate due to differences in the tumours included (eloquent versus non-eloquent locations) and variations in the image guidance tools used in the control arms (usually selective utilisation of neuronavigation). There were significant concerns regarding risk of bias in all the included studies, especially for the study using DTI-neuronavigation. All studies included patients with high grade glioma, with one study also including patients with low grade glioma. The extent of resection was increased with iMRI (risk ratio (RR) (incomplete resection) 0.13, 95% CI 0.02 to 0.96, low quality evidence), 5-ALA (RR 0.55, 95% CI 0.42 to 0.71) and DTI-neuronavigation (RR 0.35, 95% CI 0.20 to 0.63, very low quality evidence). Insufficient data were available to evaluate the effects of neuronavigation on extent of resection. Reporting of adverse events was incomplete, with a suggestion of significant reporting bias. Overall, reported events were low in most studies, but there was concern that surgical resection using 5-ALA may lead to more frequent early neurological deficits. There was no clear evidence of improvement in overall survival (OS) with 5-ALA (hazard ratio (HR) 0.82, 95% CI 0.62 to 1.07) or DTI-neuronavigation (HR 0.57, 95% CI 0.32 to 1.00) in patients with high grade glioma. Progression-free survival (PFS) data were not available in the appropriate format for analysis. Data for quality of life (QoL) were only available for one study and suffered from significant attrition bias. There is low to very low quality evidence (according to GRADE criteria) that image guided surgery using iMRI, 5-ALA or DTI-neuronavigation increases the proportion of patients with high grade glioma that have a complete tumour resection on post-operative MRI. There is a theoretical concern that maximising the extent of resection may lead to more frequent adverse events but this was poorly reported in the included studies. Effects of image guided surgery on survival and QoL are unclear. Further research, including studies of ultrasound guided surgery, is needed.

Our search strategy was up to date as of March 2013. We found four trials looking at four different types of tools to help improve the amount of tumour that is removed. The tumour that they looked at was usually high grade glioma but one study also included patients with low grade glioma. Imaging interventions used during surgery included magnetic resonance imaging (iMRI) during surgery to assess the amount of remaining tumour, or a fluorescent dye (5-aminolevulinic acid (5-ALA)) to mark out the tumour. Two trials used pre-operative imaging to map out the location of a tumour, which was then used at the time of surgery to guide the resection (neuronavigation). All the studies were at significant risk of bias and some were small and stopped early. Others were funded by the manufacturers of the image guidance tool involved. We found low quality evidence that using image guided surgery can lead to more of the tumour being removed surgically in some people. It has not been proven that any of the techniques that were evaluated improve overall survival. Data about how each technique can affect a patient's quality of life was poorly reported. The side effects of each technique were also poorly reported, but they did not appear to be more common with image guided surgery. There is a concern that taking out more of the tumour using 5-ALA can lead to patients having a type of stroke early after surgery but long-term the risk seems to be no different between techniques. There was very low quality evidence for neuronavigation and no trials were identified for ultrasound guidance. Evidence for image guided surgery in removing brain tumours is sparse and of low quality. Further research is needed to assess two main questions. 1. Is removing more of the tumour better for the patient in the long-term? 2. What are the risks of making a patient symptomatically worse by taking out more of the tumour, and how may this affect a patient's quality of life?

10.1002/14651858.CD009685.pub2

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This review included two randomised controlled trials involving 38 children (20 boys, 18 girls), aged 15 to 96 months, and their mothers. All children had developmental disabilities; 10 had motor disorders, but it was unclear if these motor disorders affected their gestural, vocal or verbal communication. Mothers attended eight group training sessions over 11 to 12 weeks and received two or three home visits. Outcomes were assessed immediately after training. We found no report of longer-term follow-up. One study took place at an intervention centre in Canada and the other in South Korea. Both studies recruited small numbers of participants from single centres. Since it is not possible to blind participants attending or therapists providing training to group allocation, we considered both studies to be at high risk of performance bias. We also rated one study at high risk of attrition bias, and both studies at low risk of reporting bias. There was very low-quality evidence for all outcomes assessed. There was no evidence of an effect of training for children's initiation of conversation or engagement in joint attention during interaction with their mothers. Mothers who received training became more responsive to their children's communication, but there were no differences in the extent to which they controlled conversation by directing their children. Missing data meant that we were unable to evaluate the effects of training on children's frequency of communication, frequency of spoken language in conversation, speech production, or receptive or expressive language development. There were no effects on maternal stress. We found no reports of the effects of parent training on children's use of individual communication skills, such as asking questions or providing information, on their generic participation or adverse outcomes. Neither did we find reports of mothers' satisfaction with treatment, its acceptability or their compliance with it. There is only limited, very low quality evidence that parent-mediated communication interventions may be associated with improvements in interaction between mothers and their preschool children who have motor disorders. The indirectness of the study samples and high risk of bias in the included the studies significantly limits our confidence in the evidence, as do issues with study design and lack of detail in results. It is not clear if training has been tested with children whose motor disorders limit the consistency and accuracy of movements underpinning spoken or gestural communication. Some speech and language therapists currently provide communication training for parents. Further research, with larger numbers of children whose movement disorders affect their speech and gestures, coupled with detailed reporting of children's baseline skills, is needed to test whether communication training for parents can help them to promote the communication development of their young children with movement disorders.

We searched for studies published up to July 2017. We found only two studies that reported the effects of parent communication training; one study took place at an intervention centre in Canada, the other in South Korea. The studies involved 38 children (20 boys, 18 girls), aged 15 to 96 months, and their mothers. Both studies compared parent communication training with no intervention for communication problems. Mothers attended eight group training sessions 11 to 12 weeks with two or three home visits. The studies involved children with a range of developmental difficulties; most had intellectual disability, 10 had movement disorders (cerebral palsy). However, the extent to which children's movement disorder affected their communication was not clear; all children appeared to have good use of their hands for gesture and pointing, and impairment of speech was not reported. Results were assessed immediately after training. We found no report of results at a later date (longer-term follow-up). In the two small studies, it appears that mothers may have responded more frequently to their child's interaction following parent-mediated communication training. However, there was no associated reduction in mothers' directiveness (such as their use of commands) in conversation and no change in maternal stress. For the children, we found no evidence for change in children's initiation of conversation or of joint attention in interaction with others. Studies did not report any negative effects of training, mothers' adherence to guidance within the training or the acceptability of the programmes. We were not able to evaluate the effects of parent-mediated communication intervention and frequency of children's communication, their use of spoken language in conversation with their parents, their speech production or their language development because the data were not available. We have no reports of children's development of individual communication skills, such as learning to ask questions, and no reports of defects of the intervention on their generic participation or harms arising from the intervention. Finally, we found no reports of maternal satisfaction with the treatment. We judged the evidence from the included studies to be of very low quality because of issues with study design and a lack of detail in the results presented, and because it was not clear whether children's movement disorders affected their communication. Research with larger numbers of families of children whose movement disorders affect their speech and gesture is needed, to test whether communication training for parents can help them to promote the communication development of their young children with movement disorders.

10.1002/14651858.CD012507.pub2

cochrane-simplification-train-154

cochrane-simplification-train-154

Two small studies involving 116 children, mainly boys between 10 and 18 years of age, met the inclusion criteria. One study was conducted in a school setting, the other at a specialised clinic. Both studies used three months of a combination of omega-3 and omega-6 supplements as the intervention compared with placebo. Although both studies had generally low risk of bias, we judged the risk of reporting bias as unclear in one study, and as high in the other study. In addition, one of the studies was funded by industry and reported active company involvement in the study. None of the studies reported data on the primary outcomes of reading, writing, spelling and mathematics scores, as assessed by standardised tests. Evidence of low quality indicates that supplementation of PUFAs did not increase the risk of gastrointestinal disturbances (risk ratio 1.43, 95% confidence interval 0.25 to 8.15; two studies, 116 children). Investigators reported no other adverse effects. Both studies reported attention deficit hyperactivity disorder (ADHD)-related behaviour outcomes. We were unable to combine the results in a meta-analysis because one study reported findings as a continuous outcome, and the other as a dichotomous outcome. No other secondary outcomes were reported. We excluded one study because it used a cointervention (carnosine), and five other studies because they did not provide a robust diagnosis of a specific learning disorder. We identified one ongoing study and found three studies awaiting classification. Evidence is insufficient to permit any conclusions about the effect of PUFAs on the learning abilities of children with specific learning disorders. Well-designed RCTs with clearly defined populations of children with specific learning disorders who have been diagnosed by standardised diagnostic criteria are needed.

The evidence is current to November 2015. We found two small studies involving 116 children that met our inclusion criteria. Both studies gave children a combination of omega-3 and omega-6 capsules as the intervention for three months. Most of these studies involved boys between 10 and 18 years of age - one was conducted in a school setting, and the other at a specialised clinic. One of the studies was funded by the company that supplied the omega-3 and omega-6 supplements. Another study could not be included in this review because investigators added carnosine (an amino acid that is highly concentrated in the brain) to the PUFAs. Carnosine and PUFAs might have similar effects, so it would not be possible to separate the effects of the two ingredients. Review authors excluded five studies because it was not confirmed that a specific learning disorder was diagnosed in these children. None of the included studies reported effects of PUFAs on reading, writing, spelling or mathematical abilities of children. Evidence of low quality (because studies included few participants and showed evidence of bias) suggests that using PUFAs did not increase the risk of minor disturbances to the digestive system. Included studies reported no other types of adverse effects. Both studies reported on ADHD-related behaviour. However, the format of available data did not allow us to readily combine them or to reach any conclusions. Included studies reported no other secondary outcomes. Evidence is not sufficient to support or refute the use of PUFAs in children with specific learning disorders.

10.1002/14651858.CD009398.pub3

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cochrane-simplification-train-155

From 16,144 citations, 71 papers described IQCODE test accuracy. We included 10 papers (11 independent datasets) representing data from 2644 individuals (n = 379 (14%) with dementia). Using IQCODE cut-offs commonly employed in clinical practice (3.3, 3.4, 3.5, 3.6) the sensitivity and specificity of IQCODE for diagnosis of dementia across the studies were generally above 75%. Taking an IQCODE threshold of 3.3 (or closest available) the sensitivity was 0.80 (95% CI 0.75 to 0.85); specificity was 0.84 (95% CI 0.78 to 0.90); positive likelihood ratio was 5.2 (95% CI 3.7 to 7.5) and the negative likelihood ratio was 0.23 (95% CI 0.19 to 0.29). Comparative analysis suggested no significant difference in the test accuracy of the 16 and 26-item IQCODE tests and no significant difference in test accuracy by language of administration. There was little difference in sensitivity across our predefined diagnostic cut-points. There was substantial heterogeneity in the included studies. Sensitivity analyses removing potentially unrepresentative populations in these studies made little difference to the pooled data estimates. The majority of included papers had potential for bias, particularly around participant selection and sampling. The quality of reporting was suboptimal particularly regarding timing of assessments and descriptors of reproducibility and inter-observer variability. Published data suggest that if using the IQCODE for community dwelling older adults, the 16 item IQCODE may be preferable to the traditional scale due to lesser test burden and no obvious difference in accuracy. Although IQCODE test accuracy is in a range that many would consider 'reasonable', in the context of community or population settings the use of the IQCODE alone would result in substantial misdiagnosis and false reassurance. Across the included studies there were issues with heterogeneity, several potential biases and suboptimal reporting quality.

We searched differing databases of published research for all papers relating to the accuracy of IQCODE for selecting those with dementia. We found eleven studies that tested diagnostic accuracy of IQCODE in community dwelling individuals, we were able to combine their findings to give a summary result. We compared two forms of IQCODE questionnaire and found that a short form with fewer questions was just as accurate as the original longer questionnaire. The overall accuracy of IQCODE was reasonable although not perfect. If IQCODE were to be used on its own for assessing large populations of older adults, it would label many people with dementia who do not have the disease and also miss the diagnosis in a substantial proportion.

10.1002/14651858.CD010079.pub2

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cochrane-simplification-train-156

From the 9330 reports found by our searches, 39 studies were eligible for this review with effect estimate and measure of precision extracted for 190 comparisons of IPD-MA and AD-MA. We classified the quality of studies as ‘no important flaws’ (29 (74%) studies) or ‘possibly important flaws’ (10 (26%) studies). A median of 4 (interquartile range (IQR): 2 to 6) comparisons were made per study, with 6 (IQR 4 to 11) trials and 1225 (542 to 2641) participants in IPD-MAs and 7 (4 to 11) and 1225 (705 to 2541) for the AD-MAs. One hundred and forty-four (76%) comparisons were made on the main treatment effect meta-analysis and 46 (24%) made using results from analyses to explore treatment effect modifiers. There is agreement in statistical significance between the IPD-MA and AD-MA for 152 (80%) comparisons, 23 of which disagreed in direction of effect. There is disagreement in statistical significance for 38 (20%) comparisons with an excess proportion of IPD-MA detecting a statistically significant result that was not confirmed with AD-MA (28 (15%)), compared with 10 (5%) comparisons with a statistically significant AD-MA that was not confirmed by IPD-MA. This pattern of disagreement is consistent for the 144 main effect analyses but not for the 46 comparisons of treatment effect modifier analyses. Conclusions from some IPD-MA and AD-MA differed even when based on identical trials, participants (but not necessarily identical follow-up) and treatment effect measures. The average difference between IPD-MA and AD-MA in z scores, ratio effect estimates and standard errors is small but limits of agreement are wide and include important differences in both directions. Discrepancies between IPD-MA and AD-MA do not appear to increase as the differences between trials and participants increase. IPD offers the potential to explore additional, more thorough, and potentially more appropriate analyses compared to those possible with AD. But in many cases, similar results and conclusions can be drawn from IPD-MA and AD-MA. Therefore, before embarking on a resource-intensive IPD-MA, an AD-MA should initially be explored and researchers should carefully consider the potential added benefits of IPD.

Meta-analysis is a statistical technique to combine results from separate research studies. A meta-analysis can be performed using summary data published in a study report, referred to as aggregate data (AD), or using data collected on each individual participant in the study, referred to as individual participant data (IPD). A meta-analysis of individual participant data (IPD-MA) can take longer and be more expensive than a meta-analysis of aggregate data (AD-MA), but the IPD-MA can be more reliable and can answer much more detailed questions than an AD-MA. We searched for studies, published up to 7 January 2016, that compared results of IPD-MA with AD-MA. We found that four times out of five, similar conclusions can be drawn, but in one out of five cases the two different types of meta-analyses gave different results and conclusions. As we could not reliably identify when an IPD-MA and AD-MA will differ most using these studies, we recommend that an AD-MA should be done first before doing an IPD-MA. If there are shortcomings with the AD-MA, researchers should then consider the possible benefits of IPD whilst remembering the extra work involved.

10.1002/14651858.MR000007.pub3

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cochrane-simplification-train-157

Twelve studies (2215 participants) met the inclusion criteria and compared pharmacy-based management with treatment as usual. Two studies (291 participants) also included an active control (both used patient information leaflets providing information about the prescribed antidepressant). Neither of these studies reported depression symptom change. A narrative synthesis of results on acceptability of the intervention was inconclusive, with one study reporting better acceptability of pharmacy-based management and the other better acceptability of the active control. One study reported that participants in the pharmacy-based management group had better medication adherence than the control participants. One study reported adverse events with no difference between groups. The studies reported no other outcomes. Meta-analyses comparing pharmacy-based management with treatment as usual showed no evidence of a difference in the effect of the intervention on depression symptom change (dichotomous data; improvement in symptoms yes/no: risk ratio (RR), 0.95, 95% confidence interval (CI) 0.86 to 1.05; 4 RCTs, 475 participants; moderate-quality evidence; continuous data: standard mean difference (SMD) -0.04, 95% CI -0.19 to 0.10; 5 RCTs, 718 participants; high-certainty evidence), or acceptability of the intervention (RR 1.09, 95% CI 0.81 to 1.45; 12 RCTs, 2072 participants; moderate-certainty evidence). The risk of non-adherence was reduced in participants receiving pharmacy-based management (RR 0.73, 95% CI 0.61 to 0.87; 6 RCTs, 911 participants; high-certainty evidence). We were unable to meta-analyse data on diagnosis of depression, frequency of primary care appointments, quality of life, or social functioning. We found no evidence of a difference between pharmacy-based management for depression in adults compared with treatment as usual in facilitating depression symptom change. Based on numbers of participants leaving the trials early, there may be no difference in acceptability between pharmacy-based management and controls. However, there was uncertainty due to the low-certainty evidence.

