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cochrane-simplification-train-500

cochrane-simplification-train-500

Twenty-one trials (2372 participants) met the inclusion criteria for quantitative synthesis. There were large variations in the exercise programme's content, mode of delivery, frequency and duration, participant's symptoms, duration of symptoms, outcomes measured, methodological quality and reporting. Comparator groups were varied and included normal care; education; and attention controls such as home visits, sham gel and wait list controls. Risk of bias was high in one and unclear risk in five studies regarding the randomisation process, high for 11 studies regarding allocation concealment, high for all 21 studies regarding blinding, and high for three studies and unclear for five studies regarding attrition. Studies did not provide information on adverse effects. There was moderate quality evidence that exercise reduced pain by an absolute percent reduction of 6% (95% confidence interval (CI) -9% to -4%, (9 studies, 1058 participants), equivalent to reducing (improving) pain by 1.25 points from 6.5 to 5.3 on a 0 to 20 scale and moderate quality evidence that exercise improved physical function by an absolute percent of 5.6% (95% CI -7.6% to 2.0%; standardised mean difference (SMD) -0.27, 95% CI -0.37 to -0.17, equivalent to reducing (improving) WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) function on a 0 to 100 scale from 49.9 to 44.3) (13 studies, 1599 participants)). Self-efficacy was increased by an absolute percent of 1.66% (95% CI 1.08% to 2.20%), although evidence was low quality (SMD 0.46, 95% CI 0.34 to 0.58, equivalent to improving the ExBeliefs score on a 17 to 85 scale from 64.3 to 65.4), with small benefits for depression from moderate quality evidence indicating an absolute percent reduction of 2.4% (95% CI -0.47% to 0.5%) (SMD -0.16, 95% CI -0.29 to -0.02, equivalent to improving depression measured using HADS (Hospital Anxiety and Depression Scale) on a 0 to 21 scale from 3.5 to 3.0) but no clinically or statistically significant effect on anxiety (SMD -0.11, 95% CI -0.26 to 0.05, 2% absolute improvement, 95% CI -5% to 1% equivalent to improving HADS anxiety on a 0 to 21 scale from 5.8 to 5.4; moderate quality evidence). Five studies measured the effect of exercise on health-related quality of life using the 36-item Short Form (SF-36) with statistically significant benefits for social function, increasing it by an absolute percent of 7.9% (95% CI 4.1% to 11.6%), equivalent to increasing SF-36 social function on a 0 to 100 scale from 73.6 to 81.5, although the evidence was low quality. Evidence was downgraded due to heterogeneity of measures, limitations with blinding and lack of detail regarding interventions. For 20/21 studies, there was a high risk of bias with blinding as participants self-reported and were not blinded to their participation in an exercise intervention. Twelve studies (with 6 to 29 participants) met inclusion criteria for qualitative synthesis. Their methodological rigour and quality was generally good. From the patients' perspectives, ways to improve the delivery of exercise interventions included: provide better information and advice about the safety and value of exercise; provide exercise tailored to individual's preferences, abilities and needs; challenge inappropriate health beliefs and provide better support. An integrative review, which compared the findings from quantitative trials with low risk of bias and the implications derived from the high-quality studies in the qualitative synthesis, confirmed the importance of these implications. Chronic hip and knee pain affects all domains of people's lives. People's beliefs about chronic pain shape their attitudes and behaviours about how to manage their pain. People are confused about the cause of their pain, and bewildered by its variability and randomness. Without adequate information and advice from healthcare professionals, people do not know what they should and should not do, and, as a consequence, avoid activity for fear of causing harm. Participation in exercise programmes may slightly improve physical function, depression and pain. It may slightly improve self-efficacy and social function, although there is probably little or no difference in anxiety. Providing reassurance and clear advice about the value of exercise in controlling symptoms, and opportunities to participate in exercise programmes that people regard as enjoyable and relevant, may encourage greater exercise participation, which brings a range of health benefits to a large population of people.

A search of medical databases up to March 2016 found 21 studies with 2372 people which considered pain, movement or both alongside psychological and social outcomes when people with pain and stiffness in their knee, hip, or both took part in exercise. Participation in exercise programmes probably slightly improves pain, physical function, depression, and ability to connect with others, and little or no difference in anxiety. It may improve belief in one's own abilities, and social function. The studies confirmed that: - people who exercised rated their pain to be 1.2 points lower on a scale of 0 to 20 after about 45 weeks (score: 5.3 with exercise compared with 6.5 with no exercise (control), an improvement of 6%). - physical function improved by about 5% over 41 weeks (exercise group improved by 5.6 points on a scale of 0 to 100 (44.3 with exercise compared with 49.9 with control)). - people's confidence in what they could do increased by 2% after 35 weeks (exercise group improved by 1.1 points on a scale of 17 to 85 (65.4 with exercise compared with 64.3 with control)). - people who exercised were 2% less depressed, or half a point on a scale of 0 to 21, after 35 weeks (3.0 points with exercise compared with 3.5 with control). - exercise made people feel less anxious about themselves by 2%, a 0.4 drop on a 0 to 21 scale, after 24 weeks (5.4 points with exercise compared with 5.8 with control). - exercise resulted in social interaction improving by 7.9 points over 36 weeks on a scale of 0 to 100, giving a change of 8% (81.5 with exercise compared with 73.6 with control). The quality of the evidence was generally moderate, but low for confidence in ability, mental health and social function. This is mainly due to varied measures, making comparison more difficult, and because people taking part knew they were exercising so may have been influenced by expectations of improvement. The studies did not report side effects. Studies lasted for different durations, so we do not know if changes occurred quickly and were maintained, or whether improvements were gradual throughout the studies. Some studies took measurements later after the programme than others. Additionally, 12 studies investigated people's opinions, beliefs and experiences of exercise, and whether exercise changed these. The quality of evidence was high overall. Initially people were confused about the characteristics of their pain, which shaped their feelings, behaviours and decisions about relieving pain. People thought movement and exercise was good for joints, but movement caused pain and they worried this might cause them harm. Lack of information from medical professionals meant people avoided physical activity and exercise for fear of causing damage. Overall, people who had taken part in exercise programmes had positive experiences, helping increase their beliefs that exercise could improve pain, physical and mental health, and general quality of life. Providing reassurance and exercise advice, challenging poor health beliefs, and providing enjoyable exercise programmes may encourage participation and benefit the health of many people.

10.1002/14651858.CD010842.pub2

cochrane-simplification-train-501

cochrane-simplification-train-501

Three trials (723 participants) were included. Only one trial used adequate outcome measures of efficacy; therefore, the results pertaining to efficacy are based on a single trial, whereas the results pertaining to adverse events are based on all three included trials. There was no overall difference in time to treatment withdrawal between the two drugs (hazard ratio (HR) of oxcarbazepine (OXC) versus carbamazepine (CBZ): 1.04, 95% confidence interval (CI) 0.78 to 1.39). Further analyses showed no significant difference in treatment withdrawal for unacceptable side effects (HR of OXC versus CBZ: 0.85, 95% CI 0.59 to 1.24) and in treatment withdrawal for inadequate seizure control (HR of OXC versus CBZ: 1.33, 95% CI 0.82 to 2.15). Oxcarbazepine and carbamazepine appeared to be similarly effective and well tolerated although the confidence intervals around estimates were wide and do not rule out the possibility of important differences existing. Significantly fewer patients on carbamazepine treatment developed nausea or vomiting, or both (odds ratio of OXC versus CBZ: 3.15, 95% CI 1.39 to 7.14). Oxcarbazepine and carbamazepine appear to be similarly effective and well tolerated. However, the possibility of important differences existing between these drugs cannot be ruled out.

In this systematic review, we summarise three studies in which oxcarbazepine and carbamazepine treatment were compared directly. We found that both drugs appear to be equally effective and to cause side effects equally often. Significantly fewer patients on carbamazepine developed nausea or vomiting during treatment.

10.1002/14651858.CD006453.pub2

cochrane-simplification-train-502

cochrane-simplification-train-502

We included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide. Endothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists.

Tradiational therapies for pulmonary arterial hypertension include prostacyclin and its analogues, calcium channel blockers, nitric oxide (NO), and important adjunctive therapies, such as anticoagulants and oxygen. Endothelin receptor antagonists have recently been proposed as an alternative to these traditional therapies. This review includes twelve trials on 1471 participants. Endothelin receptor antagonists can improve exercise capacity, symptoms, and cardiopulmonary haemodynamic variables in people with symptomatic pulmonary arterial hypertension over a period of three to six months treatment. There is uncertainty as to whether endothelin receptor antagonists reduce mortality in this population. The most severe potential side effect was hepatic toxicity which was not common in these short-term trials.

10.1002/14651858.CD004434.pub5

cochrane-simplification-train-503

cochrane-simplification-train-503

We included one unpublished and seven published studies (total of 808 participants); four more studies and 478 more participants than the 2011 review. Six trials included young children aged one to four years receiving sucrose or candy lollypops for immunisation pain compared with water or no treatment. Usual care included topical anaesthetics, upright parental holding, and distraction. All studies were well designed blinded RCTs, however, five of the six studies had a high risk of bias based on small sample sizes. Two studies included school-aged children receiving sweet or unsweetened chewing gum before, or before and during, immunisation and blood collection. Both studies, conducted by the same author, had a high risk of bias based on small sample sizes. Results for the toddlers/pre-school children were conflicting. Duration of cry, using a random-effects model, was not significantly reduced by sweet taste (six trials, 520 children, WMD -15 seconds, 95% CI -54 to 24, I2 = 94%). Composite pain score at time of first needle was reported in four studies (n = 121 children). The scores were not significantly different between the sucrose and control group (SMD -0.26, 95% CI -1.27 to 0.75, I2 = 86%). A Children's Hospital of Eastern Ontario Pain Scale score > 4 was significantly less common in the sucrose group compared to the control group in one study (n = 472, RR 0.55, 95% CI 0.45 to 0.67; RD -0.29, 95% CI -0.37 to -0.20; NNTB 3, 95% CI 3 to 5; tests for heterogeneity not applicable. For school-aged children, chewing sweet gum before needle-related painful procedures (two studies, n = 111 children) or during the procedures (two studies, n = 103 children) did not significantly reduce pain scores. A comparison of the Faces Pain Scale scores in children chewing sweet gum before the procedures compared with scores of children chewing unsweetened gum revealed a WMD of -0.15 (95% CI -0.61 to 0.30). Similar results were found when comparing the chewing of sweet gum with unsweetened gum during the procedure (WMD 0.23, 95% CI -0.28 to 0.74). The Colored Analogue Scale for children chewing sweet gum compared to unsweetened gum before the procedure was not significantly different (WMD 0.24 (-0.69 to 1.18)) nor was it different when children chewed the gum during the procedure (WMD 0.86 (95% CI -0.12 to 1.83)). There was no heterogeneity for any of these analyses in school-aged children (I2 = 0%). Based on the eight studies included in this systematic review update, two of which were subgroups of small numbers of eligible toddlers from larger studies, and three of which were pilot RCTs with small numbers of participants, there is insufficient evidence of the analgesic effects of sweet tasting solutions or substances during acutely painful procedures in young children between one and four years of age. Further rigorously conducted, adequately powered RCTs are warranted in this population. Based on the two studies by the same author, there was no evidence of analgesic effects of sweet taste in school-aged children. As there are other effective evidence-based strategies available to use in this age group, further trials are not warranted. Despite the addition of four studies in this review, conclusions have not changed since the last version of the review.