We searched medical databases for well-designed studies that compared a group of adults with depression who received additional help with their depression medicines from their pharmacy with a group of adults with depression who received their treatment as usual. The evidence is current to 14 December 2018. We found 12 studies with over 2000 adults taking part. They compared pharmacy-based support with treatment as usual, for example, basic information about their medicines or signposting to other services only. We found that additional support given by the pharmacist was no better at reducing people's depression than their treatment as usual. The studies also showed that people may have liked both approaches the same, although we are uncertain about the results as the evidence was of low certainty. The studies did show that people who received support from their pharmacy were more likely to take their antidepressants as prescribed. We were not able to combine information from the included studies on other outcomes we were interested in (diagnosis of depression, frequency of healthcare appointments, quality of life, social functioning, or side effects). We found no difference in effectiveness when people with depression received additional support from a pharmacist compared with treatment as usual.

10.1002/14651858.CD013299.pub2

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cochrane-simplification-train-158

Nineteen eligible trials in which 2872 infants participated were identified. Most participants were very low birth weight, but the largest single trial restricted participation to extremely low birth weight infants (N = 1202). The trials were generally of good quality. The incidence of symptomatic PDA [typical relative risk (RR) 0.44, 95% confidence interval (CI) 0.38 to 0.50] and PDA surgical ligation (typical RR 0.51, 95% CI 0.37,0.71) was significantly lower in treated infants. Prophylactic indomethacin also significantly reduced the incidence of severe intraventricular haemorrhage (typical RR 0.66, 95% CI 0.53 to 0.82). Meta-analyses found no evidence of an effect on mortality (typical RR 0.96, 95% CI 0.81 to 1.12) or on a composite of death or severe neurodevelopmental disability assessed at 18 to 36 months old (typical RR 1.02, 95% CI 0.90, 1.15). Prophylactic indomethacin has short-term benefits for preterm infants including a reduction in the incidence of symptomatic PDA, PDA surgical ligation, and severe intraventricular haemorrhage. However, there is no evidence of effect on mortality or neurodevelopment.

This review found evidence that giving all preterm infants (especially very preterm infants) indomethacin on the first day after birth reduced their risk of developing a PDA and the complications associated with PDA (including brain damage due to bleeding into the brain). However, despite these short term effects, the trials found evidence that indomethacin does not increase survival or reduce disability in the longer term.

10.1002/14651858.CD000174.pub2

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cochrane-simplification-train-159

Four randomised controlled trials have compared pramipexole with placebo in 669 patients with later Parkinson's disease. Two phase III studies were medium term (24 weeks maintenance period) and 2 phase II studies were short term (4 weeks maintenance period). The reduction in off time was significantly greater with pramipexole compared with placebo (weighted mean difference 1.8 hours; 1.2, 2.3 95% CI). No significant changes were noted in a dyskinesia rating scale in any of the 4 studies, but dyskinesia as an adverse event was reported more frequently with pramipexole. A significant improvement occurred in UPDRS complication score (part IV) in 2 studies but not in the remaining trials. Statistically significant improvements in UPDRS ADL score occurred with pramipexole in all studies. Significant improvements in UPDRS motor scores in the on state were reported in 3 of the 4 studies. Levodopa dose reduction was allowed in 3 studies and meta-analysis shows a significant difference in favour of pramipexole (weighted mean difference 115 mg; 87, 143 95% CI). Trends toward a higher incidence of dopaminergic adverse events with pramipexole only reached statistical significance regarding hallucinations. There were significantly fewer withdrawals from pramipexole. Pramipexole can be used to reduce off time, improve motor impairments and disability and reduce levodopa dose at the expense of increased dyskinetic adverse events. This conclusion is based on short and medium term trials (up to 24 weeks). Further trials are required to directly compare the newer with the older dopamine agonists.

Four trials have compared pramipexole with placebo in 669 patients with later Parkinson's disease. Two studies were medium term (24 weeks) and 2 studies were short term (4 weeks). Pramipexole significantly reduced the time patients spent in the immobile off state compared with placebo by an average of 1.8 hours. No changes occurred in a dyskinesia rating scale in any of the studies, but dyskinesia recorded as a side effect was reported more frequently with pramipexole. A significant improvement occurred in the Unified Parkinson's Disease Rating Scale (UPDRS) complication score in 2 studies but not in the remaining trials. Significant improvements in UPDRS activities of daily living score occurred with pramipexole in all studies. Significant improvements in UPDRS motor scores in the mobile on state were reported in 3 of the 4 studies. Levodopa dose reduction was allowed in 3 studies and meta-analysis showed a significant difference in favour of pramipexole. There was a suggestion of more side effects such as nausea, vomiting and dizziness with pramipexole and a definite increase in hallucinations in those given pramipexole. There were significantly fewer withdrawals from pramipexole. In conclusion, pramipexole can be used to reduce off time, improve motor impairments and disability and reduce levodopa dose at the expense of increased dyskinetic side effects. This is based on short and medium term trials (up to 24 weeks). Further trials are required to directly compare the newer with the older dopamine agonists.

10.1002/14651858.CD002261

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cochrane-simplification-train-160

We included eight trials, which randomised 365 participants. The trials all used a split-mouth design, some with more than one pair of lesions treated within the same participant. Studies took place in university or dental public health clinics in Brazil, Colombia, Denmark, Germany, Thailand, Greenland and Chile. Six studies evaluated the effects of micro-invasive treatments in the permanent dentition and two studies on the primary dentition, with caries risk ranging from low to high. Investigators measured caries risk in different studies either by caries experience alone or by using the Cariogram programme, which combines eight contributing factors, including caries experience, diet, saliva and other factors related to caries. The follow-up period in the trials ranged from one to three years. All studies used lesion progression as the primary outcome, evaluating it by different methods of reading radiographs. Four studies received industry support to carry out the research, with one of them being carried out by inventors of the intervention. We judged seven studies to be at high overall risk of bias, primarily due to lack of blinding of participants and personnel. We evaluated intervention effects for all micro-invasive therapies and analysed subgroups according to the different treatment methods reported in the included studies. Our meta-analysis, which pooled the most sensitive set of data (in terms of measurement method) from studies presenting data in a format suitable for meta-analysis, showed that micro-invasive treatment significantly reduced the odds of lesion progression compared with non-invasive treatment (e.g fluoride varnish) or oral hygiene advice (e.g to floss) (OR 0.24, 95% CI 0.14 to 0.41; 602 lesions; seven studies; I2 = 32%). There was no evidence of subgroup differences (P = 0.36). The four studies that measured adverse events reported no adverse events after micro-invasive treatment. Most studies did not report on any further outcomes. We assessed the quality of evidence for micro-invasive treatments as moderate. It remains unclear which micro-invasive treatment is more advantageous, or if certain clinical conditions or patient characteristics are better suited for micro-invasive treatments than others. The available evidence shows that micro-invasive treatment of proximal caries lesions arrests non-cavitated enamel and initial dentinal lesions (limited to outer third of dentine, based on radiograph) and is significantly more effective than non-invasive professional treatment (e.g. fluoride varnish) or advice (e.g. to floss). We can be moderately confident that further research is unlikely to substantially change the estimate of effect. Due to the small number of studies, it does remain unclear which micro-invasive technique offers the greatest benefit, or whether the effects of micro-invasive treatment confer greater or lesser benefit according to different clinical or patient considerations.

This review ​considered evidence that was up to date at 31 December 2014. We found eight relevant trials with 365 participants. These trials involved children and adults whose decay lesions (tooth decay) were randomly assigned to different micro-invasive and non-invasive treatments. There were no studies comparing micro-invasive interventions with invasive treatment (fillings). Four studies received financial support from intervention inventors or manufacturers to carry out the research. The current evidence shows that micro-invasive treatments can significantly reduce the likelihood of dental decay progression compared with the described non-invasive methods. There are too few studies to decide which micro-invasive treatment technique is best or the impact of different clinical and patient considerations. No negative side effects were reported; however, only half of the studies measured this outcome and the follow-up time of some of the studies was relatively short. Although further research could possibly change our findings, the available evidence gives us moderate confidence that micro-invasive treatments are much more effective than non-invasive treatments for stopping tooth decay.

10.1002/14651858.CD010431.pub2

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cochrane-simplification-train-161

Seventy-one studies (14,602 participants) representing 74 randomised comparisons met the inclusion criteria. Methodological quality was fair. Dose ratio 1:2: FP produced a significantly greater end of treatment FEV1 (0.04 litres (95% CI 0 to 0.07 litres), end of treatment and change in morning PEF, but not change in FEV1 or evening PEF. This applied to all drug doses, age groups, and delivery devices. No difference between FP and BDP/BUD were seen for trial withdrawals. FP led to fewer symptoms and less rescue medication use. When given at half the dose of BDP/BUD, FP led to a greater likelihood of pharyngitis. There was no difference in the likelihood of oral candidiasis. Plasma cortisol and 24 hour urinary cortisol was measured frequently but data presentation was limited. Dose ratio 1:1: FP produced a statistically significant difference in morning PEF, evening PEF, and FEV1 over BDP or BUD. The effects on exacerbations were mixed. There were no significant differences incidence of hoarseness, pharyngitis, candidiasis, or cough. Fluticasone given at half the daily dose of beclomethasone or budesonide leads to small improvements in measures of airway calibre, but it appears to have a higher risk of causing sore throat and when given at the same daily dose leads to increased hoarseness. There are concerns about adrenal suppression with Fluticasone given to children at doses greater than 400 mcg/day, but the randomised trials included in this review did not provide sufficient data to address this issue.

This review compares the effectiveness of three inhaled steroids. Fluticasone (FP) was compared with either beclomethasone (BDP) or budesonide (BUD) for treating people with chronic asthma. When FP was given to children or adults at approximately half the daily dose of either BDP or BUD, it appeared to be at least as effective as the other two drugs in improving airway opening. There was not enough information available to draw conclusions concerning the effect of these drugs on symptoms, or the risk of an acute asthma exacerbation. When given at the same dose as BDP or BUD, FP treated participants had slightly better lung function. However, at the same dose FP was also associated with increased hoarseness, although it did not lead to increased incidences of other side-effects associated with steroids such as oral thrush or sore throat.

10.1002/14651858.CD002310.pub4

cochrane-simplification-train-162

cochrane-simplification-train-162

We included five RCTs with a total of 227 participants (age range 23 to 76 years; 65% men) with acute pancreatitis pain. The opioids assessed were intravenous and intramuscular buprenorphine, intramuscular pethidine, intravenous pentazocine, transdermal fentanyl and subcutaneous morphine. One RCT, comparing subcutaneous morphine with intravenous metamizole reported non-significant reduction in the number of participants with improvements in pain intensity (primary outcome) (RR 0.50, 95% CI 0.19 to 1.33). Three studies compared analgesia using opioids with non-opioid treatments. After excluding one study that used opioids through continuous intravenous infusion, there was a decrease in the number of patients requiring supplementary analgesia (RR 0.53, 95% CI 0.30 to 0.93). In a single study, there were no differences in the number of patients requiring supplementary analgesia between buprenorphine and pethidine (RR 0.82, 95% CI 0.61 to 1.10). Pancreatitis complications were not associated with a significant difference between the drugs tested. No clinically serious or life-threatening adverse events occurred related to treatment. No differences for this outcome were found between opioid and non-opioid treatments, or for type of adverse event (nausea-vomiting and somnolence-sedation). One death in the procaine group was reported across all the trials. One RCT comparing pethidine with intramuscular buprenorphine reported non-significant differences of supplementary analgesic, adverse events or deaths. One RCT comparing fentanyl with placebo found no difference in adverse events. The findings of this review are limited by the lack of information to allow full appraisal of the risk of bias, the measurement of relevant outcomes and the small numbers of participants and events covered by the trials. Opioids may be an appropriate choice in the treatment of acute pancreatitis pain. Compared with other analgesic options, opioids may decrease the need for supplementary analgesia. There is currently no difference in the risk of pancreatitis complications or clinically serious adverse events between opioids and other analgesia options. Future research should focus on the design of trials with larger samples and the measurement of relevant outcomes for decision-making, such as the number of participants showing reductions in pain intensity. The reporting of these RCTs should also be improved to allow users of the medical literature to appraise their results accurately. Large longitudinal studies are also needed to establish the risk of pancreatitis complications and adverse events related to drugs.

For participants needing additional pain relief, combined analysis of opioids (pentazocine and morphine) showed a significant benefit when compared with non-opioid treatments. Two trials showed that buprenorphine and pentazocine were each more effective than procaine. Our confidence in the stability of these effects is low, however, due to limitations in the number of studies and participants, and the low quality of the way the trials were run and reported. No serious or life-threatening adverse events were linked to the drugs being studied. One death was reported, in a procaine group, across all the included trials. On the evidence so far, opioids may be an appropriate treatment option and might have the advantage of decreasing the need for additional pain relief. We found no clear difference in the risk of pancreatitis complications or serious adverse event between opioids and other pain relief treatments. However, the findings of this review are limited by the lack of information to allow full appraisal of the risk of bias, the measurement of relevant outcomes and the small numbers of participants covered by the trials.

10.1002/14651858.CD009179.pub2

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cochrane-simplification-train-163

The effect of interventions on self-reported physical activity (19 studies; 7598 participants) was positive and moderate (pooled SMD random effects model 0.28 95% CI 0.15 to 0.41) as was the effect of interventions (11 studies; 2195 participants) on cardio-respiratory fitness (pooled SMD random effects model 0.52 95% CI 0.14 to 0.90). There was significant heterogeneity in the reported effects as well as heterogeneity in characteristics of the interventions. The heterogeneity in reported effects was reduced in higher quality studies, when physical activity was self-directed with some professional guidance and when there was on-going professional support. Our review suggests that physical activity interventions have a moderate effect on self-reported physical activity, on achieving a predetermined level of physical activity and cardio-respiratory fitness. Due to the clinical and statistical heterogeneity of the studies, only limited conclusions can be drawn about the effectiveness of individual components of the interventions. Future studies should provide greater detail of the components of interventions.

The findings of this review indicate that professional advice and guidance with continued support can encourage people to be more physically active in the short to mid-term. More research is needed to establish which methods of exercise promotion work best in the long-term to encourage specific groups of people to be more physically active.

10.1002/14651858.CD003180.pub2

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cochrane-simplification-train-164

Fourteen studies appeared potentially relevant but only three studies (61 patients) met the entry criteria. Two studies compared a dry powder device (Turbuhaler or Rotahaler) with a pMDI for beta2-agonist delivery, and one (36 patients cross-over design) the Respimat (soft mist device for ipratropium) vs a pMDI. For the Turbuhaler and Rotahaler, none of the reported outcome measures were significantly different. The Rotahaler study used a high and low dose of medication with or without large volume spacer. The study using the Respimat showed significant increases in FEV1 when compared to a pMDI (difference in change from base line 70 ml, 95% CI 10, 130 ml). The effect on change in FVC was of similar size. There were no differences between these two devices for any other reported outcomes. Although none of the included studies required prior patient ability to use any of the inhalers (and no study mentioned device training), it was assumed that all patients randomised into the study would have undergone training in use of the study inhalers and were capable of using those devices. In patients with stable COPD, pMDI produced similar outcomes to a dry powder device for delivering beta2-agonists, but the very small number of studies and included patients does not permit firm conclusions to be drawn. The soft mist device for ipratropium was more effective than a pMDI, but the data come from one small study. There need to be further well designed randomised controlled trials to define the role of inhaler devices using bronchodilators in stable COPD.

This review involved the assessment of different inhaler devices for delivery of inhaled bronchodilators in stable chronic obstructive pulmonary disease (COPD). Studies included in this review involved pressurised metered dose inhalers (pMDI) being compared to any other handheld inhaler device containing bronchodilators. Only three randomised controlled trials met the inclusion criteria. Due to the very small number of studies included in this review, it is not possible to draw any conclusions on the use of inhaler devices containing bronchodilators in COPD. There need to be further well designed randomised controlled trials examining the role of bronchodilators in COPD.

10.1002/14651858.CD002170

cochrane-simplification-train-165

cochrane-simplification-train-165

Of 157 records reviewed, 16 were included, representing five trials. In general, the studies were small and had inconsistent methodological rigor. Overall, the quality of evidence was rated as low. Each study used a different MOIT protocol. A total of 196 patients were studied (106 MOIT, 90 control) and all were children. Three studies were blinded and two used an avoidance diet control.  Sixty-six patients (62%) in the MOIT group were able to tolerate a full serving of milk (about 200 mL) compared to seven (8%) of the control group (RR 6.61, 95% CI 3.51 to 12.44). In addition, 27 (25%) in the MOIT group could ingest a partial serving of milk (10 to 184 mL) while none could in the control group (RR 9.34, 95% CI 2.72 to 32.09). None of the studies assessed the patients following a period off immunotherapy. Adverse reactions were common (97 of 106 MOIT patients had at least one symptom), although most were local and mild. Because of variability in reporting methods, adverse effects could not be combined quantitatively. For every 11 patients receiving MOIT, one required intramuscular epinephrine. One patient required it on two occasions. Studies to date have involved small numbers of patients and the quality of evidence is generally low. The current evidence shows that MOIT can lead to desensitization in the majority of individuals with IMCMA although the development of long-term tolerance has not been established. A major drawback of MOIT is the frequency of adverse effects, although most are mild and self-limited. The use of parenteral epinephrine is not infrequent. Because there are no standardized protocols, guidelines would be required prior to incorporating desensitization into clinical practice.

We identified randomized controlled trials that compared oral immunotherapy to placebo or continued avoidance diet in children and adults with cow's milk allergy. Five studies satisfied our inclusion criteria. In total there were 196 participants (106 in the treatment group and 90 in the control), all of whom were children. In general, the quality of the studies was low. Because the trials involved small numbers and there were problems with the way they were done, further research is needed. The current evidence shows that oral immunotherapy can help a majority of allergic children tolerate a full serving of milk, as long as they continue drinking this amount each day. However, it is not known if this protection is continued if the immunotherapy is stopped for some time. Side effects during oral immunotherapy are frequent and most patients will have at least some mild symptoms. In the studies we included, for every 11 patients who received oral immunotherapy, one needed to be treated with epinephrine injection at some point for a serious allergic reaction to the therapy.

10.1002/14651858.CD009542.pub2

cochrane-simplification-train-166

cochrane-simplification-train-166

Eleven completed, randomised trials comparing intravenous glycerol and control were considered. Analysis of death during the scheduled treatment period for acute ischaemic and/or haemorrhagic stroke was possible in 10 trials where 482 glycerol treated patients were compared with 463 control patients. Glycerol was associated with a non-significant reduction in the odds of death within the scheduled treatment period (odds ratio (OR) 0.78, 95% confidence intervals (CI) 0.58 to 1.06). Among patients with definite or probable ischaemic stroke, glycerol was associated with a significant reduction in the odds of death during the scheduled treatment period (OR 0.65, 95% CI 0.44 to 0.97). However, at the end of the scheduled follow-up period, there was no significant difference in the odds of death (OR 0.98, 95% CI 0.73 to 1.31). Functional outcome was reported in only two studies but there were non-significantly more patients who had a good outcome at the end of scheduled follow up (OR 0.73, 95% CI 0.37 to 1.42). Haemolysis seems to be the only relevant adverse effect of glycerol treatment. This systematic review suggests a favourable effect of glycerol treatment on short term survival in patients with probable or definite ischaemic stroke but the confidence intervals were wide and the magnitude of the treatment effect may be only minimal. Due to the relatively small number of patients, and that the trials were performed in the pre-CT era, the results must be interpreted cautiously. The lack of evidence of benefit in long term survival does not support the routine or selective use of glycerol treatment in patients with acute stroke.

The review found some evidence that glycerol improves the short term survival after stroke, but there was not enough evidence to decide whether glycerol helps avoid disability after stroke. Adverse effects of glycerol treatment did not happen often, but a small number of treated patients were found to have blood in their urine (this disappeared after the glycerol treatment was stopped). More research is needed.

10.1002/14651858.CD000096.pub2

cochrane-simplification-train-167

cochrane-simplification-train-167

Twenty-seven studies (1,011 participants) were included. Three studies were rated as low risk of bias. Seven studies were rated as high risk of bias and 17 were rated as unclear risk of bias due to insufficient information. Seventeen trials compared different formulations of EN, 13 studies compared one or more elemental formulas to a non-elemental formula, three studies compared EN diets of similar protein composition but different fat composition, and one study compared non-elemental diets differing in glutamine enrichment. Meta-analysis of 11 trials (378 participants) demonstrated no difference in remission rates. Sixty-four per cent (134/210) of patients in the elemental group achieved remission compared to 62% (105/168) of patients in the non-elemental group (RR 1.02, 95% CI 0.88 to 1.18; GRADE very low quality). A per-protocol analysis (346 participants) produced similar results (RR 1.04, 95% CI 0.91 to 1.18). Subgroup analyses performed to evaluate the different types of elemental and non-elemental diets (elemental, semi-elemental and polymeric) showed no differences in remission rates. An analysis of 7 trials including 209 patients treated with EN formulas of differing fat content (low fat: < 20 g/1000 kCal versus high fat: > 20 g/1000 kCal) demonstrated no difference in remission rates (RR 1.03; 95% CI 0.85 to 1.26). Very low fat content (< 3 g/1000 kCal) and very low long chain triglycerides demonstrated higher remission rates than higher content EN formulas. There was no difference between elemental and non-elemental diets in adverse event rates (RR 1.00, 95% CI 0.63 to 1.60; GRADE very low quality), or withdrawals due to adverse events (RR 1.29, 95% CI 0.80 to 2.09; GRADE very low quality). Common adverse events included nausea, vomiting, diarrhea and bloating. Ten trials compared EN to steroid therapy. Meta-analysis of eight trials (223 participants) demonstrated no difference in remission rates between EN and steroids. Fifty per cent (111/223) of patients in the EN group achieved remission compared to 72% (133/186) of patients in the steroid group (RR 0.77, 95% CI 0.58 to 1.03; GRADE very low quality). Subgroup analysis by age showed a difference in remission rates for adults but not for children. In adults 45% (87/194) of EN patients achieved remission compared to 73% (116/158) of steroid patients (RR 0.65, 95% CI 0.52 to 0.82; GRADE very low quality). In children, 83% (24/29) of EN patients achieved remission compared to 61% (17/28) of steroid patients (RR 1.35, 95% CI 0.92 to 1.97; GRADE very low quality). A per-protocol analysis produced similar results (RR 0.93, 95% CI 0.75 to 1.14). The per-protocol subgroup analysis showed a difference in remission rates for both adults (RR 0.82, 95% CI 0.70 to 0.95) and children (RR 1.43, 95% CI 1.03 to 1.97). There was no difference in adverse event rates (RR 1.39, 95% CI 0.62 to 3.11; GRADE very low quality). However, patients on EN were more likely to withdraw due to adverse events than those on steroid therapy (RR 2.95, 95% CI 1.02 to 8.48; GRADE very low quality). Common adverse events reported in the EN group included heartburn, flatulence, diarrhea and vomiting, and for steroid therapy acne, moon facies, hyperglycemia, muscle weakness and hypoglycemia. The most common reason for withdrawal was inability to tolerate the EN diet. Very low quality evidence suggests that corticosteroid therapy may be more effective than EN for induction of clinical remission in adults with active CD. Very low quality evidence also suggests that EN may be more effective than steroids for induction of remission in children with active CD. Protein composition does not appear to influence the effectiveness of EN for the treatment of active CD. EN should be considered in pediatric CD patients or in adult patients who can comply with nasogastric tube feeding or perceive the formulations to be palatable, or when steroid side effects are not tolerated or better avoided. Further research is required to confirm the superiority of corticosteroids over EN in adults. Further research is required to confirm the benefit of EN in children. More effort from industry should be taken to develop palatable polymeric formulations that can be delivered without use of a nasogastric tube as this may lead to increased patient adherence with this therapy

The researchers found twenty-seven studies (1,011 participants) that fulfilled the search criteria. Eleven of these studies, which included 378 patients, compared elemental to non-elemental diets at producing remission in Crohn's disease. Eight studies, which included 352 patients, investigated enteral nutrition compared to steroid therapy at inducing remission in Crohn's disease. The researchers searched the medical literature extensively up to July 5, 2017. Very low quality evidence suggests that steroids may be more effective than enteral nutrition for induction of remission in adults with active Crohn's disease. Very low quality evidence also suggests that enteral nutrition may be more effective than steroids for induction of remission in children with active Crohn's disease. There was no difference in remission rates between elemental and non-elemental diets. An increase in side effects was not seen with elemental diets compared to non-elemental diets, nor with enteral nutrition compared to steroids. Common side effects experienced with enteral nutrition included vomiting, diarrhea, heartburn and flatulence . Common side effects associated with steroid use included acne, moon facies, muscle weakness, hyperglycemia (high blood sugar) and hypoglycemia (low blood sugar) . Patients on enteral nutrition were more likely to withdraw from the study due to side effects than those on steroids. The most common reason for study withdrawal was inability to tolerate the taste of the enteral nutrition diet. Enteral nutrition should be considered in pediatric Crohn's patients or in adult patients who can comply with nasogastric tube feeding or perceive the formulations to be palatable, or when steroid side effects are not tolerated or better avoided. Further research is required to confirm the superiority of corticosteroids over EN in adults. Further research is required to confirm the benefit of EN in children. More effort from industry should be taken to develop palatable polymeric formulations that can be delivered without use of a nasogastric tube as this may lead to increased patient compliance with this therapy.

10.1002/14651858.CD000542.pub3

cochrane-simplification-train-168

cochrane-simplification-train-168

We included 6 studies (2 full reports, 2 abstracts, 1 brief communication, and 1 letter), with a total of 544 participants. Risk of bias was unclear in several studies because of insufficient reporting. Five studies compared FAE with placebo, and one study compared FAE with methotrexate. All studies reported data at 12 to 16 weeks, and we identified no longer-term studies. When FAE were compared with placebo, we could not perform meta-analysis for the primary outcome of PASI score because the three studies that assessed this outcome reported the data differently, although all studies reported a significant reduction in PASI scores with FAE. Only 1 small study designed for psoriatic arthritis reported on the other primary outcome of participants discontinuing treatment due to adverse effects (2 of 13 participants on FAE compared with none of the 14 participants on placebo; risk ratio (RR) 5.36, 95% confidence interval (CI) 0.28 to 102.1; 27 participants; very low-quality evidence). However, these findings are uncertain due to indirectness and a very wide confidence interval. Two studies, containing 247 participants and both only reported as abstracts, allowed meta-analysis for PASI 50, which showed superiority of FAE over placebo (RR 4.55, 95% CI 2.80 to 7.40; low-quality evidence), with a combined PASI 50 of 64% in those given FAE compared with a PASI 50 of 14% for those on placebo, representing a number needed to treat to benefit of 2. The same studies reported more participants achieving PASI 75 with FAE, but we did not pool the data because of significant heterogeneity; none of the studies measured PASI 90. One study reported significant improvement in participants' quality of life (QoL) with FAE, measured with Skindex-29. However, we could not compute the mean difference because of insufficient reporting in the abstract. More participants experienced adverse effects, mainly gastrointestinal disturbance and flushing, on FAE (RR 4.72, 95% CI 2.45 to 9.08; 1 study, 99 participants; moderate-quality evidence), affecting 76% of participants given FAE and 16% of the placebo group (representing a number needed to treat to harm of 2). The other studies reported similar findings or did not report adverse effects fully. One study of 54 participants compared methotrexate (MTX) with FAE. PASI score at follow-up showed superiority of MTX (mean Difference (MD) 3.80, 95% CI 0.68 to 6.92; 51 participants; very low-quality evidence), but the difference was not significant after adjustment for baseline disease severity. The difference between groups for the proportion of participants who discontinued treatment due to adverse effects was uncertain because of imprecision (RR 0.19, 95% CI 0.02 to 1.53; 1 study, 51 participants; very low-quality evidence). Overall, the number of participants experiencing common nuisance adverse effects was not significantly different between the 2 groups, with 89% of the FAE group affected compared with 100% of the MTX group (RR 0.89, 95% CI 0.77 to 1.03; 54 participants; very low-quality evidence). Flushing was more frequent in those on FAE, with 13 out of 27 participants affected compared with 2 out of 27 given MTX. There was no significant difference in the number of participants who attained PASI 50, 75, and 90 in the 2 groups (very low-quality evidence) whereas this study did not measure the effect of treatments on QoL. The included studies reported no serious adverse effects of FAE and were too small and of limited duration to provide evidence about rare or delayed effects. Evidence suggests that FAE are superior to placebo and possibly similar in efficacy to MTX for psoriasis; however, the evidence provided in this review was limited, and it must be noted that four out of six included studies were abstracts or brief reports, restricting study reporting. FAE are associated with nuisance adverse effects, including flushing and gastrointestinal disturbance, but short-term studies reported no serious adverse effects.

Our review included six randomised control trials (RCTs) that involved 544 participants. Five RCTs compared FAE with placebo, and one compared FAE with methotrexate. The outcomes we were interested in measuring were the Psoriasis Area and Severity Index (PASI), which is a psoriasis severity score, and the proportion of participants who discontinued treatment because of adverse (side) effects that are common but sufficiently serious that the drug had to be stopped, such as severe diarrhoea, infections, or cutaneous malignancy. It was difficult to pool and compare results because outcome measures differed between the studies. Three studies reported significant benefit with FAE when compared with placebo after 12 to 16 weeks of treatment, but we could not combine these results in a statistical analysis to show the overall difference. The included studies did not fully examine the chance of discontinuing FAE treatment because of adverse effects, which is uncertain. One study showed that individuals on FAE are nearly five times more likely to develop nuisance adverse effects; the most common were diarrhoea and abdominal cramps, flushing, reversible protein loss in the urine, and raised levels of eosinophil blood cells. Two RCTs were similar enough to allow the combination of their results and found that FAE were better than placebo when measured by the proportion of individuals who experienced at least a 50% improvement in their psoriasis severity score. One study reported improvement of individuals' quality of life with FAE in comparison with placebo, but the significance of this difference could not be calculated. The benefit of FAE was similar to methotrexate after 12 weeks when changes in disease severity from the start to the end of the trial were compared. The number of individuals experiencing nuisance adverse effects with these two treatments was not significantly different. The included studies, which were too small and of limited duration to provide evidence about rare or delayed effects, reported no serious adverse effects of FAE. The risk of study bias, which means any factors that may systematically deviate away from the true findings, was unclear in most studies. This may be because most of the studies were conducted decades ago or were incompletely reported. Several analyses comparing FAE with placebo and methotrexate were limited because the studies were small or did not provide enough information to establish how these treatments compare with each other. Therefore, the overall quality of the evidence was low when comparing FAE with placebo and very low when comparing FAE with methotrexate. Future RCTs should use standard psoriasis outcome measures, including a validated quality of life scale, to enable the comparison and combination of results. They should be longer in duration or have longer follow-up phases to provide evidence about any delayed adverse effects.

10.1002/14651858.CD010497.pub2

cochrane-simplification-train-169

cochrane-simplification-train-169

We found no additional RCTs for inclusion in this update. This review includes one RCT dating from the 1960s with an overall high risk of bias. The RCT included 2307 healthy participants, all of whom were included in analyses. This trial compared the effect of an adenovirus vaccine against placebo. No statistically significant difference in common cold incidence was found: there were 13 (1.14%) events in 1139 participants in the vaccines group and 14 (1.19%) events in 1168 participants in the placebo group (risk ratio 0.95, 95% confidence interval 0.45 to 2.02; P = 0.90). No adverse events related to the live vaccine were reported. The quality of the evidence was low due to limitations in methodological quality and a wide 95% confidence interval. This Cochrane Review was based on one study with low-quality evidence. We found no conclusive results to support the use of vaccines for preventing the common cold in healthy people compared with placebo. We identified a need for well-designed, adequately powered RCTs to investigate vaccines for the common cold in healthy people. Any future trials on medical treatments for preventing the common cold should assess a variety of virus vaccines for this condition. Outcome measures should include common cold incidence, vaccine safety, and mortality related to the vaccine.

We found no new studies in this update. This review includes one previously identified randomised controlled trial performed in 1965. This study involved 2307 healthy people at a training facility for the United States Navy and evaluated the effect of a live weakened (attenuated) adenovirus vaccine compared to a fake vaccine (placebo). This study was funded by a government institution. There were no differences in the frequency of occurrence of the common cold between those who received the vaccine compared to those who received a fake vaccine. There were no adverse events related to the vaccine. However, due to the low numbers of people included in the study and numbers of colds, as well as flaws in the study design, our confidence in the results is low. Further research may be able to clarify if vaccines can prevent common cold, since the current evidence does not support the use of adenovirus vaccine to prevent common cold in healthy people. We assessed the quality of the evidence as low due to high risk of bias and low numbers of people included in the study and numbers of colds, which resulted in imprecision.

10.1002/14651858.CD002190.pub5

cochrane-simplification-train-170

cochrane-simplification-train-170

We included four RCTs involving 438 patients (220 patients in the drain group and 218 in the no-drain group). There was no evidence of a difference between the two groups in mortality (RR 1.73, 95% CI 0.38 to 7.84); re-operations (RR 2.49, 95% CI 0.71 to 8.74); post-operative complications (pneumonia: RR 1.18, 95% CI 0.55 to 2.54; wound infection: RR 1.23, 95% CI 0.47 to 3.23; intra-abdominal abscess: RR 1.27, 95% CI 0.29 to 5.51; anastomotic leak: RR 0.93, 95% CI 0.06 to 14.47); or initiation of soft diet (MD 0.15 days, 95% CI -0.07 to 0.37). However, the addition of a drain prolonged the operation time (MD 9.07 min, 95% CI 2.56 to 15.57) and post-operative hospital stay (MD 0.69 day, 95% CI 0.18 to 1.21) and led to drain-related complications. Additionally, we should note that 30-day mortality and re-operations are very rare events and, as a result, very large numbers of patients would be required to make any sensible conclusions about whether the two groups were similar. The overall quality of the evidence according to the GRADE approach was 'very low' for mortality and re-operations, and 'low' for post-operative complications, operation time, and post-operative length of stay. We found no convincing evidence to support routine drain use after gastrectomy for gastric cancer.