Study characteristics: We found six studies focused on young children aged one to four years; two of these studies were included in the original review and four were new studies. The two studies included in the original review used a low concentration of sucrose, just 12%, which is not considered sweet enough for the pain reducing effects. Three of the four new studies were small pilot studies, conducted to inform full trials, and only one study of sweet solutions in young children included large numbers of children. When we compared results of all six studies, only two showed that sugar water (sucrose) reduced pain during injections. However, the four studies that showed no effect all included small numbers of children, therefore they were not considered large enough to detect significant differences in pain. Further well conducted trials with large enough numbers of young children are needed to work out if sweet taste effectively reduces their pain and distress during needles. For older school-aged children, there were two studies published by the same author, both of which were included in the original review. Neither study showed that sweet taste helped to reduce pain. As other studies show that strategies such as distraction and topical anaesthetics can effectively reduce needle pain in school-aged children, further studies of sweet taste for pain management in school-aged children are not warranted. Study funding sources: Of the six studies including young children, two did not acknowledge receipt of research funding. For the remaining four: a state-wide nursing fund supported two of the pilot studies, an internal research institute provided support for the remaining pilot study and another study was supported in part by a Maternal and Child Health grant. The two studies including school-aged children, conducted by the same author, were supported by a grant from the Canadian Institutes of Health Research.

10.1002/14651858.CD008408.pub3

cochrane-simplification-train-504

cochrane-simplification-train-504

Forty one trials (n=4935 women) were included. The evidence suggested that GnRHas were more effective at symptom relief than no treatment/placebo. There was no statistically significant difference between GnRHas and danazol for dysmenorrhoea RR 0.98 (95%CI 0.92 to 1.04; P = 0.53). This equates to 3 fewer women per 1000 (95%CI 12 to 6) with symptomatic pain relief in the GnRHa group. More adverse events were reported in the GnRHa group. There was a benefit in overall resolution for GnRHas RR1.10 (95%CI 1.01 to 1.21, P=0.03) compared with danazol. There was no statistically significant difference in overall pain between GnRHas and levonorgestrel SMD -0.25 (95%CI -0.60 to 0.10, P=0.46). Evidence was limited on optimal dosage or duration of treatment for GnRHas. No route of administration appeared superior to another. GnRHas appear to be more effective at relieving pain associated with endometriosis than no treatment/placebo. There was no evidence of a difference in pain relief between GnRHas and danazol although more adverse events reported in the GnRHa groups. There was no evidence of a difference in pain relief between GnRHas and levonorgestrel and no studies compared GnRHas with analgesics.

Endometriosis is a common condition affecting women of child-bearing age, and is usually due to the presence of endometrial tissue in places other than the uterus. Common symptoms include pain and infertility. GnRHas are a group of drugs often used to treat endometriosis by decreasing hormone levels. This review found evidence to suggest treatment with a GnRHa improved symptom relief compared with no treatment or placebo. There was no evidence of a statistically significant difference when compared with danazol or intra-uterine progestagen. However, there more side effects in the GnRHa group compared with the danazol group. There is not enough evidence to make clear if higher or lower doses of GnRHa are better, or which length of treatment is best.

10.1002/14651858.CD008475.pub2

cochrane-simplification-train-505

cochrane-simplification-train-505

Five trials with a total of 924 participants met the inclusion criteria; 5% of participants were HIV positive. Only one small trial was methodologically adequate. The two largest trials (818 participants) had unclear allocation concealment and included < 90% of randomized participants in the analysis. There was no statistically significant difference in between the regimens for cure (RR 1.00, 95% CI 0.96 to 1.04; 553 participants, 2 trials) or relapse (RR 1.23, 95% CI 0.45 to 3.35; 448 participants, 2 trials). The number of adverse events was not significantly different (RR 1.42, 95% CI 0.88 to 2.31; 714 participants, 3 trials), though the RR increased with rifabutin dose: 150 mg (RR 0.98, 95% CI 0.45 to 2.12; 264 participants, 2 trials); and 300 mg (RR 1.78, 95% CI 0.94 to 3.34; 450 participants, 2 trials). However, lack of dose adjustment by weight in the relevant trials complicates interpretation of this relationship. The replacement of rifampicin by rifabutin for first-line treatment of tuberculosis is not supported by the current evidence. HIV-positive people with tuberculosis, the group most likely to benefit from the rifabutin use, are under-represented in trials to date, and further trials in this group would be useful.

This review identified five trials involving 924 people, but none were of high quality. The review found no significant differences between rifabutin- and rifampicin-containing treatment in curing tuberculosis and preventing relapse, but higher doses of rifabutin might be associated with more adverse effects and there was no evidence that it could shorten treatment. However, very few people with HIV and tuberculosis, who are most likely to benefit from use of rifabutin due to its lack of interaction with antiretroviral drugs, were included in the trials. Better quality clinical trials are needed to understand the place of rifabutin in the treatment of people with tuberculosis, particularly those who also have HIV.

10.1002/14651858.CD005159.pub2

cochrane-simplification-train-506

cochrane-simplification-train-506

The updated search retrieved 535 records; we included 13 parallel-designed RCTs comparing IMSI and ICSI (four studies were added since the previous version), comprising 2775 couples (IMSI = 1256; ICSI = 1519). We are uncertain if IMSI improves live birth rates (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.89 to 1.39; 5 studies, 929 couples; I² = 1%), miscarriage rates per couple (RR 1.07, 95% CI 0.78 to 1.48; 10 studies, 2297 couples; I² = 0%, very-low quality evidence), and miscarriage rate per pregnancy (RR 0.90, 95% CI 0.68 to 1.20; 10 studies, 783 couples; I² = 0%, very-low quality evidence). We are uncertain if IMSI improves clinical pregnancy rates (RR 1.23, 95% CI 1.11 to 1.37; 13 studies, 2775 couples; I² = 47%, very-low quality evidence). None of the included studies reported congenital abnormalities. We judged the evidence for all outcomes to be of very low-quality. We downgraded the quality of the evidence due to limitations of the included studies (risk of bias), inconsistency of results, and a strong indication of publication bias. The current evidence from randomised controlled trials does not support or refute the clinical use of intracytoplasmic sperm injection (intracytoplasmic morphologically selected sperm injection (IMSI). We are very uncertain of the chances of having a live birth and of the risk of having a miscarriage. We found very low-quality evidence that IMSI may increase chances of a clinical pregnancy, which means that we are still very uncertain about any real difference. We did not find any trials reporting on the risk of congenital abnormalities. Well-designed and sufficiently powered trials are still required.

We found 13 randomised controlled trials (four more than in the previous version), evaluating 2775 couples, that compared regular ICSI with IMSI for assisted reproduction. These studies were funded by fertility centres and universities. Based on the very low-quality evidence that we found, we are uncertain of the benefit of IMSI over ICSI. The chance of having a live birth with IMSI was between 20% and 32%, compared to 25% with ICSI. For women with a 7% risk of miscarriage with regular ICSI, the risk with IMSI was between 5% and 10%. The clinical pregnancy rate with IMSI was between 35% and 44%, compared with 32% with ICSI. We downgraded the quality of the evidence because of limitations in the included studies (risk of bias), inconsistency of the observed effect across studies, and high risk of publication bias. There was no evidence concerning congenital abnormalities. We conclude that the current evidence is very limited for suggesting using IMSI instead of ICSI in clinical practice.

10.1002/14651858.CD010167.pub3

cochrane-simplification-train-507

cochrane-simplification-train-507

Sixteen orlistat (n = 10,631), 10 sibutramine (n = 2623) and four rimonabant trials (n = 6365) met inclusion criteria. Attrition rates averaged 30% to 40%. Compared to placebo, orlistat reduced weight by 2.9 kg (95% confidence interval (CI) 2.5 to 3.2 kg), sibutramine by 4.2 kg (95% CI 3.6 to 4.7 kg), and rimonabant by 4.7 kg (95% CI 4.1 to 5.3 kg). Patients on active drug therapy were significantly more likely to achieve 5% and 10% weight loss thresholds. Placebo-controlled weight losses were consistently lower in patients with diabetes. Orlistat reduced diabetes incidence, improved total cholesterol, LDL-cholesterol, blood pressure, and glycaemic control in patients with diabetes but increased rates of gastrointestinal side effects and slightly lowered HDL levels. Sibutramine improved HDL and triglyceride levels but raised blood pressure and pulse rate. Rimonabant improved HDL-cholesterol, triglyceride and blood pressure levels and glycaemic control in patients with diabetes but increased the risk of mood disorders. Orlistat, sibutramine and rimonabant have been studied in trials of one year or longer. Internal validity of studies was limited by high attrition rates. All three antiobesity agents are modestly effective in reducing weight and have differing effects on cardiovascular risk and adverse effects profiles. Longer and more methodologically rigorous studies of anti-obesity drugs that are powered to examine endpoints such as mortality and cardiovascular morbidity are required.

This review assessed the long-term benefits and risks of approved anti-obesity drugs in clinical trials of 1 to 4 years duration. Sixteen orlistat (10,631 patients), 10 sibutramine (2623 patients) and four rimonabant (6635 patients) studies were examined. High drop-out rates (30% to 40%) were a limitation of nearly all studies. Compared to placebo, all three drugs reduced weight by around five kg or less and orlistat reduced the number of high-risk patients who developed diabetes. No data to show that any of the three drugs lowers the risk of death or cardiovascular disease were found. The most prominent side effects were gastrointestinal for orlistat, cardiovascular for sibutramine (raised blood pressure and/or pulse rate) and psychiatric for rimonabant (mood disorders). In Europe, rimonabant is contraindicated for patients with severe depression and/or patients who are treated with antidepressive medications. Rimonabant is furthermore not recommended for patients with other untreated psychiatric conditions. We conclude that: 1. average weight losses with current anti-obesity agents appear modest but may be of clinical benefit, and 2. better studies designed to examine mortality and cardiovascular morbidity are required to fully evaluate any potential benefit of such agents.