This review included four RCTs involving 438 patients that investigated the benefits and harms of routine abdominal drainage post-gastrectomy for gastric cancer. There was no evidence of a difference between the two groups in deaths, post-operative complications, and initiation of a soft diet. The results showed that drains increased harms by prolonging operation time and post-operative hospital stay, and led to drain-related complications without providing any additional benefit for patients with gastric cancer undergoing gastrectomy. There was no convincing evidence to support the routine use of drains after gastrectomy for gastric cancer. The overall quality of the evidence according to the GRADE approach was 'very low' for deaths and re-operations, and 'low' for post-operative complications, operation time, and post-operative length of stay. This review included only four RCTs, and not all of the included studies reported all outcomes that we were assessing. Therefore, the quality was mainly limited by insufficient data.

10.1002/14651858.CD008788.pub3

cochrane-simplification-train-171

cochrane-simplification-train-171

The overall quality of the evidence was low to very low. The main limitations were serious risk of bias related to blinding of participants and personnel, indirectness and imprecision. We identified 16 RCTs comparing a device versus no treatment (two studies; 90 women), hormonal treatment versus no treatment or placebo (two studies; 136 women), device combined with hormonal treatment versus no treatment (one study; 20 women), barrier gel versus no treatment (five studies; 464 women), device with graft versus device without graft (three studies; 190 women), one type of device versus another device (one study; 201 women), gel combined with hormonal treatment and antibiotics versus hormonal treatment with antibiotics (one study; 52 women) and device combined with gel versus device (one study; 120 women). The total number of participants was 1273, but data on 1133 women were available for analysis. Only two of 16 studies included 100% infertile women; in all other studies, the proportion was variable or unknown. No study reported live birth, but some (five studies) reported outcomes that were used as surrogate outcomes for live birth (term delivery or ongoing pregnancy). Anti-adhesion therapy versus placebo or no treatment following operative hysteroscopy. There was insufficient evidence to determine whether there was a difference between the use of a device or hormonal treatment compared to no treatment or placebo with respect to term delivery or ongoing pregnancy rates (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.42 to 2.12; 107 women; 2 studies; I² = 0%; very-low-quality evidence). There were fewer IUAs at second-look hysteroscopy using a device with or without hormonal treatment or hormonal treatment or barrier gels compared with no treatment or placebo (OR 0.35, 95% CI 0.21 to 0.60; 560 women; 8 studies; I² = 0%; low-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) was 9 (95% CI 5 to 17). Comparisons of different anti-adhesion therapies following operative hysteroscopy It was unclear whether there was a difference between the use of a device combined with graft versus device only for the outcome of ongoing pregnancy (OR 1.48, 95% CI 0.57 to 3.83; 180 women; 3 studies; I² = 0%; low-quality evidence). There were fewer IUAs at second-look hysteroscopy using a device with or without graft/gel or gel combined with hormonal treatment and antibiotics compared with using a device only or hormonal treatment combined with antibiotics, but the findings of this meta-analysis were affected by evidence quality (OR 0.55, 95% CI 0.36 to 0.83; 451 women; 5 studies; I² = 0%; low-quality evidence). Implications for clinical practice The quality of the evidence ranged from very low to low. The effectiveness of anti-adhesion treatment for improving key reproductive outcomes or for decreasing IUAs following operative hysteroscopy in subfertile women remains uncertain. Implications for research More research is needed to assess the comparative safety and (cost-)effectiveness of different anti-adhesion treatments compared to no treatment or other interventions for improving key reproductive outcomes in subfertile women.

We searched for studies that randomly compared any treatment versus no treatment, placebo (pretend treatment) or any other intervention. Outcomes were live birth, clinical pregnancy, miscarriage and presence or severity of scar tissue at the second-look procedure. We found 16 studies. Treatments included using a device versus no treatment (two studies; 90 women), hormonal treatment versus no treatment or placebo (two studies; 136 women), device combined with hormonal treatment versus no treatment (one study; 20 women), barrier gel versus no treatment (five studies; 464 women), device with the use of membranes of the afterbirth of newborn babies versus device without membranes (three studies; 190 women), one type of device versus another device (one study; 201 women), gel combined with hormonal treatment and antibiotics versus hormonal treatment with antibiotics (one study; 52 women) or device combined with gel versus device (one study; 120 women). From 1273 randomly assigned women, data on 1133 women were available for analysis. In only two studies, all women had difficulty becoming pregnant. Most studies (14/16) were at high risk of bias for at least one reason. As no study reported live births, we also included data on term delivery or ongoing pregnancy, which five studies reported. It was unclear whether there was a difference between anti-adhesion treatment compared to no treatment (two studies; 107 women) or to other treatment (three studies; 180 women) for increasing the chance of a liveborn baby, a term delivery or an ongoing pregnancy. The use of some anti-adhesion therapies (device with or without hormonal treatment or hormonal treatment or gels) (eight studies; 560 women) may diminish the risk of scar tissue formation compared to no treatment. We would expect that out of 1000 women treated by surgery, between 153 and 365 women would develop scar tissue after using gels, compared with 545 women when no treatment was used. The evidence was current to 6 June 2017. The overall quality of the study evidence ranged from very low to low. There were limitations to the studies, for example, a serious risk of bias related to participants and investigators knowing what treatment was given. More research is needed before anti-adhesion treatment can be offered in everyday clinical practice after surgery of the womb in women having difficulty becoming pregnant.

10.1002/14651858.CD011110.pub3

cochrane-simplification-train-172

cochrane-simplification-train-172

Of the 556 potentially relevant studies only two met the inclusion criteria. One of those was excluded as the trial was abandoned prematurely and reported only preliminary results. The only analysed trial enrolled 551 participants receiving first-line chemotherapy (methotrexate) followed by whole brain radiotherapy (WBR) or receiving chemotherapy only (methotrexate followed by cytarabine in case of incomplete response). In this non-inferiority trial, the intention-to-treat (ITT) population consisted of 411 participants and the per-protocol (PP) population of 318 participants. We judged the potential for risk of bias in this open-label study as moderate. The estimated effect of chemotherapy plus WBR on survival was similar to that with chemotherapy alone but due to a wide CI we could not rule out the superiority of either therapy. This applied to both the ITT population (HR 1.01, 95% CI 0.79 to 1.30; P = 0.94) and the PP population (HR 1.06, 95% CI 0.80 to 1.40; P = 0.71) (moderate-quality evidence). Due to the low number of participants and a risk of detection bias we found low-quality evidence for an improvement in progression-free survival in participants in the ITT population receiving WBR in addition to chemotherapy (HR 0.79, 95% CI 0.63 to 0.99; P = 0.041). An improvement in PFS was also observed with WBR plus chemotherapy in participants in the PP population, but the CI was slightly wider and the result not significant (HR 0.82,95% CI 0.64 to 1.07; P = 0.14). Treatment-related mortality and health-related quality of life were not evaluated. Treatment-related neurotoxicity was assessed clinically in 79 participants, revealing signs of neurotoxicity in 49% of those receiving chemotherapy plus radiotherapy and in 26% of those receiving chemotherapy only (RR 1.85, 95% CI 0.98 to 3.48; P = 0.054) (very-low-quality evidence). In summary, the currently available evidence (one RCT) is not sufficient to conclude that WBR plus chemotherapy and chemotherapy alone have similar effects on overall survival in people with PCNSL. The findings suggest that the addition of radiotherapy (WBR) to chemotherapy may increase progression-free survival, but may also increase the incidence of neurotoxicity compared to chemotherapy only (methotrexate monotherapy). As the role of chemoradiotherapy in the treatment of PCNSL remains unclear, further prospective, randomised trials are needed before definitive conclusions can be drawn.

We searched all databases for relevant studies published between January 1950 and February 2014. We included only one study that enrolled 551 participants and treated one half with methotrexate followed by WBR, and the other half with methotrexate alone. If participants in the latter group did not respond sufficiently to methotrexate alone, another drug, cytarabine, was given. Participants of a minimum of 18 years of age were enrolled at 75 centres in Germany between May 2000 and May 2009. When we analysed the data regarding the effect of chemotherapy plus WBR or chemotherapy alone on overall survival, the results were imprecise and either treatment could have been superior to the other. Another outcome we considered in addition to overall survival was progression-free survival (PFS), a state in which the disease does not get any worse. The addition of radiotherapy to chemotherapy had a positive effect on PFS, slightly extending the period in which the disease did not progress in comparison to that acheived with chemotherapy alone. The authors did not analyse treatment-related mortality.We also looked at whether treatment resulted in any damage to healthy brain tissue during treatment. We found no evidence that treatment-related symptoms of brain function impairment were more common in the group of participants receiving chemotherapy plus radiotherapy than in those receiving chemotherapy alone. We consider the quality of the evidence body as moderate to low, as we included only one trial with a small number of participants. As the included study did not analyse adverse events in all participants, we consider the quality of the evidence for the outcome of neurotoxicity as very low. In summary, the currently available evidence (one randomised controlled trial) is not sufficient to conclude that WBR plus chemotherapy and chemotherapy alone have similar effects on overall survival in people with PCNSL. The addition of WBR to chemotherapy may increase progression-free survival, but could possibly also increase levels of toxic effects on the brain. Further prospective randomised trials are needed before definitive conclusions can be drawn about the role of adding radiotherapy to chemotherapy in the treatment of PCNSL.

10.1002/14651858.CD009211.pub2

cochrane-simplification-train-173

cochrane-simplification-train-173

There are no identifiable studies that have evaluated the association between parenteral calcium supplementation in critically ill ICU patients and the following outcomes: mortality, multiple organ dysfunction, ICU and hospital length of stay, costs, and complications of calcium administration. Serum ionized calcium concentration was reported in 5 studies (12 trial arms, 159 participants). These trials showed a small but significant increase in serum ionized calcium concentration after calcium administration. These trials showed considerable statistical heterogeneity and differed extensively in the population studied (adult versus neonate), the indication (hypocalcemia versus prophylaxis) and threshold of hypocalcemia for which parenteral calcium was administered, and the timing of subsequent measurement of serum ionized calcium concentration to the extent that we consider a pooled estimate almost inappropriate. There is no clear evidence that parenteral calcium supplementation impacts the outcome of critically ill patients.

Several epidemiological studies of critically ill patients highlight a direct association between low levels of calcium (hypocalcemia) and mortality, though whether this association is causal is unknown. On the other hand, despite prior studies detailing associations between hypocalcemia and poor outcome, there is evidence to suggest that calcium supplementation in critical illness may be deleterious. Five randomized controlled trials with 159 participants were detected. All of the five included studies were conducted in the USA. No trial evaluated the association between parenteral calcium supplementation in critically ill intensive care unit patients and the following outcomes: mortality, multiple organ dysfunction, intensive care unit and hospital length of stay, costs, and complications of calcium administration. Some data on laboratory measurements (serum calcium) could be extracted. Nonetheless, these data provide little to guide the care of intensive care unit patients. The question of greater importance, "Does correcting hypocalcemia in critically ill patients provide any benefit in reducing mortality, the development of organ dysfunction, or the allocation of resources ?" remains to be answered. At present, the evidence base for guidelines regarding calcium administration in intensive care unit patients is poor.

10.1002/14651858.CD006163.pub2

cochrane-simplification-train-174

cochrane-simplification-train-174

We included 14 studies (in 18 trial reports), involving 1047 pregnant women at risk of preterm birth with 1077 newborns. However, three of the included studies did not report on this review's outcomes of interest. We carried out two main comparisons: ambroxol versus antenatal corticosteroids (betamethasone); and ambroxol versus placebo or no treatment. Seven RCTs provided data for our comparison of ambroxol versus corticosteroid (betamethasone) and two trials contributed data to our comparison of ambroxol compared to placebo or no treatment. The included studies were generally judged as having either 'low' risk of bias or 'unclear' risk of bias (because the trial reports provided insufficient details about methods of sequence generation, allocation concealment and blinding). Primary outcomes There was no clear evidence of a difference in the incidence of RDS among newborns born to women who received ambroxol when compared to newborns of women who were given the corticosteroid, betamethasone (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.59 to 1.07, seven RCTs, 728 women/758 newborns, moderate quality evidence) or placebo/no treatment (average RR 0.74; 95% CI 0.46 to 1.20, two studies, 204 women/204 newborns,T2= 0.07; I2= 53%, low-quality evidence). Results were imprecise and consistent with appreciable benefit as well as negligible effect. Similarly, there was no clear evidence of a difference in the rates of perinatal mortality between the group of women who received ambroxol and women in the corticosteroid (betamethasone) group (RR 0.51, 95% CI 0.23 to 1.12, six studies, 648 women/657 newborns, moderate quality evidence) or the placebo/no treatment group (RR 0.61; 95% CI 0.19 to 1.98, one study, 116 women/116 newborns, low-quality evidence). In terms of maternal adverse effects, there was no clear differences (in nausea or vomiting) between those women who received ambroxol compared to either those women who received corticosteroids (betamethasone) (average RR 3.45; 95% CI 0.34 to 35.51, three studies, 305 women, T2= 2.82; I2= 67%, very low-quality evidence), or women who received placebo or no treatment (RR 1.79; 95% CI 0.45 to 7.13, one study, 116 women, low-quality evidence). No other adverse effects (e.g. diarrhoea, gastric irritation and headache) were reported in the included studies. Secondary outcomes For the review's secondary outcomes, none of the included studies reported on the incidence of bronchopulmonary dysplasia, periventricular haemorrhage, necrotising enterocolitis or rate of maternal mortality. One small trial (involving 88 women) comparing ambroxol with placebo or no treatment, reported no difference between groups in terms of the need for mechanical ventilation in the neonate (RR 0.94; 95% CI 0.73 to 1.21, 88 women/88 babies, low-quality evidence) or the administration of pulmonary surfactant (RR 1.19; 95% CI 0.61 to 2.30, one RCT, 88 women/88 babies, low-quality evidence). This review is based on very low to moderate quality evidence from 14 small trials (many are published in the form of conference abstracts with minimal methodological details provided). There is insufficient evidence to support or refute the practice of giving ambroxol to women at risk of preterm birth for preventing neonatal RDS, perinatal mortality and adverse effects. More research is needed in order to fully evaluate the benefits and risks of this intervention.

We did not identify any trials comparing ambroxol with dexamethasone (corticosteroid) in this review. Nor did we identify any trials comparing ambroxol combined with corticosteroid versus corticosteroid alone, or placebo/no treatment. The review identified 14 small studies involving a total of 1047 women (and their 1077 newborns), that compared ambroxol with corticosteroid (betamethasone), or to placebo/no treatment. Three of the studies did not report on the outcomes of interest for this review. The results of the review are based on very low to moderate quality evidence. There were no clear evidence of differences in the incidence of RDS or perinatal mortality in newborns of women who were given ambroxol when compared with newborns of women who received either a corticosteroid (betamethasone) or placebo/no treatment. Similarly, there was no clear difference between groups in terms of nausea and vomiting (the only maternal adverse effects that were reported). For the review's secondary outcomes, none of the included studies reported on the incidence of bronchopulmonary dysplasia, periventricular haemorrhage, necrotising enterocolitis or rate of maternal mortality. One small study (comparing ambroxol with placebo/no treatment) found no difference between groups for the neonatal outcomes of 'need for mechanical ventilation' or 'administration of pulmonary surfactant'. There is insufficient evidence to support or refute the practice of giving ambroxol to pregnant women at risk of preterm birth for preventing neonatal RDS. More research in this area is necessary in order to evaluate the effectiveness and safety of this intervention.