10.1002/14651858.CD004094.pub2

cochrane-simplification-train-508

cochrane-simplification-train-508

We included 15 studies from the earlier review and two new studies (17 studies, 1342 participants) in seven neuropathic pain conditions. Eight cross-over studies with 302 participants had a median of 36 participants, and nine parallel group studies with 1040 participants had a median of 84 participants. Study quality was modest, though most studies were at high risk of bias due to small size. There was no first-tier or second-tier evidence for amitriptyline in treating any neuropathic pain condition. Only third-tier evidence was available. For only two of seven studies reporting useful efficacy data was amitriptyline significantly better than placebo (very low quality evidence). More participants experienced at least one adverse event; 55% of participants taking amitriptyline and 36% taking placebo. The risk ratio (RR) was 1.5 (95% confidence interval (CI) 1.3 to 1.8) and the number needed to treat for an additional harmful outcome was 5.2 (3.6 to 9.1) (low quality evidence). Serious adverse events were rare. Adverse event and all-cause withdrawals were not different, but were rarely reported (very low quality evidence). Amitriptyline has been a first-line treatment for neuropathic pain for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many people with neuropathic pain. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline should continue to be used as part of the treatment of neuropathic pain, but only a minority of people will achieve satisfactory pain relief. Limited information suggests that failure with one antidepressant does not mean failure with all.

In March 2015 we performed searches to look for new studies in adults with neuropathic pain of at least moderate intensity. We found only two additional small studies that did not provide any good quality evidence for either benefit or harm. This is disappointing, but we can still make useful comments about the drug. Amitriptyline probably does not work in neuropathic pain associated with human immunodeficiency virus (HIV) or treatments for cancer. Amitriptyline probably does work in other types of neuropathic pain, though we cannot be certain of this. Our best guess is that amitriptyline provides pain relief in about 1 in 4 (25%) more people than does placebo, and about 1 in 4 (25%) more people than placebo report having at least one adverse event, which may be troublesome, but probably not serious. We cannot trust either figure based on the information available. The most important message is that amitriptyline probably does give really good pain relief to some people with neuropathic pain, but only a minority of them; amitriptyline will not work for most people.

10.1002/14651858.CD008242.pub3

cochrane-simplification-train-509

cochrane-simplification-train-509

Twenty-eight studies on 907 participants were included in the review. Study sample size was generally small (range 5 to 96 people) and overall quality was generally poor due to inadequate blinding and allocation procedures. Meta-analyses were limited by heterogeneity of outcome measurement and inadequate reporting of data. In people experiencing AECOPD, ACT use was associated with small but significant short-term reductions in the need for increased ventilatory assistance (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05 to 0.85; data from four studies on 171 people), the duration of ventilatory assistance (mean difference (MD) -2.05 days, 95% CI -2.60 to -1.51; mean duration for control groups seven days; data from two studies on 54 people) and hospital length of stay (MD -0.75 days, 95% CI -1.38 to -0.11; mean duration for control groups nine days; one study on 35 people). Data from a limited number of studies revealed no significant long-term benefits of ACTs on the number of exacerbations or hospitalisations, nor any short-term beneficial effect on health-related quality of life (HRQoL) as measured by the St. George's Respiratory Questionnaire (SGRQ) total score (MD -2.30, 95% CI -11.80 to 7.20; one study on 59 people). In people with stable COPD, data from single studies revealed no significant short-term benefit of ACTs on the number of people with exacerbations (OR 3.21, 95% CI 0.12 to 85.20; one study on 30 people), significant short-term improvements in HRQoL as measured by the SGRQ total score (MD -6.10, 95% CI -8.93 to -3.27; one study on 15 people) and a reduced long-term need for respiratory-related hospitalisation (OR 0.27, 95% CI 0.08 to 0.95; one study on 35 participants). The magnitude of effect of PEP-based ACTs on the need for increased ventilatory assistance and hospital length of stay was greater than for non-PEP ACTs, however we found no statistically significant subgroup differences. There was one report of vomiting during treatment with postural drainage and head-down tilt. Evidence from this review indicates that airway clearance techniques are safe for individuals with COPD and confer small beneficial effects on some clinical outcomes. Consideration may be given to the use of airway clearance techniques for patients with COPD in both acute and stable disease, however current studies suggest that the benefits achieved may be small.

This review comprised 28 studies of 907 participants, with the quality of evidence being generally poor. Performing ACTs during an acute flare-up of COPD reduced the likelihood of needing mechanical assistance to breathe, as well as the length of time for which it was required. Time spent in hospital was slightly reduced, but there was little evidence to suggest any benefit on future flare-ups or health-related quality of life. Performing ACTs during stable COPD did not appear to affect flare-ups or hospitalisations, however it may improve health-related quality of life. Techniques which involve breathing out against a positive expiratory pressure resistance may provide greater benefits than other types of ACTs. The lack of adverse events observed in this review suggests that ACTs are safe for individuals with COPD.

10.1002/14651858.CD008328.pub2

cochrane-simplification-train-510

cochrane-simplification-train-510

We included eight studies in the review. All outcomes were short term (less than six months). There were clear differences in a number of outcomes in favour of the yoga group, although these were based on one study each, with the exception of leaving the study early. These included mental state (improvement in Positive and Negative Syndrome Scale, 1 RCT, n = 83, RR 0.70 CI 0.55 to 0.88, medium-quality evidence), social functioning (improvement in Social Occupational Functioning Scale, 1 RCT, n = 83, RR 0.88 CI 0.77 to 1, medium-quality evidence), quality of life (average change 36-Item Short Form Survey (SF-36) quality-of-life subscale, 1 RCT, n = 60, MD 15.50, 95% CI 4.27 to 26.73, low-quality evidence), and leaving the study early (8 RCTs, n = 457, RR 0.91 CI 0.6 to 1.37, medium-quality evidence). For the outcome of physical health, there was not a clear difference between groups (average change SF-36 physical-health subscale, 1 RCT, n = 60, MD 6.60, 95% CI -2.44 to 15.64, low-quality evidence). Only one study reported adverse effects, finding no incidence of adverse events in either treatment group. This review was subject to a considerable number of missing outcomes, which included global state, change in cognition, costs of care, effect on standard care, service intervention, disability, and activities of daily living. Even though we found some positive evidence in favour of yoga over standard-care control, this should be interpreted cautiously in view of outcomes largely based each on one study with limited sample sizes and short-term follow-up. Overall, many outcomes were not reported and evidence presented in this review is of low to moderate quality - -too weak to indicate that yoga is superior to standard-care control for the management of schizophrenia.

We included eight short-term studies (less than six months) that randomised people with schizophrenia to either receive sessions of yoga or standard care in this review. The yoga programmes described varied from 45 minutes to 1 hour in length, and from 8 sessions to a maximum of 36 sessions. We found these studies by electronic searching of the Cochrane Schizophrenia Group's register in January 2015. All studies continued prescribed antipsychotic treatment for the participants. Some results suggest that yoga may be beneficial for people with schizophrenia. Yoga may be beneficial to mental state, social functioning and quality of life but the available evidence is weak and needs to be treated with a good degree of caution. No adverse effects were found by the one trial that reported this outcome. Several other important outcomes were not addressed by the studies, including changes in cognition, economic considerations, and daily living activities. There was not enough good-quality evidence in this review to claim that yoga should be prescribed as an add-on to standard care for schizophrenia. Evidence was limited and weak. The number of included studies was small, and only short-term follow-up was reported. More, larger, and long-term trials that focus on important outcomes are therefore necessary. Ben Gray, Senior Peer Researcher, McPin Foundation.http://mcpin.org/

10.1002/14651858.CD010554.pub2

cochrane-simplification-train-511

cochrane-simplification-train-511

One open-label, randomised, single-centre trial including 70 participants with Marfan syndrome (aged 12 to 50 years old) met the inclusion criteria. Participants were randomly assigned to propranolol (N = 32) or no treatment (N = 38) for an average duration of 9.3 years in the control group and 10.7 years in the treatment group. The initial dose of propranolol was 10 mg four times daily and the optimal dose was reached when the heart rate remained below 100 beats per minute during exercise or the systolic time interval increased by 30%. The mean (± standard error (SE)) optimal dose of propranolol was 212 ± 68 mg given in four divided doses daily. Beta-blocker therapy did not reduce the incidence of all-cause mortality (RR 0.24, 95% CI 0.01 to 4.75; participants = 70; low-quality evidence). Mortality attributed to Marfan syndrome was not reported. Non-fatal serious adverse events were also not reported. However, study authors report on pre-defined, non-fatal clinical endpoints, which include aortic dissection, aortic regurgitation, cardiovascular surgery and congestive heart failure. Their analysis showed no difference between the treatment and control groups in these outcomes (RR 0.79, 95% CI 0.37 to 1.69; participants = 70; low-quality evidence). Beta-blocker therapy did not reduce the incidence of aortic dissection (RR 0.59, 95% CI 0.12 to 3.03), aortic regurgitation (RR 1.19, 95% CI 0.18 to 7.96), congestive heart failure (RR 1.19, 95% CI 0.18 to 7.96) or cardiovascular surgery, (RR 0.59, 95% CI 0.12 to 3.03); participants = 70; low-quality evidence. The study reports a reduced rate of aortic dilatation measured by M-mode echocardiography in the treatment group (aortic ratio mean slope: 0.084 (control) vs 0.023 (treatment), P < 0.001). The change in systolic and diastolic blood pressure, total adverse events and withdrawal due to adverse events were not reported in the treatment or control group at study end point. We judged this study to be at high risk of selection (allocation concealment) bias, performance bias, detection bias, attrition bias and selective reporting bias. The overall quality of evidence was low. We do not know whether a statistically significant reduced rate of aortic dilatation translates into clinical benefit in terms of aortic dissection or mortality. Based on only one, low-quality RCT comparing long-term propranolol to no treatment in people with Marfan syndrome, we could draw no definitive conclusions for clinical practice. High-quality, randomised trials are needed to evaluate the long-term efficacy of beta-blocker treatment in people with Marfan syndrome. Future trials should report on all clinically relevant end points and adverse events to evaluate benefit versus harm of therapy.

We included one study of 70 participants aged 12 to 50 years old with Marfan syndrome, who were assigned to either a beta-blocker called propranolol or no treatment for an average duration of 9.3 years in the control (no treatment) group and 10.7 years in the treatment group. This study was supported by grants from the National Institute of Health, the US Food and Drug Administration, and the National Marfan Foundation. Propranolol compared to no treatment did not reduce mortality or morbidity, including aortic dissection, aortic regurgitation (leaking of the aortic valve causing reverse blood flow into the heart), heart failure (inability to pump enough blood around the body), and heart surgery. However, it reduced the rate of enlargement of the aortic diameter. Harms have not been fully reported in this study. We judged this trial to have high risk of bias and low-quality evidence. This study provides inadequate evidence to inform people with Marfan syndrome, their families and care-providers.

10.1002/14651858.CD011103.pub2

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cochrane-simplification-train-512

We included 30 RCTs (6235 women) comparing different intra-vaginal oestrogenic preparations with each other and with placebo. The evidence was low to moderate quality; limitations were poor reporting of study methods and serious imprecision (effect estimates with wide confidence intervals) 1. Oestrogen ring versus other regimens Other regimens included oestrogen cream, oestrogen tablets and placebo. There was no evidence of a difference in improvement in symptoms (participant assessment) either between oestrogen ring and oestrogen cream (odds ratio (OR) 1.33, 95% CI 0.80 to 2.19, two RCTs, n = 341, I2 = 0%, low-quality evidence) or between oestrogen ring and oestrogen tablets (OR 0.78, 95% CI 0.53 to 1.15, three RCTs, n = 567, I2 = 0%, low-quality evidence). However, a higher proportion of women reported improvement in symptoms following treatment with oestrogen ring compared with placebo (OR 12.67, 95% CI 3.23 to 49.66, one RCT, n = 67). With respect to endometrial thickness, a higher proportion of women who received oestrogen cream showed evidence of increase in endometrial thickness compared to those who were treated with oestrogen ring (OR 0.36, 95% CI 0.14 to 0.94, two RCTs, n = 273; I2 = 0%, low-quality evidence). This may have been due to the higher doses of cream used. 2. Oestrogen tablets versus other regimens Other regimens in this comparison included oestrogen cream, and placebo. There was no evidence of a difference in the proportions of women who reported improvement in symptoms between oestrogen tablets and oestrogen cream (OR 1.06, 95% CI 0.55 to 2.01, two RCTs, n = 208, I2 = 0% low-quality evidence). A higher proportion of women who were treated with oestrogen tablets reported improvement in symptoms compared to those who received placebo using a fixed-effect model (OR 12.47, 95% CI 9.81 to 15.84, two RCTs, n = 1638, I2 = 83%, low-quality evidence); however, using a random-effect model did not demonstrate any evidence of a difference in the proportions of women who reported improvement between the two treatment groups (OR 5.80, 95% CI 0.88 to 38.29). There was no evidence of a difference in the proportions of women with increase in endometrial thickness between oestrogen tablets and oestrogen cream (OR 0.31, 95% CI 0.06 to 1.60, two RCTs, n = 151, I2 = 0%, low-quality evidence). 3. Oestrogen cream versus other regimens Other regimens identified in this comparison included isoflavone gel and placebo. There was no evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and isoflavone gel (OR 2.08, 95% CI 0.08 to 53.76, one RCT, n = 50, low-quality evidence). However, there was evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and placebo with more women who received oestrogen cream reporting improvement in symptoms compared to those who were treated with placebo (OR 4.10, 95% CI 1.88 to 8.93, two RCTs, n = 198, I2 = 50%, low-quality evidence). None of the included studies in this comparison reported data on endometrial thickness. There was no evidence of a difference in efficacy between the various intravaginal oestrogenic preparations when compared with each other. However, there was low-quality evidence that intra-vaginal oestrogenic preparations improve the symptoms of vaginal atrophy in postmenopausal women when compared to placebo. There was low-quality evidence that oestrogen cream may be associated with an increase in endometrial thickness compared to oestrogen ring; this may have been due to the higher doses of cream used. However there was no evidence of a difference in the overall body of evidence in adverse events between the various oestrogenic preparations compared with each other or with placebo.

We found 30 randomised controlled trials comparing intravaginal oestrogenic preparations with one another or with placebo in a total of 6235 postmenopausal women undergoing treatment for the symptoms of vaginal atrophy. The evidence is current to April 2016. There was no evidence of a difference in the proportions of women who reported improvement in symptoms of vaginal atrophy between the following treatment comparisons: oestrogen ring and oestrogen cream, oestrogen ring and oestrogen tablets, oestrogen tablets and oestrogen cream, oestrogen cream and isoflavone gel. However, a higher proportion of women reported improvement in symptoms in the following active treatments compared with placebo: oestrogen ring versus placebo, oestrogen tablets versus placebo and oestrogen cream versus placebo. In the case of oestrogen tablets versus placebo and using a random-effect model for analysis of the data because of substantial heterogeneity, there was no longer evidence of a difference in effect on improvement in symptoms. With respect to safety, a higher proportion of women who received oestrogen cream showed evidence of increase in endometrial thickness compared to those who were treated with oestrogen ring, which may have been due to the higher doses of cream used. However, there was no evidence of a difference in the proportions of women with increase in thickness of the lining of the womb between oestrogen tablets and oestrogen cream. The evidence was of low quality for both improvement in symptoms as reported by women and increase in endometrial thickness. The main limitations of the evidence were poor reporting of study methods, and lack of precision (i.e. effect estimates with wide confidence intervals) in the findings for both outcomes.

10.1002/14651858.CD001500.pub3

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Eight RCTs (with 719 participants) were included in this update. The trials were small in size and methodological quality was poor. Viral detection was performed in 38% of participants, among whom 56% had positive results. Mortality between corticosteroids and control groups was non-significant (RR, 0.93, 95% CI 0.70 to 1.24). At 1 to 3 months follow-up, left ventricular ejection fraction (LVEF) was higher in the corticosteroids group compared to the control group (MD 7.36%, 95% CI 4.94 to 9.79), but there was substantial heterogeneity. Benefits were observed in LVEF in two trials with 200 children given corticosteroids (MD 9.00%, 95% CI 7.48 to 10.52). New York Heart Association (NYHA) class and left ventricular end-stage systole diameter (LVESD) were not affected. Creatine phosphokinase (CPK) (MD -104.00 U/L, 95% CI -115.18 to -92.82), Isoenzyme of creatine phosphate MB (CKMB) (MD 10.35 U/L, 95% CI 8.92 to 11.78), were reduced in the corticosteroids group compared to the control group, although the evidence is limited to small participant numbers. There were insufficient data on adverse events. For people diagnosed with viral myocarditis and low LVEF, corticosteroids do not reduce mortality. They may improve cardiac function but the trials were of low quality and small size so this finding must be regarded as uncertain. High-quality, large-scale RCTs should be careful designed to determine the role of corticosteroid treatment for viral myocarditis. Adverse events should also be carefully evaluated.

The effect of hormone treatment on viral myocarditis remains controversial. The review authors conducted a thorough search of the medical literature. Eight randomised trials with 719 patients which met the inclusion criteria compared hormone treatment plus conventional therapy with no hormone. Hormone treatment did not reduce mortality from viral myocarditis. Improvements in heart function were found but the trials were of low quality and small size so this finding must be regarded as uncertain. Further trials comparing hormone treatment in people suffering viral myocarditis with placebo are warranted. There are no conflicts of interest in the review.

10.1002/14651858.CD004471.pub3

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From 69 identified references, nine RCTs (6,584 patients) met inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.74; 95% CI 0.66 to 0.83) and related hospitalisations (OR 0.64; 95% CI 0.51 to 0.82) compared to placebo or ipratropium. When applied to an annual baseline risk of 45% for exacerbations and 10% for hospitalisation, the number of patients needed to treat with tiotropium for one year were 14 (95% CI 11 to 22) to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one hospitalisation compared to placebo and ipratropium. Reductions in these endpoints compared to long-acting ß2-agonists were not statistically significant. Similar patterns were evident for quality-of-life and symptom scales. Increases in FEV1 and FVC from baseline were significantly larger with tiotropium than with placebo, ipratropium and long-acting ß2-agonists over 6 to 12 months. The decline in trough FEV1 from steady state was 30 ml (95% CI 7 to 53 ml) less with tiotropium than with placebo or ipratropium over one year; no data on decline in FEV1 from steady state were available for long-acting ß2-agonists. Dry mouth was increased by tiotropium. Tiotropium reduced COPD exacerbations and related hospitalisations compared to placebo and ipratropium. It also improved health-related quality-of-life and symptom scores among patients with moderate and severe disease, and may have slowed decline in FEV1. Additional long-term studies are required to evaluate its effect on mortality and change in FEV1 to clarify its role in comparison to, or in combination with, long-acting ß2-agonists and to assess its effectiveness in mild and very severe COPD.

The evidence from the trials in the review indicates that, compared with a placebo and ipratropium, tiotropium does reduce exacerbations and related hospitalisations and improves quality of life and symptoms in people with moderately severe COPD, although the evidence with regards to decline in lung function is less clear. Tiotropium caused dry mouth. Compared with other commonly used drugs in COPD, such as long-acting beta agonists (including salmeterol), there is not enough evidence for us to draw reliable conclusions. In order to better understand the effects of this drug we need long-term studies (over several years), studies conducted in mild and severe COPD, and additional studies that measure outcomes in relation to other agents used in the treatment of this condition.

10.1002/14651858.CD002876.pub2

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We identified 6 randomised controlled trials and 1 quasi-randomised controlled trial for inclusion in the review; the total number of participants was 392. The trials had some risk of bias because five of the trials did not blind outcome assessors to treatment allocation. The interventions included ant, bee, and wasp immunotherapy in children or adults with previous systemic or large local reactions to a sting, using sublingual (one trial) or subcutaneous (six trials) VIT. We found that VIT is effective for preventing systemic allergic reaction to an insect sting, which was our primary outcome measure. This applies whether the sting occurs accidentally or is given intentionally as part of a trial procedure. In the trials, 3/113 (2.7%) participants treated with VIT had a subsequent systemic allergic reaction to a sting, compared with 37/93 (39.8%) untreated participants (risk ratio [RR] 0.10, 95% confidence interval [CI] 0.03 to 0.28). The efficacy of VIT was similar across studies; we were unable to identify a patient group or mode of treatment with different efficacy, although these analyses were limited by small numbers. We were unable to confirm whether VIT prevents fatal reactions to insect stings, because of the rarity of this outcome. Venom immunotherapy was also effective for preventing large local reactions to a sting (5 studies; 112 follow-up stings; RR 0.41, 95% CI 0.24 to 0.69) and for improving quality of life (mean difference [MD] in favour of VIT 1.21 points on a 7-point scale, 95% CI 0.75 to 1.67). We found a significant risk of systemic adverse reaction to VIT treatment: 6 trials reported this outcome, in which 14 of 150 (9.3%) participants treated with VIT and 1 of 135 (0.7%) participants treated with placebo or no treatment suffered a systemic reaction to treatment (RR 8.16, 95% CI 1.53 to 43.46; 2 studies contributed to the effect estimate). Our analysis of 11 observational studies found systemic adverse reactions occurred in 131/921 (14.2%) participants treated with bee venom VIT and 8/289 (2.8%) treated with wasp venom VIT. We found venom immunotherapy using extracted insect venom to be an effective therapy for preventing further allergic reactions to insect stings, which can improve quality of life. The treatment carries a small but significant risk of systemic adverse reaction.

From analysis of 7 studies, which included 392 participants, we found that this treatment reduces the chance of having a serious allergic reaction to an insect sting by 90%, a consistent finding between studies. Venom immunotherapy also significantly improves the quality of life of people who have had a serious allergic reaction to an insect sting by reducing anxiety and possible limitation of activities caused by fear of insects. However, almost 1 in 10 people treated with venom immunotherapy during the trials had an allergic reaction to their treatment. We were unable to find out whether venom immunotherapy prevents fatal allergic reactions to insect stings, because these are so rare. The decision whether to start venom immunotherapy depends on an accurate diagnosis, followed by careful assessment of a person's risk of having another allergic reaction to a sting, the degree to which the insect sting allergy affects their quality of life, and the risk of an allergic reaction to their treatment.