10.1002/14651858.CD009708.pub2

cochrane-simplification-train-175

cochrane-simplification-train-175

We included 11 cohort studies, evaluating a total of 6502 participants undergoing 7018 procedures: 2529 underwent a nipple-sparing mastectomy (NSM), 818 underwent skin-sparing mastectomy (SSM) and 3671 underwent traditional mastectomy, also known as modified radical mastectomy (MRM). No participants underwent areola-sparing mastectomy. There was a high risk of confounding for all reported outcomes. For overall survival, the hazard ratio (HR) for NSM compared to SSM was 0.70 (95% CI 0.28 to 1.73; 2 studies; 781 participants) and the HR for NSM compared to MRM was 0.72 (95% CI 0.46 to 1.13; 2 studies, 1202 participants). Local recurrence was evaluated in two studies, the HR for NSM compared to MRM was 0.28 (95% CI 0.12 to 0.68; 2 studies, 1303 participants). The overall risk of complications was different in NSM when compared to other types of mastectomy in general (RR 0.10, 95% CI 0.01 to 0.82, 2 studies, P = 0.03; 1067 participants). With respect to skin necrosis, there was no evidence of a difference with NSM compared to other types of mastectomy, but the confidence interval was wide (RR 4.22, 95% CI 0.59 to 30.03, P = 0.15; 4 studies, 1948 participants). We observed no difference among the three types of mastectomy with respect to the risk of local infection (RR 0.95, 95% CI 0.44 to 2.09, P = 0.91, 2 studies; 496 participants). Meta-analysis was not possible when assessing cosmetic outcomes and quality of life, but in general the NSM studies reported a favourable aesthetic result and a gain in quality of life compared with the other types of mastectomy. The quality of evidence was considered very low for all outcomes due to the high risk of selection bias and wide confidence intervals. The findings from these observational studies of very low-quality evidence were inconclusive for all outcomes due to the high risk of selection bias.

The evidence is current to September 2014. We included 11 studies involving 6502 participants having 7018 surgical procedures (some participants had surgery on both breasts). Out of these, 2529 participants underwent nipple-sparing mastectomy, while there were no participants who had an areola-sparing mastectomy, 818 participants underwent skin-sparing mastectomy and 3671 underwent a traditional mastectomy. All participants in the studies were women and most of them (99.2%) had invasive breast cancer or ductal carcinoma in situ. We compared nipple-sparing mastectomy to conventional mastectomy and skin-sparing mastectomy in two different analyses. It was not possible to conclude whether or not survival following nipple-sparing mastectomy was similar to traditional mastectomy and skin-sparing mastectomy. Results were also inconclusive for differences in local recurrence and adverse events following different types of mastectomy. In practice the decision to select nipple-sparing mastectomy over other types of mastectomy should be done through shared decision making after extensive discussion of the risks and benefits. Generally the nipple-sparing mastectomy studies reported a favourable aesthetic result and a gain in quality of life compared with the other types of mastectomy. However, due to the lack of numerical data, it was not possible to pool the results of different studies. The quality of the evidence included in this review was very low. The studies had a number of methodological flaws. Poor reporting meant that the effect of the type of mastectomy on survival could not be determined for a number of studies. Also, differences between surgery groups in tumour stage and whether or not adjuvant radiotherapy was used may have affected the results. This is likely to have an impact on the findings and future research is likely to change the current findings.

10.1002/14651858.CD008932.pub3

cochrane-simplification-train-176

cochrane-simplification-train-176

We identified five studies (one cluster RCT, three RCTs and one NRCT), evaluating the effectiveness of dental auxiliaries compared with dentists in providing dental care traditionally provided by dentists, eligible for inclusion in this review. The included studies, which involved 13 dental auxiliaries, six dentists, and more than 1156 participants, evaluated two clinical tasks/techniques: placement of preventive resin fissure sealants and the atraumatic restorative technique (ART). Two studies were conducted in the US, and one each in Canada, Gambia and Singapore. Of the four studies evaluating effectiveness in placing preventive resin fissure sealants, three found no evidence of a difference in retention rates of those placed by dental auxiliaries and dentists over a range of follow-up periods (six to 24 months). One study found that fissure sealants placed by a dental auxiliary had lower retention rates than one placed by a dentist after 48 months (9.0% with auxiliary versus 29.1% with dentist). The same study reported that the net reduction after 48 months in the number teeth exhibiting caries (dental decay) was lower for teeth treated by the dental auxiliary than the dentist (3 with auxiliary versus 60 with dentist, P value < 0.001). One study showed no evidence of a difference in dental decay after treatment with fissure sealants between groups. The one study comparing the effectiveness of dental auxiliaries and dentists in performing ART reported no difference in survival rates of the restorations (fillings) after 12 months. All studies were at high risk of bias and the overall quality of the evidence was very low, as assessed using the GRADE approach. In addition, four of the included studies were more than 20 years old; the materials used and the techniques assessed were out of date. We found no eligible studies comparing the effectiveness of dental auxiliaries and dentists in the diagnosis of oral diseases and conditions, in delivering oral health education and other aspects of health promotion, or studies assessing participants' perspectives including the acceptability of care received. None of the included studies reported adverse effects. In addition, we found no studies comparing the costs and cost-effectiveness of dental auxiliaries and dentists, their impact on access and equity of access to care that met the pre-specified inclusion criteria. We only identified five studies for inclusion in this review, all of which were at high risk of bias and four were published more than 20 years ago, highlighting the paucity of high-quality evaluations of the relative effectiveness, cost-effectiveness and safety of dental auxiliaries compared with dentists in performing clinical tasks. No firm conclusions could be drawn from the present review about the relative effectiveness of dental auxiliaries and dentists.

We searched the literature up to November 2013 and found five studies (involving 13 dental auxiliaries, six dentists, and more than 1156 participants) evaluating the effectiveness of dental auxiliaries compared with dentists in providing care traditionally delivered by dentists for inclusion in this review. These studies evaluated only two clinical tasks/techniques: placement of preventive resin sealants, which are designed to prevent dental decay in the pits and grooves of back teeth; and the atraumatic restorative technique (ART), which is a method of filling teeth that does not require motorised instruments (e.g. dental drills). Two studies were conducted in the US, and one in each of Canada, Gambia and Singapore. Of the four studies comparing dental auxiliaries and dentists in placing preventive sealants, three found no differences between the two groups in the proportion of sealants that were still intact over different time periods (six to 24 months). One study found that fewer sealants placed by a dental auxiliary were still intact after 48 months than those placed by a dentist. The same study reported that dental decay was more likely to develop in teeth that had been sealed by the dental auxiliary than the dentist, whereas another study reported no evidence of a difference between the groups. The one study comparing the effectiveness of dental auxiliaries and dentists in performing ART reported no evidence of a difference in the proportion that needed replacing or that had developed new decay after 12 months. None of the studies reported adverse events. In addition, none of the studies compared the costs and cost effectiveness of dental auxiliaries and dentists, or considered any impacts on access to care. Too few studies were included in this review to draw any firm conclusions about the relative effectiveness of dental auxiliaries and dentists. The included studies, of which four were more than 20 years old, were of low quality, had few participants and only considered two clinical tasks. This review highlights the lack of high-quality studies comparing the effectiveness, and cost-effectiveness, of dental auxiliaries and dentists in performing dental care traditionally delivered by dentists.

10.1002/14651858.CD010076.pub2

cochrane-simplification-train-177

cochrane-simplification-train-177

At present, eligible first line trials for this meta-analysis were available for bevacizumab (5 trials including 3101 patients) and vatalanib (1 trial which included 1168 patients). The overall HR´s for PFS (0.61, 95% CI 0.45 - 0.83) and OS (0.81, 95% 0.73 - 0.90) for the comparison of first-line chemotherapy, with or without bevacizumab, confirms significant benefits in favour of the patients treated with bevacizumab. However, the effect on PFS shows significant heterogeneity. For second-line chemotherapy, with or without bevacizumab, a benefit in both PFS (HR 0.61, 95% CI 0.51 - 0.73) and OS (HR 0.75, 95% CI 0.63-0.89) was demonstrated in a single, randomized trial. While differences in treatment-related deaths and 60-day mortality were not significant, higher incidences in grade III/IV hypertension, arterial thrombembolic events and gastrointestinal perforations were observed in the patients treated with bevacizumab. For valatanib, currently available data showed a non-significant benefit in PFS and OS. The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both PFS and OS in first-and second-line therapy.

Data from 5 randomized trials, which included a total of 3101 patients and evaluated the effect of bevacizumab, are currently available. Furthermore, data from one study, which included a total of 1168 patients and evaluated the effect of valatinib is published. The addition of bevacizumab to chemotherapy prolongs both progression-free survival from about 7.1 to 9.7 months when used as primary treatment and overall survival from about 17.7 to 20.5 months after prior use of chemotherapy (so called "second-line therapy") for metastatic colorectal cancer. However, the magnitude of the effect on progression-free survival is variable and probably depends on the type of chemotherapy to which it is associated. Vatalanib has no significant effect on progression-free and overall survival. Adverse effects of bevacizumab include increased frequencies of high blood pressure, arterial thromboembolic events and bowel perforations.

10.1002/14651858.CD005392.pub3

cochrane-simplification-train-178

cochrane-simplification-train-178

Ten studies were included in the review. Selected studies addressed different psychosocial interventions for five distinct disorders or health complaints. There is good evidence that problem-solving treatment by general practitioners is effective for major depression. The evidence concerning the remaining interventions for other health complaints (reattribution or cognitive behavioural group therapy for somatisation, cognitive behavioural therapy for unexplained fatigue, counselling for smoking cessation, behavioural interventions to reduce alcohol reduction) is either limited or conflicting. In general, there is little available evidence on the use of psychosocial interventions by general practitioners. Of the psychosocial interventions reviewed, problem-solving treatment for depression may offer promise, although a stronger evidence-base is required and the effectiveness in routine practice remains to be demonstrated. More research is required to improve the evidence-base on this subject.

The reviewers found no strong evidence for the effectiveness (or ineffectiveness) of psychosocial interventions by general practitioners. Of the psychosocial interventions reviewed, problem-solving treatment for depression seems the most promising tool for GPs, although its effectiveness in daily practice remains to be demonstrated.

10.1002/14651858.CD003494.pub2

cochrane-simplification-train-179

cochrane-simplification-train-179

We included eleven RCTs involving 1836 caregiver participants. Nine interventions were delivered directly to the caregiver. Seven of these provided support in the caring role, another involved a family life review, and one grief therapy. None provided practical support. The other two interventions aimed to support caregivers indirectly via patient care. Overall the risk of bias is unclear, as all trials under-reported methods. There is low quality evidence that interventions directly supporting the caregiver significantly reduce psychological distress in the short term (8 trials: standardised mean difference (SMD) -0.15; 95% confidence interval (CI) -0.28 to -0.02). There is also low quality evidence that these interventions in the short term may marginally improve coping skills and quality of life, but neither results were statistically significant (7 trials: SMD -0.05; 95% CI -0.24 to 0.14; 6 trials: SMD 0.08; 95% CI -0.11 to 0.26, respectively). One study assessed physical outcomes, specifically sleep improvement, and found no difference (median effect 0.00). No study measured health service use or adverse outcomes. In one study, however, a subgroup of intervention participants had higher levels of family conflict. Evidence was less clear on the indirect interventions. While both trials in this category found that supporting the patient may reduce psychological distress, none of the four assessments were statistically significant. There were no evaluations of coping with the caring role, quality of life, service use or adverse outcomes. In one trial there was no difference between trial arms in the proportion of caregivers reporting good physical health. There is evidence that supportive interventions may help reduce caregivers' psychological distress. These findings suggest that practitioners should enquire about the concerns of caregivers and should consider that they may benefit from additional support. There is, however, a need for further research to explore the benefits identified, and to assess the interventions' effects on physical health, and potential harms. Trials need to report their methods fully.

We found 11 trials involving 1836 caregiver participants in total. The trials commonly evaluated an intervention that provided emotional support and advice on coping. Two studies aimed to help support the family and friends indirectly by addressing the needs of the patient. Apart from one trial providing patient care, none provided practical support. Trials compared those who received the intervention with those who did not, to see if the intervention helped the family, family member or friend cope with their caring role. Trials commonly evaluated the intervention by measuring whether it improved the caregiver's general wellbeing. The review found that interventions that directly support the family and/or friends help them to cope emotionally, and may help them to cope with their role in caring and improve their quality of life. There were few assessments of the impact of the interventions on physical health; one study found overall no difference in sleep improvement. No study looked at whether the interventions increased or decreased the carers' health service use or looked for potential harms, although higher levels of family conflict was identified in some participants in one trial. Interventions that aimed to help support the family and/or friends indirectly via patient care, may also help them cope emotionally. There were no assessments on whether the indirect interventions helped them cope with their role in caring, improved quality of life, increased or decreased their health service use, or had potential harms. In one of these trials there was no difference in caregiver physical health between those whose friend or relative had received the additional patient care, and those who had not. The findings of some studies included in this review may be at risk of bias, because they under-report key design features and may have been conducted poorly.

10.1002/14651858.CD007617.pub2

cochrane-simplification-train-180

cochrane-simplification-train-180

We included six randomised controlled trials (RCTs) with a total of 822 participants. Two trials compared liquid enema reduction plus glucagon versus liquid enema alone. One trial compared liquid enema plus dexamethasone versus liquid enema alone. Another trial compared air enema plus dexamethasone versus air enema alone, and two trials compared use of liquid enema versus air enema. We identified three ongoing trials. We judged all included trials to be at risk of bias owing to omissions in reported methods. We judged five of six trials as having high risk of bias in at least one domain. Therefore, the quality of the evidence (GRADE) for outcomes was low. Interventions and data presentation varied greatly across trials; therefore meta-analysis was not possible for most review outcomes. Enema plus glucagon versus enema alone It is uncertain whether use of glucagon improves the rate of successful reduction of intussusception when compared with enema alone (reported in two trials, 218 participants; RR 1.09, 95% CI 0.94 to 1.26;low quality of evidence). No trials in this comparison reported on the number of children with bowel perforation(s) nor on the number of children with recurrent intussusception. Enema plus dexamethasone versus enema alone Use of the adjunct, dexamethasone, may be beneficial in reducing intussusception recurrence with liquid or air enema (two trials, 299 participants; RR 0.14, 95% CI 0.03 to 0.60; low quality of evidence). This equates to a number needed to treat for an additional beneficial outcome of 13 (95% CI 8 to 37). It is uncertain whether use of the adjunct, dexamethasone, improves the rate of successful reduction of intussusception when compared with enema alone (reported in two trials, 356 participants; RR 1.01, 95% CI 0.92 to 1.10;low quality of evidence). Air enema versus liquid enema Air enema may be more successful than liquid enema for reducing intussusception (two trials, 199 participants; RR 1.28, 95% CI 1.10 to 1.49; low quality of evidence). This equates to a number needed to treat for an additional beneficial outcome of 6 (95% CI 4 to 19). No trials in this comparison reported on the number of children with bowel perforation(s) or on the number of children with recurrent intussusception nor any intraoperative complications, such as bowel perforation, or other adverse effects. Only one trial reported postoperative complications, but owing to the method of reporting used, a quantitative analysis was not possible. We identified no studies that exclusively evaluated surgical interventions for management of intussusception. This review identified a small number of trials that assessed a variety of interventions. All included trials provided evidence of low quality and were subject to serious concerns about imprecision, high risk of bias, or both. Air enema may be superior to liquid enema for successfully reducing intussusception in children; however, this finding is based on a few studies including small numbers of participants. Dexamethasone as an adjuvant may be more effective in reducing intussusception recurrence rates following air enema or liquid enema, but these results are also based on a few studies of small numbers of participants. This review highlights several points that need to be addressed in future studies, including reducing the risk of bias and including relevant outcomes. Specifically, surgical trials are lacking, and future research is needed to address this evidence gap.

Evidence is current to September 2016. We identified six randomised studies, with a total of 822 participants, that explored the management of intussusception in children and assessed different types of interventions. We also identified three ongoing trials. The main outcome was the number of children with a successfully reduced intussusception. Furthermore, outcomes included the number of children returning with a recurrent intussusception and evaluation of harms (adverse events) resulting from the interventions. Evidence from two studies suggests that using air for the enema to reduce intussusception is superior to using liquid for the enema. Evidence from two studies also suggests that giving the child with intussusception a steroid medication, such as dexamethasone, may reduce the recurrence of intussusception, irrespective of whether liquid or air is used for the enema. We identified only sparse information on intraoperative and postoperative complications and on other adverse events. Of the six trials identified, we considered all to be potentially biased owing to lack of detail in reporting of how each study was undertaken. We found lack of consistency in how outcomes were defined and measured. All included studies were subject to serious concerns of imprecision based on few events, wide confidence intervals,or high risk of bias, Overall, we concluded that the quality of evidence provided by these studies was low, and that the real effects may differ significantly from those noted in these studies. Further research is needed to help doctors better understand the most effective way to manage intussusception in children.