10.1002/14651858.CD008838.pub2

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Studies of prophylactic administration of protein free SS note a variable improvement in the respiratory status and a decrease in respiratory distress syndrome in infants who receive prophylactic protein free SS. The meta-analysis supports a decrease in the risk of pneumothorax (typical relative risk 0.67, 95% CI 0.50, 0.90), pulmonary interstitial emphysema (typical relative risk 0.68, 95% CI 0.50, 0.93), and neonatal mortality (typical relative risk 0.70, 95% CI 0.58, 0.85). No differences were seen in the risk of intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity and cerebral palsy. The meta-analysis supports an increase in the risk of patent ductus arteriosus associated with prophylactic SS administration (typical relative risk 1.11, 95% CI 1.00, 1.22), and an increase in the risk of pulmonary hemorrhage (typical relative risk 3.28, 95% CI 1.50, 7.16). Prophylactic intratracheal administration of protein free synthetic surfactant to infants at risk of developing respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who receive prophylactic protein free SS have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, and a decreased risk of neonatal mortality. Infants who receive prophylactic protein free SS have an increased risk of developing patent ductus arteriosus and pulmonary hemorrhage.

The review of trials found evidence that synthetic surfactant reduced the risk of RDS in babies considered at risk. Babies who receive prophylactic synthetic surfactant have a decreased risk of RDS, pneumothorax (air in the lung cavity) and death. However, babies who receive prophylactic synthetic surfactant have an increased risk of developing lung hemorrhage and patent ductus arteriosus, an open vessel that channels blood from the lungs to the body. Although this can lead to potentially life threatening complications, the overall benefits of surfactant treatment outweigh the risks.

10.1002/14651858.CD001079.pub2

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The searches identified 69 trials, of which 19 (2565 participants) met our inclusion criteria. Fifteen trials compared dornase alfa to placebo or no dornase alfa (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa to hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years. Dornase alfa compared to placebo or no treatment Dornase alfa improved forced expiratory volume at one second at one month (four trials, 248 participants), three months (one trial, 320 participants; moderate-quality evidence), six months (one trial, 647 participants; high-quality evidence) and two years (one trial, 410 participants). Limited low-quality evidence showed no difference between groups for changes in quality of life. There was a decrease in pulmonary exacerbations with dornase alfa in trials of up to two years (moderate-quality evidence). One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs. Dornase alfa: daily versus alternate day One cross-over trial (43 children) found no differences between treatment regimens for lung function, quality of life or pulmonary exacerbations (low-quality evidence). Dornase alfa compared to other medications that improve airway clearance Results for these comparisons were mixed. One trial (43 children) showed a greater improvement in forced expiratory volume at one second for dornase alfa compared to hypertonic saline (low-quality evidence), and one trial (23 participants) reported no difference in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol (low-quality evidence). One trial (23 participants) found a difference in quality of life favouring dornase alfa when compared to dornase alfa plus mannitol (low-quality evidence); other comparisons found no difference in this outcome (low-quality evidence). No trials in any comparison reported any difference between groups in the number of pulmonary exacerbations (low-quality evidence). When all comparisons are assessed, dornase alfa did not cause significantly more adverse effects than other treatments, except voice alteration and rash. There is evidence to show that, compared with placebo, therapy with dornase alfa improves lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.

We included 19 trials with 2565 people with cystic fibrosis; 15 trials (2447 people) compared dornase alfa to placebo (a dummy treatment with no active medication) or no dornase alfa treatment; two trials (32 people) compared daily dornase to hypertonic saline; one trial (48 people) compared daily dornase alfa with hypertonic saline and alternate day dornase alfa; and one trial (38 people) compared dornase alfa to mannitol and the combination of both drugs. People from all age groups (infants through to adults) took part in the trials which lasted from six days to three years. Dornase alfa compared to placebo or no treatment We found that dornase alfa improves lung function within one month when compared to a placebo or no treatment and this improvement was also seen in longer trials lasting from six months to two years (eight trials; 1708 participants). There were also fewer exacerbations (flare up of lung inflammation) in these longer trials. One trial found that the cost savings from dornase alfa offset 18% to 38% of the medication costs. Dornase alfa - daily versus alternate day One trial (43 children) found no differences between treatment schedules for lung function, quality of life or pulmonary exacerbations. Dornase alfa compared to other medications that improve airway clearance The results from trials comparing dornase alfa to hypertonic saline or mannitol were mixed. One trial (43 children) showed a greater improvement in lung function with dornase alfa compared to hypertonic saline and one trial (23 participants) reported no difference in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol. In one trial (23 participants) quality of life scores were better with dornase alfa alone than with dornase alfa plus mannitol; other drug comparisons found no difference between treatments for quality of life. No trials in any comparison of treatments reported any difference between groups in the number of pulmonary exacerbations. Overall, no serious side effects were reported, with only rash and a change in voice seen more frequently in those people taking dornase alfa. However, it is not definitively clear from the current evidence if dornase alfa is better than other medications such as hypertonic saline or mannitol. The quality of evidence from the trials comparing dornase alfa to placebo or no treatment was moderate to high for lung function results, but only one trial reported any changes in quality of life so the evidence for this outcome is limited. Also, there were few trials comparing different treatment schedules of dornase alfa (e.g. once a day versus twice a day) or comparing dornase alfa to other medications which help with clearing secretions, so current evidence from these trials is limited and of low quality.

10.1002/14651858.CD001127.pub4

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We included ten studies involving data from 944 adults, all male. Five trials involved primarily cognitive behavioural interventions (CBT) (n = 664). Of these, four compared CBT with no treatment or wait list control, and one compared CBT with standard care. Only one study collected data on the primary outcome. The largest study (n = 484) involved the most complex intervention versus no treatment. Long-term outcome data are reported for groups in which the mean years 'at risk' in the community are similar (8.3 years for treatment (n = 259) compared to 8.4 in the control group (n = 225)). There was no difference between these groups in terms of the risk of reoffending as measured by reconviction for sexual offences (risk ratio (RR) 1.10; 95% CI 0.78 to 1.56). Four trials (n = 70) compared one behavioural programme with an alternative behavioural programme or with wait list control. No meta-analysis was possible for this comparison. For two studies (both cross-over, n = 29) no disaggregated data were available. The remaining two behavioural studies compared imaginal desensitisation with either covert sensitisation or as part of adjunctive drug therapy (n = 20 and 21, respectively). In these two studies, results for the primary outcome (being 'charged with anomalous behaviour') were encouraging, with only one new charge for the treated groups over one year in the former study, and in the latter study, only one new charge (in the drug-only group) over two years. One study compared psychodynamic intervention with probation. Results for this study (n = 231) indicate a slight trend in favour of the control group (probation) over the intervention (group therapy) in terms of sexual offending as measured by rearrest (RR 1.87; 95% CI 0.78 to 4.47) at 10-year follow-up. Data for adverse events, 'sexually anomalous urges' and for secondary outcomes thought to be 'dynamic' risk factors for reoffending, including anger and cognitive distortions, were limited. The inescapable conclusion of this review is the need for further randomised controlled trials. While we recognise that randomisation is considered by some to be unethical or politically unacceptable (both of which are based on the faulty premise that the experimental treatment is superior to the control – this being the point of the trial to begin with), without such evidence, the area will fail to progress. Not only could this result in the continued use of ineffective (and potentially harmful) interventions, but it also means that society is lured into a false sense of security in the belief that once the individual has been treated, their risk of reoffending is reduced. Current available evidence does not support this belief. Future trials should concentrate on minimising risk of bias, maximising quality of reporting and including follow-up for a minimum of five years 'at risk' in the community.

We identified 10 relevant studies involving data from 944 adults, all male. Few of these studies provided information about the primary outcome of this review, which was reoffending. This was usually because studies did not collect data for a sufficiently long period outside prison or the treatment setting. Many studies relied on other outcome measures (for example, anger or social skills) chosen by investigators in the hope that they were linked in some way with future offending, although it cannot be stated with certainty that such connections reliably predict reoffending. Five of the trials we found involved 664 men and used primarily cognitive behavioural interventions (CBT). In the largest study, which had the most complex and intense 'package' of treatment both within and outside of prison, there was no difference between the group who had received CBT and those who had not in terms of the risk of reoffending as measured by reconviction for sexual offences. One study, involving 231 men, compared psychodynamic intervention with standard care, which was probation, and suggested that probation was mildly superior in terms of reducing reoffending. Behavioural programmes were looked at in four trials involving 70 men. For two studies, not enough data were reported to assess the effectiveness of treatment. For the remaining two, encouraging results with regards to reconvictions and self-reported urges have to be treated with caution as the studies are relatively old, meaning that many participants would not now seek or be offered treatment, as some of the targeted behaviours have been decriminalised. Data for adverse events, 'sexually anomalous urges' and for secondary outcomes thought to be 'dynamic' risk factors for reoffending, including anger and cognitive distortions, were limited. We concluded that further randomised controlled trials are urgently needed in this area, so that society is not lured into a false sense of security in the belief that once the individual has been treated, then their risk of reoffending is reduced. Currently, the evidence does not support this belief.

10.1002/14651858.CD007507.pub2

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We included four trials, containing 2018 patients. The subjects were mostly white people (female: 26% to 56%), with a median age of 58 to 66 years. About half of them had histologically proven adenocarcinoma. Of the 2018 patients, 83% to 99% had their status measured using the Eastern Cooperative Oncology Group performance status, and had a score of 0 to 1 (which is usually considered as physically "fit"). All four studies provided data on overall survival, progression-free survival, one-year survival rate, objective response rate, and serious adverse events, with two studies (1901 patients) investigating the effect of cetuximab on quality of life as well. The risk of bias was low for the data on overall survival and one-year survival rate, and high for the data on all other outcomes, mainly due to lack of blinding. Compared with chemotherapy alone, chemotherapy plus cetuximab improved overall survival (10.5 months versus 8.9 months; HR 0.87, 95% CI 0.79 to 0.96), one-year survival rate (45% versus 40%; RR 1.13, 95% CI 1.02 to 1.25), and objective response rate (30% versus 23%; RR 1.31, 95% CI 1.14 to 1.51). The difference in progression-free survival was at the limit of the statistical significance (4.9 months versus 4.4 months; HR 0.91, 95% CI 0.83 to 1.00). No significant difference in quality of life between the two treatment arms was reported by the two relevant studies. Patients in the cetuximab group experienced more acneiform rash (11.2% versus 0.3%; RR 37.36, 95% CI 10.66 to 130.95), hypomagnesemia (5.3% versus 0.8%; RR 6.57, 95% CI 1.13 to 38.12), infusion reaction (3.9% versus 1.1%; RR 3.50, 95% CI 1.76 to 6.94), diarrhoea (4.8% versus 2.3%; RR 2.10, 95% CI 1.26 to 3.48), hypokalaemia (6.3% versus 3.6%; RR 1.74, 95% CI 1.02 to 2.99), febrile neutropenia (10.6% versus 7.6%; RR 1.40, 95% CI 1.10 to 1.77), and leukopenia (58.1% versus 42.7%; RR 1.36, 95% CI 1.17 to 1.58) than did those in the control group. The difference in other adverse events did not reach statistical significance. According to the reports of original studies, the adverse events were generally manageable. There were no cetuximab-related deaths. The quality of the evidence is high for overall survival and one-year survival rate, but low for most secondary outcomes. The combination of chemotherapy plus cetuximab is better than chemotherapy alone as the first-line treatment of advanced NSCLC in improving overall survival, while inducing higher rates of some reportedly manageable adverse events.

This review of 2018 patients, from four trials, found that adding cetuximab (a newly developed agent) to standard treatment, prolonged the survival time of advanced NSCLC patients by about 1.5 months, and deferred the progression of cancer by about 0.5 month. One year after the treatment, 45% of the patients receiving standard treatment plus cetuximab, and 40% of the patients receiving standard treatment alone were still alive. However, the effects of cetuximab on quality of life of patients were uncertain. Seven types of adverse events, mainly involving skin and blood, occurred much more in the patients receiving cetuximab, while other adverse events seemed to occur equally in both groups. The adverse events were reported as generally manageable. No deaths related to cetuximab were reported. In summary, high quality evidence shows that the use of cetuximab combined with standard treatment leads to better survival than standard treatment alone, in improving survival of patients with advanced NSCLC.

10.1002/14651858.CD009948.pub2

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Twenty randomised trials met our inclusion criteria; 16 parallel trials (977 infants) and four cross-over trials (88 infants). No studies were blinded and the quality of evidence for outcomes assessed varied from moderate to low. We found no difference in the primary outcome, death before hospital discharge, between VTV modes versus PLV modes (typical RR 0.75, 95% CI 0.53 to 1.07; low quality evidence). However, there was moderate quality evidence that the use of VTV modes resulted in a reduction in the primary outcome, death or BPD at 36 weeks' gestation (typical RR 0.73, 95% CI 0.59 to 0.89; typical NNTB 8, 95% CI 5 to 20) and the following secondary outcomes: rates of pneumothorax (typical RR 0.52, 95% CI 0.31 to 0.87; typical NNTB 20, 95% CI 11 to 100), mean days of mechanical ventilation (MD -1.35 days, 95% CI -1.83 to -0.86), rates of hypocarbia (typical RR 0.49, 95% CI 0.33 to 0.72; typical NNTB 3, 95% CI 2 to 5), rates of grade 3 or 4 intraventricular haemorrhage (typical RR 0.53, 95% CI 0.37 to 0.77; typical NNTB 11, 95% CI 7 to 25) and the combined outcome of periventricular leukomalacia with or without grade 3 or 4 intraventricular haemorrhage (typical RR 0.47, 95% CI 0.27 to 0.80; typical NNTB 11, 95% CI 7 to 33). VTV modes were not associated with any increased adverse outcomes. Infants ventilated using VTV modes had reduced rates of death or BPD, pneumothoraces, hypocarbia, severe cranial ultrasound pathologies and duration of ventilation compared with infants ventilated using PLV modes. Further studies are needed to identify whether VTV modes improve neurodevelopmental outcomes and to compare and refine VTV strategies.

In a search updated to January 2017, review authors identified 20 studies for inclusion in the review. Sixteen studies (977 infants) compared two separate groups of infants treated with a volume-targeted mode of ventilation compared with a pressure-limited mode of ventilation. In four studies (84 infants), the infants were treated with both modes of ventilation in a cross-over design (where infants had ventilation with one method and were then swapped over to the second method). Most of the studies were of moderate to low quality and none of them were blinded to those who assessed therapy. The most important results from this review were based on data from eight to 12 studies including 584 to 771 infants. Babies ventilated using volume-targeted modes of ventilation were more likely to survive free of lung damage. They needed ventilator assistance for a shorter duration and were less likely to develop pneumothorax (a condition when air escapes from the lung into the chest). They had more stable carbon dioxide levels in the blood, and had fewer brain ultrasound abnormalities. There was no evidence that volume-targeted modes were more likely to harm the infant than traditional pressure-limited modes. More research is needed to understand whether volume-targeted modes also lead to improvements in the development of movement and intellect. More research is also needed comparing different volume-targeting techniques. Low to moderate quality as none of the studies were blinded and there were issues with study design in some of the studies.

10.1002/14651858.CD003666.pub4

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Eleven studies (672 participants) were included in the review. Four studies assessed the efficacy of single doses of various opioid and non-opioid analgesics; a pooled analysis of these studies was not performed but in each study opioids reduced pain more than placebo. There were no differences between analgesic drugs in these studies. Seven studies were between one and six weeks in duration and assessed six different oral opioids (dextropropoxyphene, codeine, tramadol, tilidine, pentazocine, morphine), either alone or combined with non-opioid analgesics. The only strong opioid investigated was controlled-release morphine sulphate, in a single study with 20 participants. Six studies compared an opioid to placebo. Opioids were superior to placebo in patient-reported global impression of change (3 studies, 324 participants: relative risk (RR) 1.44, 95% CI 1.03 to 2.03) but not for the number of withdrawals due to inadequate analgesia (4 studies, 345 participants: RR 0.82, 95% CI 0.34 to 2.0). Adverse events (most commonly nausea, vomiting, dizziness and constipation) were more frequent in patients receiving opioids compared to placebo (4 studies, 371 participants: odds ratio 3.90, 95% CI 2.31 to 6.56); the pooled risk ratio for withdrawal due to adverse events was 2.67 (3 studies, 331 participants: 95% CI 0.52 to 13.75). One study compared an opioid (codeine with paracetamol) to an NSAID (diclofenac) and found no difference in efficacy or safety between interventions. There is limited evidence that weak oral opioids may be effective analgesics for some patients with RA, but adverse effects are common and may offset the benefits of this class of medications. There is insufficient evidence to draw conclusions regarding the use of weak opioids for longer than six weeks, or the role of strong opioids.

There were no studies in people with rheumatoid arthritis that looked at the effects of weak opioids taken for more than six weeks. There were not enough studies of strong opioids to draw conclusions about their effects in rheumatoid arthritis. What is rheumatoid arthritis and what are opioids? When you have rheumatoid arthritis your immune system, which normally fights infection, attacks the lining of your joints. This makes your joints swollen, stiff and painful. The small joints of your hands and feet are usually affected first. There is no cure for rheumatoid arthritis at present, so the treatments aim to relieve the pain and stiffness and improve your ability to move. Opioids are powerful pain-relieving substances that range in strength from relatively mild, such as codeine, to strong, such as morphine. Some examples of weak opioids are codeine (for example Panadeine Forte®) and tramadol (for example Tramal). Some examples of strong opioids are oxycodone (for example Percocet, Endone), morphine and fentanyl (for example Duragesic). They can be taken in a pill form, as an injection or as a patch placed on the skin. Common opioid side-effects include nausea, constipation and drowsiness. Best estimate of what happens to people with rheumatoid arthritis who take opioids Patient-reported global impression of change -18 more people out of 100 reported a 'good' or 'very good' improvement in the symptoms of their rheumatoid arthritis after treatment with opioids for between one and six weeks (18% absolute improvement) -57 people out of 100 reported a 'good' or 'very good' improvement in symptoms -40 people out of 100 who took a placebo reported a 'good' or 'very good' improvement in symptoms Side-effects -30 more people out of 100 experienced at least one side-effect during treatment with opioids for between one and six weeks (30% absolute difference) -51 people out of 100 had at least one side-effect -21 people out of 100 who took a placebo had at least one side-effect

10.1002/14651858.CD003113.pub3

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We included 32 RCTs with 2844 adult participants. Twenty-six assessed upper-limb and six assessed lower-limb blocks. Seventeen compared ultrasound with peripheral nerve stimulation (PNS), and nine compared ultrasound combined with nerve stimulation (US + NS) against PNS alone. Two studies compared ultrasound with anatomical landmark technique, one with a transarterial approach, and three were three-arm designs that included US, US + PNS and PNS. There were variations in the quality of evidence, with a lack of detail in many of the studies to judge whether randomization, allocation concealment and blinding of outcome assessors was sufficient. It was not possible to blind practitioners and there was therefore a high risk of performance bias across all studies, leading us to downgrade the evidence for study limitations using GRADE. There was insufficient detail on the experience and expertise of practitioners and whether experience was equivalent between intervention and control. We performed meta-analysis for our main outcomes. We found that ultrasound guidance produces superior peripheral nerve block success rates, with more blocks being assessed as sufficient for surgery following sensory or motor testing (Mantel-Haenszel (M-H) odds ratio (OR), fixed-effect 2.94 (95% confidence interval (CI) 2.14 to 4.04); 1346 participants), and fewer blocks requiring supplementation or conversion to general anaesthetic (M-H OR, fixed-effect 0.28 (95% CI 0.20 to 0.39); 1807 participants) compared with the use of PNS, anatomical landmark techniques or a transarterial approach. We were not concerned by risks of indirectness, imprecision or inconsistency for these outcomes and used GRADE to assess these outcomes as being of moderate quality. Results were similarly advantageous for studies comparing US + PNS with NS alone for the above outcomes (M-H OR, fixed-effect 3.33 (95% CI 2.13 to 5.20); 719 participants, and M-H OR, fixed-effect 0.34 (95% CI 0.21 to 0.56); 712 participants respectively). There were lower incidences of paraesthesia in both the ultrasound comparison groups (M-H OR, fixed-effect 0.42 (95% CI 0.23 to 0.76); 471 participants, and M-H OR, fixed-effect 0.97 (95% CI 0.30 to 3.12); 178 participants respectively) and lower incidences of vascular puncture in both groups (M-H OR, fixed-effect 0.19 (95% CI 0.07 to 0.57); 387 participants, and M-H OR, fixed-effect 0.22 (95% CI 0.05 to 0.90); 143 participants). There were fewer studies for these outcomes and we therefore downgraded both for imprecision and paraesthesia for potential publication bias. This gave an overall GRADE assessment of very low and low for these two outcomes respectively. Our analysis showed that it took less time to perform nerve blocks in the ultrasound group (mean difference (MD), IV, fixed-effect -1.06 (95% CI -1.41 to -0.72); 690 participants) but more time to perform the block when ultrasound was combined with a PNS technique (MD, IV, fixed-effect 0.76 (95% CI 0.55 to 0.98); 587 participants). With high levels of unexplained statistical heterogeneity, we graded this outcome as very low quality. We did not combine data for other outcomes as study results had been reported using differing scales or with a combination of mean and median data, but our interpretation of individual study data favoured ultrasound for a reduction in other minor complications and reduction in onset time of block and number of attempts to perform block. There is evidence that peripheral nerve blocks performed by ultrasound guidance alone, or in combination with PNS, are superior in terms of improved sensory and motor block, reduced need for supplementation and fewer minor complications reported. Using ultrasound alone shortens performance time when compared with nerve stimulation, but when used in combination with PNS it increases performance time. We were unable to determine whether these findings reflect the use of ultrasound in experienced hands and it was beyond the scope of this review to consider the learning curve associated with peripheral nerve blocks by ultrasound technique compared with other methods.