10.1002/14651858.CD006476.pub3

cochrane-simplification-train-181

cochrane-simplification-train-181

We included 10 studies that analysed a total of 5903 participants. One study was assessed as being at low risk of bias, two were assessed as being at unclear risk of bias, with the remaining seven being at high risk of bias. The main finding of the review was that, over 2.5 to 3 years of use, a fluoride toothpaste containing 10% xylitol may reduce caries by 13% when compared to a fluoride-only toothpaste (PF -0.13, 95% CI -0.18 to -0.08, 4216 children analysed, low-quality evidence). The remaining evidence on children, from small single studies with risk of bias issues and great uncertainty associated with the effect estimates, was insufficient to determine a benefit from xylitol products. One study reported that xylitol syrup (8 g per day) reduced caries by 58% (95% CI 33% to 83%, 94 infants analysed, low quality evidence) when compared to a low-dose xylitol syrup (2.67 g per day) consumed for 1 year. The following results had 95% CIs that were compatible with both a reduction and an increase in caries associated with xylitol: xylitol lozenges versus no treatment in children (very low quality body of evidence); xylitol sucking tablets versus no treatment in infants (very low quality body of evidence); xylitol tablets versus control (sorbitol) tablets in infants (very low quality body of evidence); xylitol wipes versus control wipes in infants (low quality body of evidence). There was only one study investigating the effects of xylitol lozenges, when compared to control lozenges, in adults (low quality body of evidence). The effect estimate had a 95% CI that was compatible with both a reduction and an increase in caries associated with xylitol. Four studies reported that there were no adverse effects from any of the interventions. Two studies reported similar rates of adverse effects between study arms. The remaining studies either mentioned adverse effects but did not report any usable data, or did not mention them at all. Adverse effects include sores in the mouth, cramps, bloating, constipation, flatulence, and loose stool or diarrhoea. We found some low quality evidence to suggest that fluoride toothpaste containing xylitol may be more effective than fluoride-only toothpaste for preventing caries in the permanent teeth of children, and that there are no associated adverse-effects from such toothpastes. The effect estimate should be interpreted with caution due to high risk of bias and the fact that it results from two studies that were carried out by the same authors in the same population. The remaining evidence we found is of low to very low quality and is insufficient to determine whether any other xylitol-containing products can prevent caries in infants, older children, or adults.

Authors from the Cochrane Oral Health Group carried out this review of existing studies and the evidence is current up to 14 August 2014. It includes 10 studies published from 1991 to 2014 in which 7969 participants were randomised (5903 of whom were included in the analyses) to receive xylitol products or a placebo (a substitute without xylitol) or no treatment, and the amount of tooth decay was compared. One study included adults, the others included children aged from 1 month to 13 years. The products tested were the kind that are held in the mouth and sucked (lozenges, sucking tablets and sweets) or slowly released through a dummy/pacifier, as well as toothpastes, syrups, and wipes. There is some evidence to suggest that using a fluoride toothpaste containing xylitol may reduce tooth decay in the permanent teeth of children by 13% over a 3 year period when compared to a fluoride-only toothpaste. Over this period, there were no side effects reported by the children. The remaining evidence we found did not allow us to conclude whether or not any other xylitol-containing products can prevent tooth decay in infants, older children, or adults. The evidence presented is of low to very low quality due to the small amount of available studies, uncertain results, and issues with the way in which they were conducted.

10.1002/14651858.CD010743.pub2

cochrane-simplification-train-182

cochrane-simplification-train-182

We found one RCT and one quasi-RCT that met the inclusion criteria after independent and duplicate review of the search results. The studies used different anti-VEGF agents and different study groups which were not directly comparable. One multi-centre RCT (BRAVO) conducted in the USA randomised 397 individuals and compared monthly intravitreal ranibizumab (0.3 mg and 0.5 mg) injections with sham injection. The study only included individuals with non-ischaemic BRVO. Although repeated injections of ranibizumab appeared to have a favourable effect on the primary outcome, approximately 50% of the ranibizumab 0.3 mg group and 45% of the ranibizumab 0.5 mg group received rescue laser treatment which may have an important effect on the primary outcome. In addition, during the six-month observation period 93.5% of individuals in the sham group received intravitreal ranibizumab (0.5 mg). This cross-over design limits the ability to compare the long-term impact of ranibizumab versus a pure control group. The second trial was a small study (n = 30) from Italy with limitations in study design that reported a benefit of as-required intravitreal bevacizumab (1.25 mg) over laser photocoagulation in MO secondary to BRVO. We present the evidence from these trials and other interventional case series. The available RCT evidence suggests that repeated treatment of non-ischaemic MO secondary to BRVO with the anti-VEGF agent ranibizumab may improve clinical and visual outcomes at six and 12 months. However, the frequency of re-treatment has not yet been determined and the impact of prior or combined treatment with laser photocoagulation on the primary outcome is unclear. Results from ongoing studies should assess not only treatment efficacy but also, the number of injections needed for maintenance and long-term safety and the effect of any prior treatment.

Recent studies have suggested that an injection of anti-vascular endothelial growth factor (anti-VEGF) in the eye may be of benefit to patients with BRVO. In this review, we appraise and present the level of current evidence for the use of anti-VEGF injections in the treatment of macular oedema after BRVO. In total, we found one randomised controlled trial and one quasi-randomised controlled trial. One study from the USA. had 397 participants and compared anti-VEGF injections with sham injections. It demonstrated a potential benefit of repeated anti-VEGF injections to improve vision (at least 15 letters) at one year. A second study with 30 participants, conducted in Italy, compared anti-VEGF injections with laser photocoagulation and did not demonstrate an improvement in vision (of at least 15 letters) of anti-VEGF injections over laser photocoagulation at one year. Antiangiogenic treatment was well tolerated in these studies, but since the studies were only of one year duration, we were unable to discuss long-term effects. There are several ongoing studies which undoubtedly will add to the evidence available.

10.1002/14651858.CD009510.pub2

cochrane-simplification-train-183

cochrane-simplification-train-183

We included 25 studies (712 participants). Three studies were parallel RCTs and the others were cross-over RCTs. Nineteen studies compared fixed reduction of dialysate temperature (below 36°C) and standard dialysate temperature (37°C to 37.5°C). Most studies were of unclear or high risk of bias. Compared with standard dialysate, it is uncertain whether fixed reduction of dialysate temperature improves IDH rate (8 studies, 153 participants: rate ratio 0.52, 95% CI 0.34 to 0.80; very low certainty evidence); however, it might increase the discomfort rate compared with standard dialysate (4 studies, 161 participants: rate ratio 8.31, 95% CI 1.86 to 37.12; very low certainty evidence). There were no reported dropouts due to adverse events. No study reported death, acute coronary syndrome or stroke. Three studies compared isothermal dialysate and thermoneutral dialysate. Isothermal dialysate might improve the IDH rate compared with thermoneutral dialysate (2 studies, 133 participants: rate ratio 0.68, 95% CI 0.60 to 0.76; I2 = 0%; very low certainty evidence). There were no reports of discomfort rate (1 study) or dropouts due to adverse events (2 studies). No study reported death, acute coronary syndrome or stroke. Reduction of dialysate temperature may prevent IDH, but the conclusion is uncertain. Larger studies that measure important outcomes for HD patients are required to assess the effect of reduction of dialysate temperature. Six ongoing studies may provide much-needed high quality evidence in the future.

The quality of included studies was generally very low due to the risk of bias, small sample size, and a lack of information. We found very low quality evidence that fixed reduction of dialysate temperature decreased the incidence of IDH compared with standard dialysate and increased the discomfort rate. When patient discomfort is minimal, reduction of the dialysate temperature may be an option to reduce IDH. However, no study reported the long-term outcomes such as death or heart disorders. There is limited data suggesting that the reduction of dialysate temperature may prevent IDH, but the conclusion is very uncertain. Larger studies that measure important outcomes such as IDH or mortality for HD patients are required to assess the effect of reducing dialysate temperature.

10.1002/14651858.CD012598.pub2

cochrane-simplification-train-184

cochrane-simplification-train-184

This systematic review identified 12 randomized controlled trials (RCTs) including 774 patients that assessed melatonin for treating preoperative anxiety, postoperative anxiety or both. Four of the 12 studies compared melatonin, placebo and midazolam, whereas the remaining eight studies compared melatonin and placebo only. The quality of the evidence for our primary outcome (melatonin versus placebo for preoperative anxiety) was high. More than half of the included studies had a low risk of selection bias and at least 75% of the included studies had a low risk of attrition, performance and detection bias. Most of the included studies had an unclear risk of reporting bias. Eight out the 10 studies that assessed the effect of melatonin on preoperative anxiety using a visual analogue scale (VAS) (ranging from 0 to 100 mm, higher scores indicate greater anxiety) showed a reduction compared to placebo. The reported estimate of effect (relative effect -13.36, 95% confidence interval (CI) -16.13 to -10.58; high quality evidence) was based on a meta-analysis of seven studies. Two studies did not show any difference between melatonin and placebo. Two studies comparing melatonin with midazolam using a VAS found no evidence of a difference in preoperative anxiety between the two groups (relative effect -1.18, 95% CI -2.59 to 0.23; low quality evidence). Eight studies assessed the effect of melatonin on postoperative anxiety. Four of these studies measuring postoperative anxiety 90 minutes postoperatively using a VAS did not find any evidence of a difference between melatonin and placebo (relative effect -3.71, 95% CI -9.26 to 1.84). Conversely, two studies showed a reduction of postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) when comparing melatonin with placebo (relative effect -5.31, 95% CI -8.78 to -1.84; moderate quality evidence). Two studies comparing melatonin with midazolam using a VAS did not find any evidence of a difference between the two groups in postoperative anxiety (relative effect -2.02, 95% CI -5.82 to 1.78). When compared to placebo, melatonin given as premedication (tablets or sublingually) can reduce preoperative anxiety in adults (measured 50 to 100 minutes after administration). Melatonin may be equally as effective as standard treatment with midazolam in reducing preoperative anxiety in adults (measured 50 to 100 minutes after administration). The effect of melatonin on postoperative anxiety (measured 90 minutes and 6 hours after surgery) in adults is mixed but suggests an overall attenuation of the effect compared to preoperatively.

The evidence was current to April 2013. We found 12 studies involving 774 patients. The age of the participants, in the studies, ranged from 19 to 80 years. Types of surgery and anaesthesia varied. The melatonin doses varied from 3 to14 mg and were administered 50 to 100 minutes before surgery. Midazolam (a benzodiazepine) doses ranged from 3.5 to 15 mg. We reran the search in October 2014. We will deal with any studies of interest when we update the review. Four studies compared melatonin, placebo and midazolam; eight studies compared melatonin and placebo only. Comparing the effect of melatonin with placebo, melatonin may reduce preoperative anxiety. It may also reduce postoperative anxiety compared with placebo, measured six hours after surgery. When comparing the effect of melatonin with midazolam preoperatively, there was no difference in anxiety. Postoperatively, there was no difference when comparing the effect of melatonin with placebo on anxiety measured 90 minutes after surgery or when comparing the effect of melatonin with midazolam. The quality of the evidence varied by outcome. We are confident that melatonin reduces anxiety preoperatively from the short term data in the review. We are less certain of this effect six hours postoperatively. Whether the anxiety reducing effect of melatonin can be applied to all surgical patients remains unclear, as many factors influence the risk of anxiety; among these are age, gender, type of surgery, type of anaesthesia, and cultural and religious differences. Younger age and female gender are independent risk factors for anxiety and this may be a limitation as four studies only included women and three only included patients older than 60 years. Eight studies were carried out in Middle-East countries; this might be a limitation with regard to generalizability. Melatonin compared to placebo, given as premedication (tablets or under the tongue (sublingually)) reduced preoperative anxiety (measured 50 to 100 minutes after administration). Melatonin may be equally as effective as standard treatment with midazolam in reducing preoperative anxiety (measured 50 to 100 minutes after administration). When compared to placebo, melatonin may reduce postoperative anxiety (six hours after surgery).

10.1002/14651858.CD009861.pub2

cochrane-simplification-train-185

cochrane-simplification-train-185

We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from two randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials. In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; nine randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events. We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy.

We included 14 randomised clinical trials with 867 participants. All randomised clinical trials compared intravenous infusion of flumazenil versus an inactive placebo (dummy infusion, e.g. a salt solution). The duration of treatment ranged from 10 minutes to 72 hours. Ten randomised clinical trials included participants with overt hepatic encephalopathy; three included participants with minimal hepatic encephalopathy; and one randomised clinical trial included participants with overt or minimal hepatic encephalopathy. The analyses showed no effect of flumazenil on all-cause mortality (deaths of any cause) compared with placebo. People who received flumazenil were more likely to recover from their hepatic encephalopathy than people given a placebo. We found little information about serious side effects. Overall, the evidence for the effect of flumazenil on hepatic encephalopathy was of low quality; only one randomised clinical trial included had a low risk of bias.

10.1002/14651858.CD002798.pub4

cochrane-simplification-train-186

cochrane-simplification-train-186

Thirty-one studies fulfilled the inclusion criteria, with a total of 4662 participants (of which 4522 were receiving the drugs relevant to our comparison) and presented data that could be used for at least one comparison. The trial centres were located in Europe (especially Scandinavia), Japan and Northern America. When comparing perphenazine with placebo, for our primary outcome of clinical response, results favoured perphenazine with significantly more people receiving placebo rated as either 'no better or deterioration' for global state than people receiving perphenazine (1 RCT, n = 61 RR 0.32 CI 0.13 to 0.78, very low quality evidence). More people receiving placebo relapsed, although not a statistically significant number (1 RCT, n = 48, RR 0.14 CI 0.02 to 1.07, very low quality evidence). Death was not reported in the perphenazine versus placebo comparison. Experiences of dystonia were equivocal between groups (1 RCT, n = 48, RR 1.00 CI 0.07 to 15.08, very low quality evidence); other outcomes not reported in this comparison include serious adverse events, economic outcomes, and service use and hospitalisation. For the comparison of perphenazine versus any other antipsychotic drugs, no real differences in effect between the drugs were found. There was no significant difference between groups for those considered 'no better or deterioration' (17 RCTs, n = 1879, RR 1.04 CI 0.91 to 1.17, very low quality evidence). For mental state outcome of 'no effect' of the study drug, there was again no significant difference between groups (4 RCTs, n = 383, RR 1.24 CI 0.61 to 2.52, very low quality evidence). Death was not reported in any of the included studies. There was no significant difference in rates of dystonia with perphenazine versus any other antipsychotic drugs (4 RCTs, n = 416, RR 1.36 CI 0.23 to 8.16, very low quality evidence), nor was there a significant difference between groups for serious adverse events (2 RCTs, n = 1760, RR 0.98 CI 0.68 to 1.41, very low quality evidence). Although perphenazine has been used in randomised trials for more than 50 years, incomplete reporting and the variety of comparators used make it impossible to draw clear conclusions. All data for the main outcomes in this review were of very low quality evidence. At best we can say that perphenazine showed similar effects and adverse events as several of the other antipsychotic drugs. Since perphenazine is a relatively inexpensive and frequently used compound, further trials are justified to clarify the properties of this classical antipsychotic drug.

The aim of the review was to examine the effectiveness and safety of perphenazine for schizophrenia. A search for relevant randomised studies was run in September 2013. The review authors included 31 studies that randomised people with schizophrenia to receive either perphenazine or placebo or another antipsychotic drug. A total of 4662 people participated in these studies. The quality of evidence presented by the trials was rated by the review authors to be very low quality. It was found that perphenazine was no better or worse than other older antipsychotic drugs in treating the symptoms of schizophrenia, and like other older antipsychotic drugs, the side effects of perphenazine included tremors, uncontrollable shaking, the inability to sit still and feeling restless. Although perphenazine has been used for more than 50 years, poor studies with bad reporting of information mean that it is difficult to draw more clear findings and conclusions as to the effectiveness and safety of perphenazine. However, perphenazine is inexpensive and a popular antipsychotic drug in many countries, so further research and trials on its effectiveness and safety are much needed. Ben Gray, Senior Peer Researcher, McPin Foundation.http://mcpin.org/

10.1002/14651858.CD003443.pub3

cochrane-simplification-train-187

cochrane-simplification-train-187

We included six Cochrane Reviews, one of which compared any type of chest physiotherapy with no chest physiotherapy or coughing alone and the remaining five reviews included head-to-head comparisons of different airway clearance techniques. All the reviews were considered to have a low risk of bias. However, the individual trials included in the reviews often did not report sufficient information to adequately assess risk of bias. Many trials did not sufficiently report on outcome measures and had a high risk of reporting bias. We are unable to draw definitive conclusions for comparisons of airway clearance techniques in terms of FEV1, except for reporting no difference between PEP therapy and oscillating devices after six months of treatment, mean difference -1.43% predicted (95% confidence interval -5.72 to 2.87); the quality of the body of evidence was graded as moderate. The quality of the body of evidence comparing different airway clearance techniques for other outcomes was either low or very low. There is little evidence to support the use of one airway clearance technique over another. People with cystic fibrosis should choose the airway clearance technique that best meets their needs, after considering comfort, convenience, flexibility, practicality, cost, or some other factor. More long-term, high-quality randomised controlled trials comparing airway clearance techniques among people with cystic fibrosis are needed.