The evidence is current up to 27 August 2014. We found 32 studies with 2844 participants. Most studies compared ultrasound with electrical nerve stimulators or compared ultrasound combined with nerve stimulators against nerve stimulators alone. We reran the search in May 2015. We will deal with the 11 studies of interest when we next update the review. We combined the results of studies using statistical tests and found that nerve blocks were more likely to be assessed as adequate for surgery and were less likely to need additional anaesthetic when performed using ultrasound guidance or ultrasound guidance combined with other techniques. We also found that there were fewer complications such as 'pins and needles' or accidental punctures of blood vessels. It also took less time to perform the nerve block when ultrasound alone was used. There was variation in the quality of the studies and authors had not always made sufficient attempts to ensure that the outcome assessors were unaware of what technique had been used for the nerve block. Studies had also often not clearly explained how experienced the people giving the nerve block were. This is particularly important, as ultrasound is still a relatively new technique and some anaesthetists may have limited experience. We rated our evidence for whether the nerve blocks were sufficient and adequate for surgery as of moderate quality, but evidence for our other outcomes was either low or very low. Our evidence suggests that ultrasound is superior to other techniques for peripheral nerve blocks. However, we are unable to say whether this result depends on the experience of the practitioner in the technique being used.

10.1002/14651858.CD006459.pub3

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We identified one eligible study that examined the effect of computerised cognitive training (CCT) in 6742 participants over 50 years of age, with training and follow-up duration of six months. We considered the study to be at high risk of attrition bias and the overall quality of the evidence to be low. Researchers provided no data on our primary outcome. Results indicate that there may be a small advantage for the CCT group for executive function (mean difference (MD) -1.57, 95% confidence interval (CI) -1.85 to -1.29; participants = 3994; low-quality evidence) and a very small advantage for the control group for working memory (MD 0.09, 95% CI 0.03 to 0.15; participants = 5831; low-quality evidence). The intervention may have had little or no effect on episodic memory (MD -0.03, 95% CI -0.10 to 0.04; participants = 3090; low-quality evidence). We found low-quality evidence from only one study. We are unable to determine whether computerised cognitive training is effective in maintaining global cognitive function among healthy adults in midlife. We strongly recommend that high-quality studies be undertaken to investigate the effectiveness and acceptability of cognitive training in midlife, using interventions that last long enough that they may have enduring effects on cognitive and brain reserve, and with investigators following up long enough to assess effects on clinically important outcomes in later life.

We found that a lot of shorter studies had been conducted, but only one study met our criteria for this review. It took place in the UK and included two different types of online cognitive training. The control group participated in an online game that was not expected to have cognitive effects. This training lasted six months, and study authors measured cognition at the end of the training period. Resarchers randomised 6742 people in the study, but the dropout rate was high. We thought this put the results at high risk of bias; therefore we considered the quality of evidence provided by this study to be low, meaning that further research might well lead to different results. This study did not measure overall cognitive functioning - which we were most interested in - but it did measure some subtypes of cognitive function. The cognitive training group did slightly better on a test of reasoning, and the control group did very slightly better on a test of working memory, which is a very short-term type of memory. No evidence suggested that the groups differed in memory measured by a word-learning test. We were not able to tell whether taking part in computerised cognitive training in midlife has any lasting effects on cognitive function. We think this is an important question that should be investigated further in trials that test cognitive training over three months or longer. It will also be important for researchers to try to find the best ways to keep people motivated to persist with training.

10.1002/14651858.CD012278.pub2

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We included two studies with a total of 40 participants in the review. Exercise-based CR consisted of aerobic or resistance training or both three times per week for six to eight weeks. Exercise intensity was 50% of oxygen consumption (VO2) reserve, or ranged from 60% to 80% of heart rate reserve. Two serious adverse events were observed in one trial, in which participants did not complete the study due to infections. Furthermore, a total of four participants in each group required visits to the emergency department, although these participants did complete the study. Summary scores from the 36-item Short Form Health Survey (SF-36) and the Kansas City Cardiomyopathy Questionnaire (KCCQ) were measured as quality of life. One trial reported that the KCCQ summary score improved by 14.4 points in the exercise group compared with 0.5 points in the usual care group. The other trial reported that the SF-36 total score improved by 29.2 points in the exercise group compared with 16.3 points in the usual care group. A large difference in quality of life was observed between groups at the end of follow-up (standardised mean difference 0.88, 95% CI -0.12 to 1.88; 37 participants; 2 studies; very low-quality of evidence). However, there was no evidence for the effectiveness of exercise-based CR due to the young age of the participants, high risk of performance bias, very small sample size, and wide confidence intervals, which resulted in very low-quality evidence. Furthermore, we were not able to determine the effect of exercise-based CR on mortality, rehospitalisation, heart transplantation, and cost, as these outcomes were not reported. The evidence is currently inadequate to assess the safety and efficacy of exercise-based CR for people with implantable VADs compared with usual care. The amount of RCT evidence was very limited and of very low quality. In addition, the training duration was very short term, that is from six to eight weeks. Further high-quality and well-reported RCTs of exercise-based CR for people with implantable VADs are needed. Such trials need to collect data on events (mortality and rehospitalisation), patient-related outcomes (including quality of life), and cost-effectiveness.

We assessed the quality of the evidence for quality of life as very low due to the young age of the participants, Insufficient blinding, small number of participants, and imprecision because of wide range of confidence intervals. The effects of exercise-based CR for people with implantable VADs were not clear. The current evidence is inadequate to assess the benefits and harms of exercise-based CR for people with implantable VADs compared with usual care. The amount of randomised controlled trial evidence was very limited and of very low quality. In addition, the training duration was very short term. High-quality randomised controlled trials are needed to collect data on events (death and rehospitalisation), patient-related outcomes (including quality of life), and cost.

10.1002/14651858.CD012222.pub2

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Four randomised controlled studies met the inclusion criteria for this review, involving a total of 302 participants lasting from 29 days to 13 months; 14 studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta-analysis. One study only enrolled adult males, the remaining studies included both males and females aged 12 years and over. Risk of bias in the studies was moderate. Random sequence generation and allocation concealment was only described in the more recent study; the remaining three studies were judged to have an unclear risk of bias. All four studies documented double-blinding to the intervention, but there is some uncertainty with regards to participant blinding in one study. Some outcome data were missing from all four studies. There were no differences in either the number of respiratory exacerbations or the number of participants with an exacerbation between replacement therapy or placebo groups at any time point. Meta-analysis of most respiratory function tests showed no difference between treatment and placebo groups, but the smallest study (n = 16) reported forced vital capacity (litres) increased more in the placebo group at up to 24 hours. A further study reported a significant improvement in forced expiratory volume at one second (litres) at 30 days after participants had received their first dose of favouring the gene therapy agent, but this finding was not confirmed when combined with at second study in the meta-analysis. The more recent study (n = 140) demonstrated a small improvement in forced vital capacity (per cent predicted) at two and three months and again at 11 and 12 months for participants receiving CFTR gene replacement therapy compared to those receiving placebo. The same study reported a significant difference in the relative change in forced expiratory volume at one second (per cent predicted) at two months, three months and 12 months. One small study reported significant concerns with "influenza-like" symptoms in participants treated with CFTR gene replacement therapy; this was not reported on repeated use of the same agent in a larger recent study. There was no other evidence of positive impact on outcomes, in particular improved quality of life or reduced treatment burden. Two studies measured ion transport in the lower airways; one (n = 16) demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% confidence interval 3.77 to 9.95). The second study (n = 140) also reported significant changes toward normal values (P = 0.032); however, aggregate data were not available for analysis. In the most recent study, there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance. One study of liposome-based CFTR gene transfer therapy demonstrated some improvements in respiratory function in people with CF, but this limited evidence of efficacy does not support this treatment as a routine therapy at present. There was no evidence of efficacy for viral-mediated gene delivery. Future studies need to investigate clinically important outcome measures.

We found four studies with 302 people to include in this review. The studies lasted from 29 days to 13 months. Three of these studies included both men and women aged 12 years and over and one study only included adult men. The studies compare gene therapy to a dummy treatment (placebo) both of which are inhaled as a mist into the lungs. The studies were of different designs and used different agents. This meant we could not combine their results. Three of the studies, including the largest and most recent study, showed an improvement in some measures of lung function in people with CF given gene therapy. We did not find that any more clinically relevant outcomes such as quality of life, treatment burden or flare-up of lung disease had improved with treatment. In one study "influenza-like" symptoms were more common in people who received CFTR gene transfer agents but this was not reported when the agent was used repeatedly in a larger study. In those people who took the gene transfer agents, molecules and salt in their lower airways moved more like they do in healthy people. The limited evidence of benefit does not support this as a routine therapy at present. We recommend that future studies are designed and reported clearly so that their results can be incorporated into a systematic review. The most recent study provided detailed information on how the people were put into different treatment groups completely at random, and so we are satisfied that those taking part in the study had an equal chance of being in either group (CFTR gene transfer agent or placebo) and that no one could work out which group the next person would be put into. The other studies reported that people were put into groups at random but did not specify how, so we cannot be sure that there was an equal chance of them being in either group. We believe that the clinicians running all the studies did not know which treatment the people taking part were receiving and that in three of the studies those taking part did not know either, but we could not be sure whether the people taking part in the latest study knew which treatment they were receiving and what effect this knowledge might have on results. Unfortunately, the studies did not report all their results clearly; sometimes results were not reported in a way that we could use for the review and sometimes they were not reported at all. This reduced the certainty with which we judged the overall results.