All of the reviews were considered to be well-conducted. However, the individual trials included in the reviews often did not report enough detailed information to allow us to properly determine trial quality. Many trials did not report enough information on outcome measures; it is unclear how this missing information would influence the results. We graded the evidence for lung function when PEP was compared to vibrating (oscillating) devices as moderate, but the evidence comparing different airway clearance techniques for other outcomes, such as individual preference and quality of life was of low or very low quality. More long-term, high-quality trials (where participants are put into groups at random) which compare different airway clearance techniques among people with CF are needed.

10.1002/14651858.CD011231.pub2

cochrane-simplification-train-188

cochrane-simplification-train-188

36 trials were included but most were small and of duration less than three months. Nine trials were of six months duration (2016 patients). These longer trials were the more recent trials and generally were of adequate size, and conducted to a reasonable standard. Most trials tested the same standardised preparation of Ginkgo biloba, EGb 761, at different doses, which are classified as high or low. The results from the more recent trials showed inconsistent results for cognition, activities of daily living, mood, depression and carer burden. Of the four most recent trials to report results three found no difference between Ginkgo biloba and placebo, and one reported very large treatment effects in favour of Ginkgo biloba. There are no significant differences between Ginkgo biloba and placebo in the proportion of participants experiencing adverse events. A subgroup analysis including only patients diagnosed with Alzhiemer's disease (925 patients from nine trials) also showed no consistent pattern of any benefit associated with Ginkgo biloba. Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. The evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.

Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. Overall, evidence that Ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable. Of the four most recent trials to report results, three found no difference between Ginkgo biloba and placebo, and one reported very large treatment effects in favour of Ginkgo biloba.

10.1002/14651858.CD003120.pub3

cochrane-simplification-train-189

cochrane-simplification-train-189

We included three randomised trials with 261 participants (mean age: 60 years) comparing RFCA (159 participants) to antiarrhythmic drugs (102) for non-paroxysmal atrial fibrillation. We generally assessed the included studies as having low or unclear risk of bias across multiple domains, with reported outcomes generally lacking precision due to low event rates. Evidence showed that RFCA was superior to antiarrhythmic drugs in achieving freedom from atrial arrhythmias (RR 1.84, 95% CI 1.17 to 2.88; 3 studies, 261 participants; low-quality evidence), reducing the need for cardioversion (RR 0.62, 95% CI 0.47 to 0.82; 3 studies, 261 participants; moderate-quality evidence), and reducing cardiac-related hospitalisation (RR 0.27, 95% CI 0.10 to 0.72; 2 studies, 216 participants; low-quality evidence) at 12 months follow-up. There was substantial uncertainty surrounding the effect of RFCA regarding significant bradycardia (or need for a pacemaker) (RR 0.20, 95% CI 0.02 to 1.63; 3 studies, 261 participants; low-quality evidence), periprocedural complications, and other safety outcomes (RR 0.94, 95% CI 0.16 to 5.68; 3 studies, 261 participants; very low-quality evidence). In people with non-paroxysmal atrial fibrillation, evidence suggests a superiority of RFCA to antiarrhythmic drugs in achieving freedom from atrial arrhythmias, reducing the need for cardioversion, and reducing cardiac-related hospitalisations. There was uncertainty surrounding the effect of RFCA with significant bradycardia (or need for a pacemaker), periprocedural complications, and other safety outcomes. Evidence should be interpreted with caution, as event rates were low and quality of evidence ranged from moderate to very low.

We searched scientific databases from their inception to 1 April 2016 and found three studies where people are randomly allocated into one of two or more treatment groups (known as randomised trials). The three trials included 261 adults (mean age: 60 years) comparing catheter ablation (159 participants) to heart rhythm drugs (102) for non-paroxysmal atrial fibrillation at 12 months follow-up. When compared to participants receiving heart rhythm drugs, those participants receiving catheter ablation were more likely to be free from atrial fibrillation, had reduced risk of being hospitalised due to cardiac causes, and had a reduced risk of needing cardioversion after 12 months. There was uncertainty surrounding the effect of catheter ablation with significant bradycardia (or need for a pacemaker), periprocedural complications, and other safety outcomes. Evidence should be interpreted with caution as evidence quality ranged from moderate to very low across the different outcomes due to the limitations of the original studies. It is likely that further high-quality and adequately powered trials may affect the confidence in reported results.

10.1002/14651858.CD012088.pub2

cochrane-simplification-train-190

cochrane-simplification-train-190

Three trials involving 104 people were included. We classified one study as having low risk of bias; the others had some limitations and we classified them as having high risk of bias. Two studies (one with low risk of bias and the other with high risk of bias) applied progressive resistance training (PRT) combined with range of motion exercises and stretching; the comparison group received standard care. Pooled data demonstrated that PRT can improve shoulder pain (mean difference (MD) -6.26; 95% confidence interval (CI) -12.20 to -0.31) and shoulder disability (MD -8.48; 95% CI -15.07 to -1.88), both measured using the Shoulder Pain and Disability Index (SPADI) (range 0 to 100). Similarly, secondary outcomes were also improved: active range of motion for external rotation (MD 14.51 degrees; 95% CI 7.87 to 21.14), passive range of motion for abduction (MD 7.65 degrees; 95% CI 0.64 to 14.66), forward flexion (MD 6.20 degrees; 95% CI 0.69 to 11.71), external rotation (MD 7.17 degrees; 95% CI 2.20 to 12.14) and horizontal abduction (MD 7.34 degrees; 95% CI 2.86 to 11.83). Strength and resistance of scapular muscles was assessed in one study and the results showed a statistically significant benefit of PRT. The studies did not demonstrate a statistically significant difference in quality of life. Only two non-serious adverse events were described in the PRT group compared with none in the standard care group. One study with high risk of bias used a broad spectrum of techniques including free active exercises, stretching and postural care for a period of three months following surgery. This study did not demonstrate a difference between the exercise group and routine postoperative physiotherapy care in shoulder function and quality of life, but serious methodological limitations could explain this. No serious adverse events were reported. Limited evidence from two RCTs demonstrated that PRT is more effective than standard physiotherapy treatment for shoulder dysfunction in patients treated for head and neck cancer, improving pain, disability and range of motion of the shoulder joint, but it does not improve quality of life. However, although statistically significant the measured benefits of the intervention may be small. Other exercise regimes were not shown to be effective compared to routine postoperative physiotherapy. Further studies which apply other exercise interventions in head and neck cancer patients in the early postoperative and radiotherapy period are needed, with long-term follow-up.

This review identified three randomized controlled trials involving 104 patients. Two studies compared progressive resistance training with standard care (usual treatment process). When we combined their results we found that progressive resistance training improved shoulder pain, shoulder disability, active range of motion for external rotation, passive range of motion for abduction, forward flexion, external rotation and horizontal abduction. The size of this improvement was small. The studies did not demonstrate a statistically significant difference in quality of life. Two non-serious adverse events were reported in the progressive resistance training group and none in the standard care group. Another study compared a broad spectrum of techniques, including free active exercises, stretching, postural care, re-education of scapulothoracic postural muscles, and strength of shoulder muscles, with routine postoperative physiotherapy care for three months following surgery. This study did not demonstrate a difference between the exercise group and the routine physiotherapy care group in shoulder function or quality of life. No adverse effects were reported. Further studies which apply other exercise interventions in head and neck cancer patients in the early postoperative period and after radiotherapy are needed, with long-term follow-up.

10.1002/14651858.CD008693.pub2

cochrane-simplification-train-191

cochrane-simplification-train-191

We included two trials that recruited a total of 234 women. The overall risk of bias was low for the two studies. Both studies compared Bishop score withTVUS. The two included studies did not show any clear difference between the Bishop score and TVUS groups for the following main outcomes: vaginal birth (RR 1.07, 95% CI 0.92 to 1.25, moderate quality evidence), caesarean delivery (RR 0.81, 95% CI 0.49 to 1.34, moderate quality evidence), neonatal admission into neonatal intensive care unit (RR 1.67, 95% CI 0.41 to 6.71, moderate quality evidence). Both studies only provided median data in relation to induction-delivery interval and reported no clear difference between the Bishop and TVUS groups. Perinatal mortality was not reported in the included studies. For the review's secondary outcomes, the need for misoprostol for cervical ripening was more frequent in the TVUS group compared to the Bishop score group (RR 0.52, 95% CI 0.41 to 0.66, two studies, 234 women, moderate quality evidence). In contrast, there were no clear differences between the Bishop scope and TVUS groups in terms of meconium staining of the amniotic fluid, fetal heart rate abnormality in labour, and Apgar score less than seven. Only one trial reported median data on the induction-delivery interval and induction to active phase interval, the trialist reported no difference between the Bishop group and the TVUS group for this outcome. Neither of the included studies reported on uterine rupture. Moderate quality evidence from two small RCTs involving 234 women that compared two different methods for assessing pre-induction cervical ripening (Bishop score and TVUS) did not demonstrate superiority of one method over the other in terms of the main outcomes assessed in this review. We did not identify any data relating to perinatal mortality. Whilst use of TVUS was associated with an increased need for misoprostol for cervical ripening, both methods could be complementary. The choice of a particular method of assessing pre-induction cervical ripening may differ depending on the environment and need where one is practicing since some methods (i.e. TVUS) may not be readily available and affordable in resource-poor settings where the sequelae of labour and its management is prevalent. The evidence in this review is based on two studies that enrolled a small number of women and there is insufficient evidence to support the use of TVUS over the standard digital vaginal assessment in pre-induction cervical ripening. Further adequately powered RCTs involving TVUS and the Bishop score and including other methods of pre-induction cervical ripening assessment are warranted. Such studies need to address uterine rupture, perinatal mortality, optimal cut-off value of the cervical length and Bishop score to classify women as having favourable or unfavourable cervices and cost should be included as an outcome.

Moderate quality evidence was available from the two included studies which compared the Bishop score with transvaginal ultrasound (TVUS) (ultrasound done through the vagina). The studies were considered to be at a low risk of bias. The need for misoprostol (a drug) for softening the cervix (cervical ripening) was more common in the TVUS arm. No clear difference was seen between the two methods in terms of vaginal birth, caesarean delivery, admission of the newborn into the neonatal intensive care unit, meconium staining of the amniotic fluid, abnormal heart beat of the baby within the womb whilst the mother was in labour and Apgar score less than seven (difficulty of the baby establishing life and other life movements on its own immediately after childbirth). None of the included studies reported on tears of the womb or death of the baby just before, during or immediately after childbirth. We did not find any studies that compared Bishop score with any other methods such as the presence of vaginal fetal fibronectin or insulin-like growth factor binding protein-1. Authors conclusions Although the overall quality of evidence is moderate, there is no difference in outcomes between the two methods (Bishop score and TVUS) apart from the increased need of misoprostol in the TVUS group. Both methods could be useful to each other, or complementary as the Bishop score does not need any special equipment and uses digital examination which is required to induce labour (to insert a cervical ripening agent, rupture the membranes or separate them from the cervix) but TVUS can give additional information that may affect the course and management of the labour. The choice of a particular method may differ depending on the environment and need since TVUS requires training and may not be readily available and affordable in resource-poor countries. Future research The two included studies involved a small number of women and further studies are needed. Such studies should include outcomes such as rupture of the womb, perinatal mortality, most appropriate cut-off value for the cervical length and Bishop score to classify women as having ripe or unripe cervices, and cost.

10.1002/14651858.CD010762.pub2

cochrane-simplification-train-192

cochrane-simplification-train-192

The search identified 1178 potentially relevant titles; however, there were no published studies that were specifically designed to answer this question. Two studies met criteria for inclusion in the review and 98 children were included in the meta-analysis. There was no significant difference between groups in the proportion of children 'not cured' at follow-up (primary outcome measure), with a pooled odds ratio (OR) of 0.61 (95% confidence interval (CI) 0.24 to 1.55). However, the included studies were limited in their ability to answer the review question by the fact that all participants were infants, post acute bronchiolitis illness, and cough duration at the start of study medication was ill-defined. There is currently no evidence to support the use of ICS for treatment of subacute cough in children. However, this systematic review is limited by the small number of studies available for analysis and the size, quality and design of these studies. Further well-designed RCTs are required to support or refute the efficacy of treatment with ICS in children with subacute cough.

Data from two small studies were available for inclusion in this review; however, both studies were in infants following hospitalisation for an acute bronchiolitis illness (98 infants in total). There was no difference between groups in the proportion of children 'not cured' at follow-up. There were no significant side effects in either of these studies. Without further available evidence, recommendations for the use of inhaled corticosteroids for the treatment of subacute cough in children cannot be made. Further well-designed studies, including children over 12 months of age, are required to determine whether treatment with inhaled corticosteroids can safely and effectively reduce the severity of subacute cough in children.

10.1002/14651858.CD008888.pub2

cochrane-simplification-train-193

cochrane-simplification-train-193

A single RCT met the inclusion criteria. Our 2018 search update identified no additional trials. The included trial evaluated BIG-IV for the treatment of infant botulism and included 59 treatment participants and 63 control participants. The control group received a control immune globulin that did not have an effect on botulinum toxin. Participants were followed during the length of their hospitalization to measure the outcomes of interest. There was some violation of intention-to-treat principles, and possibly some between-treatment group imbalances among participants admitted to the intensive care unit and mechanically ventilated, but otherwise the risk of bias was low. There were no deaths in either group, making any treatment effect on mortality inestimable. There was a benefit in the treatment group on mean duration of hospitalization (BIG-IV: 2.60 weeks, 95% confidence interval (CI) 1.95 to 3.25; control: 5.70 weeks, 95% CI 4.40 to 7.00; mean difference (MD) -3.10 weeks, 95% CI -4.52 to -1.68; moderate-certainty evidence); mechanical ventilation (BIG-IV: 1.80 weeks, 95% CI 1.20 to 2.40; control: 4.40 weeks, 95% CI 3.00 to 5.80; MD -2.60 weeks, 95% CI -4.06 to -1.14; low-certainty evidence); and tube or parenteral feeding (BIG-IV: 3.60 weeks, 95% CI 1.70 to 5.50; control: 10.00 weeks, 95% CI 6.85 to 13.15; MD -6.40 weeks, 95% CI -10.00 to -2.80; moderate-certainty evidence), but not on proportion of participants with adverse events or complications (BIG-IV: 63.08%; control: 68.75%; risk ratio 0.92, 95% CI 0.72 to 1.18; absolute risk reduction 0.06, 95% CI 0.22 to -0.11; moderate-certainty evidence). We found low- and moderate-certainty evidence supporting the use of BIG-IV in infant intestinal botulism. A single RCT demonstrated that BIG-IV probably decreases the duration of hospitalization; may decrease the duration of mechanical ventilation; and probably decreases the duration of tube or parenteral feeding. Adverse events were probably no more frequent with immune globulin than with placebo. Our search did not reveal any evidence examining the use of other medical treatments including serum trivalent botulism antitoxin.

Our searches of the medical literature revealed one relevant study, which was in infant botulism. The treatment was a single dose of a medicine made from human immune proteins (human-derived botulinum immune globulin intravenous, or BIG-IV). Fifty-nine infants received BIG-IV, and 63 infants received a placebo (inactive treatment). Each study participant was followed up for the duration of their hospitalization. This study was sponsored by the California Department of Health Services. There were no deaths in either group in the trial. Infants treated with BIG-IV spent, on average, about three weeks less time in hospital (i.e. 3.1 weeks versus 5.7 weeks) than infants who received the inactive treatment, and spent about three weeks less on a ventilator (1.8 weeks versus 4.4 weeks). The average duration of tube feeding in the BIG-IV group was more than six weeks less than in the placebo group (i.e. 3.6 versus 10 weeks). The risk of harmful effects of the treatment was probably no greater with BIG-IV than with the inactive treatment. The evidence was mostly of moderate certainty (low certainty for time spent on a ventilator). The review shows that BIG-IV probably shortens hospitalization; may shorten time spent on a ventilator; and probably reduces the duration of tube feeding compared to placebo. On the other hand, we found no evidence for or against botulism antitoxin or other treatments for botulism. The evidence is up-to-date to January 2018, when we updated the searches and found no new trials.

10.1002/14651858.CD008123.pub4

cochrane-simplification-train-194

cochrane-simplification-train-194

This updated review included 24 studies; six additional studies added 1001 participants involved in comparisons of ketoprofen or dexketoprofen and placebo, with a 12% increase in participants taking ketoprofen and a 65% increase for dexketoprofen. Most participants (70%) were women. Dental studies typically involved young participants (mean age 20 to 30 years); other types of surgery involved older participants (mean age 37 to 68 years). Overall, we judged the studies at high risk of bias only for small size, which can lead to an overestimation of benefit. Ketoprofen doses ranged between 6.5 mg and 150 mg. The proportion of participants achieving at least 50% pain relief over six hours with the usual ketoprofen oral dose of 50 mg was 57%, compared to 23% with placebo, giving an NNT of 2.9 (95% CI 2.4 to 3.7) (RR 2.5, 95% CI 2.0 to 3.1; 594 participants; 8 studies; high quality evidence). Efficacy was significantly better in dental studies (NNT 1.8) than other surgery (NNT 4.2). The proportion of participants using rescue medication within six hours was lower with ketoprofen (32%) than with placebo (75%), giving a number needed to treat to prevent use of rescue medication (NNTp) of 2.3 (95% CI 1.8 to 3.1); 263 participants; 4 studies; high quality evidence). Median time to remedication estimates were poorly reported. Reports of any adverse event were similar with ketoprofen (18%) and placebo (11%) (RR 1.6, 95% CI 0.98 to 2.8; 342 participants; 5 studies; high quality evidence). No study reported any serious adverse events (very low quality evidence). Dexketoprofen doses ranged between 5 mg and 100 mg. The proportion of participants achieving at least 50% pain relief over six hours with the usual dexketoprofen oral dose of 20 mg or 25 mg was 52%, compared to 27% with placebo, giving an NNT of 4.1 (95% CI 3.3 to 5.2) (RR 2.0, 95% CI 1.6 to 2.2; 1177 participants; 8 studies; high quality evidence). Efficacy was significantly better in dental studies (NNT 2.7) than other surgery (NNT 5.7). The proportion of participants using rescue medication within six hours was lower with dexketoprofen (47%) than placebo (69%), giving an NNTp of 4.7 (95% CI 3.3 to 8.0); 445 participants; 5 studies; high quality evidence). Median time to remedication estimates were poorly reported. Reports of any adverse event were similar with dexketoprofen (14%) and placebo (10%) (RR 1.4, 95% CI 0.89 to 2.2; 536 participants, 6 studies; high quality evidence). No study reported any serious adverse events (very low quality evidence). Ketoprofen at doses of 25 mg to 100 mg is an effective analgesic in moderate to severe acute postoperative pain with an NNT for at least 50% pain relief of 2.9 with a 50 mg dose. This is similar to that of commonly used NSAIDs such as ibuprofen (NNT 2.5 for 400 mg dose) and diclofenac (NNT 2.7 for 50 mg dose). Dexketoprofen is also effective with an NNT of 4.1 in the dose range 10 mg to 25 mg. Differential efficacy between dental surgery and other types of surgery seen for both drugs is unusual. Both drugs were well tolerated in single doses.

In March 2017, we found 24 studies involving 5220 people. The main comparison was between usual oral doses of ketoprofen 50 mg and placebo, and dexketoprofen 25 mg and placebo. The studies tested single doses after wisdom tooth extraction, and after other types of surgery, mainly hip replacement and gynaecological operations. Studies included adults over a range of ages, and 7 out of 10 participants were women. The main outcome was participants having at least half of the maximum possible pain relief over the first six hours after taking the tablets. For ketoprofen, there were 594 participants in eight studies in the comparison with placebo (a dummy tablet). About 6 in 10 achieved at least half of the maximum possible pain relief with ketoprofen 50 mg compared with 2 in 10 with placebo. The number of participants who needed more painkillers within six hours was 5 in 10 with ketoprofen compared with 8 in 10 with placebo. For dexketoprofen, there were 1177 participants in eight studies in the comparison with placebo. About 5 in 10 achieved at least half of the maximum possible pain relief with dexketoprofen 25 mg compared with 3 in 10 with placebo. The number of participants who needed more painkillers within six hours was 5 in 10 with dexketoprofen compared with 7 in 10 with placebo. About 1 or 2 in 10 people had any side effects with ketoprofen, dexketoprofen, or placebo. Serious side effects were uncommon. Few people dropped out of the studies for any reason. The quality of the evidence was judged to be high for most outcomes. This research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different is low.

10.1002/14651858.CD007355.pub3

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A total of 33 trials (including 11 from the original 2008 review) involving 7453 participants were included in this review, with 28 trials providing suitable data for entry into meta-analysis. Although the interventions provided in these studies were very different from one study to another (participant numbers, duration of intervention, group versus individual intervention, setting), most of the studies were based on recognisable theoretical models, and we tried to be inclusive in considering the wide variety of available culturally appropriate health education. Glycaemic control (as measured by glycosylated haemoglobin A1c (HbA1c)) showed improvement following culturally appropriate health education at three months (mean difference (MD) -0.4% (95% confidence interval (CI) -0.5 to -0.2); 14 trials; 1442 participants; high-quality evidence) and at six months (MD -0.5% (95% CI -0.7 to -0.4); 14 trials; 1972 participants; high-quality evidence) post intervention compared with control groups who received 'usual care'. This control was sustained to a lesser extent at 12 months (MD -0.2% (95% CI -0.3 to -0.04); 9 trials; 1936 participants) and at 24 months (MD -0.3% (95% CI -0.6 to -0.1); 4 trials; 2268 participants; moderate-quality evidence) post intervention. Neutral effects on health-related quality of life measures were noted and there was a general lack of reporting of adverse events in most studies — the other two primary outcomes for this review. Knowledge scores showed improvement in the intervention group at three (standardised mean difference (SMD) 0.4 (95% CI 0.1 to 0.6), six (SMD 0.5 (95% CI 0.3 to 0.7)) and 12 months (SMD 0.4 (95% CI 0.1 to 0.6)) post intervention. A reduction in triglycerides of 24 mg/dL (95% CI -40 to -8) was observed at three months, but this was not sustained at six or 12 months. Neutral effects on total cholesterol, low-density lipoprotein (LDL) cholesterol or high-density lipoprotein (HDL) cholesterol were reported at any follow-up point. Other outcome measures (blood pressure, body mass index, self-efficacy and empowerment) also showed neutral effects compared with control groups. Data on the secondary outcomes of diabetic complications, mortality and health economics were lacking or were insufficient. Because of the nature of the intervention, participants and personnel delivering the intervention were rarely blinded, so the risk of performance bias was high. Also, subjective measures were assessed by participants who self-reported via questionnaires, leading to high bias in subjective outcome assessment. Culturally appropriate health education has short- to medium-term effects on glycaemic control and on knowledge of diabetes and healthy lifestyles. With this update (six years after the first publication of this review), a greater number of RCTs were reported to be of sufficient quality for inclusion in the review. None of these studies were long-term trials, and so clinically important long-term outcomes could not be studied. No studies included an economic analysis. The heterogeneity of the studies made subgroup comparisons difficult to interpret with confidence. Long-term, standardised, multi-centre RCTs are needed to compare different types and intensities of culturally appropriate health education within defined ethnic minority groups, as the medium-term effects could lead to clinically important health outcomes, if sustained.

This updated review found in the world literature 33 randomised controlled trials (RCTs) of culturally appropriate health education on diabetes that met the selection criteria (participants from a defined ethnic minority group living in a upper-middle-income or high-income country, over 16 years of age, diagnosed with type 2 diabetes mellitus and receiving a culturally tailored health education intervention). The median duration of the intervention was six months, and a total of 7453 participants were involved in the studies. Culturally appropriate health education improved blood sugar control among participants, compared with those receiving 'usual' care, at three, six, 12 and 24 months after the intervention was provided. Knowledge about diabetes improved, and participants attained healthier lifestyles. No information was available regarding complications of diabetes and death from any cause, and there was a general lack of reporting of adverse effects in most studies. Neutral effects were observed for health-related quality of life, blood lipids like cholesterol, blood pressure and weight. The costs of educational programmes were rarely analysed. Compared with the first review, performed in 2008 (11 studies), many more published studies were identified in this review (altogether 33 studies), strengthening the original findings that blood sugar control and knowledge of diabetes are improved when culturally appropriate health education is provided to people in ethnic minority groups diagnosed with diabetes. The effects of this improvement are shown in this update as lasting longer — up to 24 months after health education was provided in some trials. However, additional high-quality standardised RCTs of longer duration are needed, along with full evaluation of costs. Heterogeneity of the studies, in terms of populations studied, type and duration of health education provided, variety of outcomes measured and differences in timing of assessment, limits interpretation of our findings. Also, risk of bias was judged to be high for many outcomes. This evidence is up-to-date as of September 2013.

10.1002/14651858.CD006424.pub3

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No trials were included. Primary healthcare interventions and a strong family and social support network are invaluable to parents and families around the time a baby dies. However, due to the lack of high-quality randomised trials conducted in this area, the true benefits of currently existing interventions aimed at providing support for mothers, fathers and families experiencing perinatal death is unclear. Further, the currently available evidence around the potential detrimental effects of some interventions (e.g. seeing and holding a deceased baby) remains inconclusive at this point in time. However, some well-designed descriptive studies have shown that, under the right circumstances and guided by compassionate, sensitive, experienced staff, parents' experiences of seeing and holding their deceased baby is often very positive. The sensitive nature of this topic and small sample sizes, make it difficult to develop rigorous clinical trials. Hence, other research designs may further inform practice in this area. Where justified, methodologically rigorous trials are needed. However, methodologically rigorous trials should be considered comparing different approaches to support.

This review aimed to identify clinical trials to assess the effect of different types of bereavement support interventions and/or counselling for parents experiencing perinatal death. There are no included studies on this topic. For the update of this review we identified one new trial, which is currently awaiting classification. More research in this area is needed.

10.1002/14651858.CD000452.pub3

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There were eight included studies: three studies had a low risk of bias and five studies had high risk of bias. The studies compared ergot alkaloids with no uterotonic agents, with a total of 2031 women in the ergot alkaloids group and 1978 women in the placebo or no treatment group. Seven studies used the IV/IM route of administration and one study used the oral route. Ergot alkaloids (any route of administration) versus no uterotonic agents Use of ergot alkaloids in the third stage of labour decreased mean blood loss (mean difference (MD) -80.52 mL, 95% confidence interval (CI) -96.39 to -64.65 mL; women = 2718; studies = 3; moderate-quality evidence); decreased PPH of at least 500 mL (average risk ratio (RR) 0.52, 95% CI 0.28 to 0.94; women = 3708; studies = 5; I2 = 83%; low-quality evidence); increased maternal haemoglobin concentration (g/dL) at 24 to 48 hours postpartum (MD 0.50 g/dL, 95% CI 0.38 to 0.62; women = 1429; studies = 1; moderate-quality evidence); and decreased the use of therapeutic uterotonics (average RR 0.37, 95% CI 0.15 to 0.90; women = 2698; studies = 3; I2 = 89%; low-quality evidence). There were no clear differences between groups in severe PPH of at least 1000 mL (average RR 0.32, 95% CI 0.04 to 2.59; women = 1718; studies = 2; I2 = 74%; very low-quality evidence). The risk of retained placenta or manual removal of the placenta, or both, were inconsistent with high heterogeneity. Ergot alkaloids increased the risk of elevated blood pressure (average RR 2.60, 95% CI 1.03 to 6.57: women = 2559; studies = 3; low-quality evidence) and pain after birth requiring analgesia (RR 2.53, 95% CI 1.34 to 4.78: women = 1429; studies = 1; moderate-quality evidence) but there were no differences between groups in vomiting, nausea, headache or eclamptic fit. Results for IV/IM ergot alkaloids versus no uterotonic agents were similar to those for the main comparison of ergot alkaloids administered by any route, since most of the studies (seven of eight) used the IV/IM route. Only one small study (289 women) compared oral ergometrine with placebo and it showed no benefit of ergometrine over placebo. No maternal adverse effects were reported. None of the studies reported on any of our prespecified neonatal outcomes Prophylactic IM or IV injections of ergot alkaloids may be effective in reducing blood loss, reducing PPH (estimated blood loss of at least 500 mL), and increasing maternal haemoglobin. Ergot alkaloids may also decrease the use of therapeutic uterotonics, but adverse effects may include elevated blood pressure and pain after birth requiring analgesia. There were no differences between groups in terms of other adverse effects (vomiting, nausea, headache or eclamptic fit). There is a lack of evidence on the effects of ergot alkaloids on severe PPH, and retained or manual removal of placenta. There is also a lack of evidence on the oral route of administration of ergot alkaloids.

We searched for evidence in September 2017 and included eight trials involving 4009 women receiving ergometrine by mouth (orally), into the muscle (intramuscularly (IM)) or into the vein (intravenously (IV)). Of eight trials, seven included studies were analysed in this updated review. The evidence from the trials analysed suggests that ergot alkaloids may decrease mean blood loss, increase maternal haemoglobin levels in the blood, and may decrease both blood loss of at least 500 mL (PPH) and the use of therapeutic uterotonics. It is uncertain whether ergot alkaloids have any effect on numbers of women experiencing high blood loss of at least 1000 mL (severe PPH). The evidence also suggested that they may increase adverse effects such as increased blood pressure and pain after birth. They may make little or no difference between groups in terms of other adverse effects (vomiting, nausea, headache or eclamptic fit) and results were inconsistent on the risk of retained or manual removal of placenta. Most of the evidence came from trials that administered ergot alkaloids using the IM or IV route. There was only one small trial that looked at the use of oral ergot alkaloids and results were inconclusive. There were limited numbers of included studies and results between studies were not always consistent or precise. Overall quality of evidence across critical and important outcomes ranged from very low to moderate. The IV or IM route, although it may reduce blood loss and PPH, was associated with the adverse effects of raised blood pressure and pain due to contractions of the uterus. There was not enough evidence on the oral route of administering ergot alkaloids. There are other medications, namely oxytocin, syntometrine and prostaglandins (which are assessed in other Cochrane Reviews), that can be used and may be preferable.

10.1002/14651858.CD005456.pub3

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Twenty two studies evaluated the effects of ARBs in 17,900 patients with a LVEF ≤40% (mean 2.2 years). ARBs did not reduce total mortality (RR 0.87 [95% CI 0.76, 1.00]) or total morbidity as measured by total hospitalisations (RR 0.94 [95% CI 0.88, 1.01]) compared with placebo. Total mortality (RR 1.05 [95% CI 0.91, 1.22]), total hospitalisations (RR 1.00 [95% CI 0.92, 1.08]), MI (RR 1.00 [95% CI 0.62, 1.63]), and stroke (RR 1.63 [0.77, 3.44]) did not differ between ARBs and ACEIs but withdrawals due to adverse effects were lower with ARBs (RR 0.63 [95% CI 0.52, 0.76]). Combinations of ARBs plus ACEIs increased the risk of withdrawals due to adverse effects (RR 1.34 [95% CI 1.19, 1.51]) but did not reduce total mortality or total hospital admissions versus ACEI alone. Two placebo-controlled studies evaluated ARBs in 7151 patients with a LVEF >40% (mean 3.7 years). ARBs did not reduce total mortality (RR 1.02 [95% CI 0.93, 1.12]) or total morbidity as measured by total hospitalisations (RR 1.00 [95% CI 0.97, 1.05]) compared with placebo. Withdrawals due to adverse effects were higher with ARBs versus placebo when all patients were pooled irrespective of LVEF (RR 1.06 [95% CI 1.01, 1.12]). In patients with symptomatic HF and systolic dysfunction or with preserved ejection fraction, ARBs compared to placebo or ACEIs do not reduce total mortality or morbidity. ARBs are better tolerated than ACEIs but do not appear to be as safe and well tolerated as placebo in terms of withdrawals due to adverse effects. Adding an ARB in combination with an ACEI does not reduce total mortality or total hospital admission but increases withdrawals due to adverse effects compared with ACEI alone.

We found 24 trials that randomly assigned participants to take either an ARB or control substance (placebo or ACEI). These trials evaluated ARBs in 25,051 patients with heart failure and followed them for 2 years. ARBs were no better than placebo or ACE inhibitors in reducing the risk of death, disability, or hospital admission for any reason. However, more patients stopped treatment early with ARBs than with placebo due to side effects. Adding an ARB to an ACEI also did not reduce the risk of death, disability, or hospital admission for any reason as compared to ACEI alone, although more patients taking the combination stopped early due to side effects.

10.1002/14651858.CD003040.pub2

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The search identified 183 references but only five studies (total n=210) met the inclusion criteria. All of the studies were on inpatient populations and compared the intervention with standard inpatient care. One study had drama therapy as the intervention, one had role-playing, one had a social drama group and two used psychodrama. Two of the included studies were Chinese and it is difficult to know whether psychodrama and indeed inpatient psychiatric care in China is comparable with the drama interventions and inpatient care in the other included studies. There were no significant findings about the value of drama interventions for keeping inpatients engaged in treatment. Due to poor reporting very little data from the five studies could be used and there were no conclusive findings about the harms or benefits of drama therapy for inpatients with schizophrenia. Randomised studies are possible in this field. The use of drama therapy for schizophrenia and schizophrenia-like illnesses should continue to be under evaluation as its benefits, or harms, are unclear.

Randomised studies have been successfully conducted in this area but poor study reporting meant that no conclusions could be drawn from them. The benefits or harms of the use of drama therapy in schizophrenia are therefore unclear and further large, high quality studies are required to determine the true value of drama therapy for schizophrenia or schizophrenia-like illnesses.

10.1002/14651858.CD005378.pub2