10.1002/14651858.CD005599.pub5

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Five studies met the review entry criteria (5537 adults). Study populations entered the studies having previously been treated with inhaled steroids and had moderate or mild airway obstruction (mean FEV1 predicted between 65% and 84% at baseline). Most of the studies assessed treatment over a period of six months. The studies were at a low risk of selection and performance/detection bias, although we could not determine whether missing data had an impact on the results. Availablility of outcome data was satisfactory. Primary outcomes The odds ratio for exacerbations requiring oral steroids was lower with fluticasone/salmeterol but did not reach statistical significance (OR 0.89, 95% confidence interval (CI) 0.74 to 1.07, four studies, N = 4949). With an assumed risk with budesonide/formoterol of 106/1000 participants requiring oral steroids, treatment with fluticasone/salmeterol would lead to between 25 fewer and seven more people per 1000 experiencing a course of oral steroids. Although the odds of hospital admission was higher with fluticasone/salmeterol, this did not reach statistical significance (OR 1.29, 95% CI 0.68 to 2.47, four studies, 4879 participants). With an assumed risk in the budesonide/formoterol of 7/1000, between three fewer and nine more people per 1000 would be hospitalised on fluticasone/salmeterol. The odds of a serious adverse event related to asthma was higher with fluticasone/salmeterol but did not differ significantly between treatments (OR 1.47, 95% CI 0.75 to 2.86, three studies, 4054 participants). With an assumed risk in the budesonide/formoterol of 7/1000, between two fewer and 13 more people per 1000 would experience a serious adverse event on fluticasone/salmeterol. Secondary outcomes Lung function outcomes, symptoms, rescue medication, composite of exacerbations leading to either emergency department visit or hospital admission, withdrawals and adverse events did not differ statistically between treatments. Assessment of quality of life was limited to two studies, both of which gave results that did not reach statistical significance. One study reported one death out of 1000 participants on fluticasone/salmeterol and no deaths in a similar number of participants treated with budesonide/formoterol. No deaths were reported in the other studies. Statistical imprecision in the effect estimates for exacerbations and serious adverse events do not enable us to conclude that either therapy is superior. The uncertainty around the effect estimates justify further trials to provide more definitive conclusions; the overall quality of evidence based on GRADE recommendations for the three primary outcomes and withdrawals due to serious adverse events was moderate. We rated the quality of evidence for mortality to be low. Results for lung function outcomes showed that the drugs were sufficiently similar that further research is unlikely to change the effects. No trials were identified in the under-12s and research in this population is a high priority. Evaluation of quality of life is a priority for future research.

This systematic review examined randomised controlled trials comparing two commonly available combinations administered at a fixed dose through a single inhaler, fluticasone/salmeterol and budesonide/formoterol. We included five studies which recruited 5537 people. The trials were generally well designed but only recruited adults and adolescents and not children. Participants were already taking regular inhaled steroids before the studies commenced and had mild or moderate asthma based on tests of their airway. We found that the number of people who required treatment with oral steroids and admission to hospital was similar between the treatments, but due to the statistical uncertainty of this result we could not rule out important differences in favour of either drug combination. Additional trials would enable us to draw more reliable conclusions about how well these drugs work compared with each other. We also looked at serious adverse events. Again, the results did not indicate that one combination was clearly better than the other, but again these results were imprecise so we cannot be certain. However, lung function and rescue medication use were similar between the treatments. We could not assess the relative effects of these drugs on mortality because there were so few deaths which leads to statistical uncertainty; out of the five studies, one person died. Quality of life was measured in different ways in two studies and we could not determine how the treatments compared in this respect. Further studies are needed to strengthen and better explain these findings. In particular studies which assess the effects of these therapies in children and studies which measure quality of life are a priority.

10.1002/14651858.CD004106.pub4

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Thirty-nine studies examined the effect of printed educational materials for physicians, audit and feedback, educational meetings, educational outreach visits, financial and healthcare system changes, physician reminders, patient-based interventions and multi-faceted interventions. These interventions addressed the overuse of antibiotics for viral infections, the choice of antibiotic for bacterial infections such as streptococcal pharyngitis and urinary tract infection, and the duration of use of antibiotics for conditions such as acute otitis media. Use of printed educational materials or audit and feedback alone resulted in no or only small changes in prescribing. The exception was a study documenting a sustained reduction in macrolide use in Finland following the publication of a warning against their use for group A streptococcal infections. Interactive educational meetings appeared to be more effective than didactic lectures. Educational outreach visits and physician reminders produced mixed results. Patient-based interventions, particularly the use of delayed prescriptions for infections for which antibiotics were not immediately indicated effectively reduced antibiotic use by patients and did not result in excess morbidity. Multi-faceted interventions combining physician, patient and public education in a variety of venues and formats were the most successful in reducing antibiotic prescribing for inappropriate indications. Only one of four studies demonstrated a sustained reduction in the incidence of antibiotic-resistant bacteria associated with the intervention. The effectiveness of an intervention on antibiotic prescribing depends to a large degree on the particular prescribing behaviour and the barriers to change in the particular community. No single intervention can be recommended for all behaviours in any setting. Multi-faceted interventions where educational interventions occur on many levels may be successfully applied to communities after addressing local barriers to change. These were the only interventions with effect sizes of sufficient magnitude to potentially reduce the incidence of antibiotic-resistant bacteria. Future research should focus on which elements of these interventions are the most effective. In addition, patient-based interventions and physician reminders show promise and innovative methods such as these deserve further study.

Research has shown that physicians in the community (in doctors' offices and clinics) can be partly to blame for resistant bacteria. Studies have shown that physicians inappropriately prescribe antibiotics for infections caused by viruses (such as the common cold). They also prescribe antibiotics that kill a wide variety of bacteria when an antibiotic that kills specific bacteria should be prescribed. Physicians may also prescribe the wrong dose for the wrong length of time. Inappropriate prescribing is due to many factors including patients who insist on antibiotics, physicians who do not have enough time to explain why antibiotics are not necessary and therefore simply prescribe them to save time, physicians who do not know when to prescribe antibiotics or how to recognise a serious bacterial infection, or physicians who are overly cautious. To improve how physicians prescribe antibiotics in the community, methods have been studied. In this review, 39 studies were analysed to determine what works. Using printed materials to educate physicians about prescribing or to give them feedback about how they prescribed did not improve their prescribing or only improved it by a small amount. Meetings to educate physicians improved their prescribing but lectures did not. It was not clear whether personal visits to the physicians by educators worked or not or whether reminders to physicians worked or not . The use of delayed prescriptions decreased use of antibiotics without increasing the risk of serious illness. A delayed prescription means the physician gives a patient a prescription for an antibiotic a few days after the doctor visit; it is thought that if the infection is not serious it will clear up on its own over that time and the patient does not need the antibiotics. The studies also found that using many methods together, such as the ones above, worked better than using one method alone. Since there are many reasons why physicians in the community prescribe antibiotics inappropriately, one method cannot be recommended. But using many methods to change prescribing may be successful.

10.1002/14651858.CD003539.pub2

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We identified 27 studies (1549 participants) that were eligible for inclusion. These studies provided no data relating to aldosterone antagonists in addition to ACEi or ARB (or both) on patient-level outcomes including major cardiovascular events and mortality and progression to end-stage kidney disease (ESKD) requiring dialysis or transplantation. Compared with ACEi or ARB (or both), non-selective aldosterone antagonists (spironolactone) combined with ACEi or ARB (or both) significantly reduced 24-hour protein excretion (11 studies, 596 participants): SMD -0.61, 95% CI -1.08 to -0.13). There was a significant reduction in both systolic and diastolic blood pressure (BP) at the end of treatment with additional non-selective aldosterone antagonist therapy (systolic BP (10 studies, 556 participants): MD -3.44 mm Hg, 95% CI -5.05 to -1.83) (diastolic BP (9 studies, 520 participants): MD -1.73 mm Hg, 95% CI -2.83 to -0.62). However, we found that aldosterone antagonist treatment had imprecise effects at the end of treatment on GFR (9 studies, 528 participants; MD -2.55 mL/min/1.73 m², 95% CI -5.67 to 0.51), doubled the risk of hyperkalaemia (11 studies, 632 patients): RR 2.00, 95% CI 1.25 to 3.20; number needed to treat for an additional harmful outcome (NNTH): 7.2, 95% CI 3.4 to ∞) and increased the risk of gynaecomastia compared to ACEi or ARB (or both) (4 studies, 281 patients): RR 5.14, 95% CI 1.14 to 23.23; NNTH: 14.1, 95% CI 8.7 to 37.3). Most studies enrolled few patients (range 12 to 268) and were powered to observe differences in surrogate end points rather than patient-focused outcomes. Nine studies had a cross-over design and the majority of studies did not adequately report study methods to assess methods and study quality. Aldosterone antagonists reduced proteinuria and blood pressure in adults who had mild to moderate CKD and were treated with ACEi or ARB (or both), but increase hyperkalaemia and gynaecomastia. Whether adding aldosterone antagonists to ACEi or ARB (or both) reduced the risk of major cardiovascular events or ESKD in this population is unknown.

This review of available trials showed that adding aldosterone antagonist treatment to standard therapy reduced protein release into the urine and lowered blood pressure but had uncertain effects on kidney function and survival. Treatment also increases the amount of potassium in the blood which may require treatment changes, extra blood tests and is potentially harmful. Whether aldosterone blockers protect kidney function to lower the chances needing dialysis or kidney transplantation or prevent heart disease in people who have CKD is unclear and not answered by existing research.

10.1002/14651858.CD007004.pub3

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cochrane-simplification-train-529

Individual participant data were available for 480 out of a total of 517 participants (93%), from two out of three included trials. For remission outcomes, a HR of less than one indicated an advantage for phenytoin; and for first seizure and treatment failure outcomes, a HR of less than one indicated an advantage for oxcarbazepine. The results for time to treatment failure for any reason related to treatment showed a potential advantage of oxcarbazepine over phenytoin, but this was not statistically significant (pooled HR adjusted for epilepsy type: 0.78 95% CI 0.53 to 1.14, 476 participants, two trials, moderate-quality evidence). Our analysis showed that treatment failure due to adverse events occurred later on with oxcarbazepine than phenytoin (pooled HR for all participants: 0.22 (95% CI 0.10 to 0.51, 480 participants, two trials, high-quality evidence). Our analysis of time to treatment failure due to lack of efficacy showed no clear difference between the drugs (pooled HR for all participants: 1.17 (95% CI 0.31 to 4.35), 480 participants, two trials, moderate-quality evidence). We found no clear or statistically significant differences between drugs for any of the secondary outcomes of the review: time to first seizure post-randomisation (pooled HR adjusted for epilepsy type: 0.97 95% CI 0.75 to 1.26, 468 participants, two trials, moderate-quality evidence); time to 12-month remission (pooled HR adjusted for epilepsy type 1.04 95% CI 0.77 to 1.41, 468 participants, two trials, moderate-quality evidence) and time to six-month remission (pooled HR adjusted for epilepsy type: 1.06 95% CI 0.82 to 1.36, 468 participants, two trials, moderate-quality evidence). The most common adverse events reported in more than 10% of participants on either drug were somnolence (28% of total participants, with similar rates for both drugs), headache (15% of total participants, with similar rates for both drugs), dizziness (14.5% of total participants, reported by slightly more participants on phenytoin (18%) than oxcarbazepine (11%)) and gum hyperplasia (reported by substantially more participants on phenytoin (18%) than oxcarbazepine (2%)). The results of this review are applicable mainly to individuals with focal onset seizures; 70% of included individuals experienced seizures of this type at baseline. The two studies included in IPD meta-analysis were generally of good methodological quality but the design of the studies may have biased the results for the secondary outcomes (time to first seizure post-randomisation, time to six-month and 12-month remission) as seizure recurrence data were not collected following treatment failure or withdrawal from the study. In addition, misclassification of epilepsy type may have impacted on results, particularly for individuals with generalised onset seizures. High-quality evidence provided by this review indicates that treatment failure due to adverse events occurs significantly later with oxcarbazepine than phenytoin. For individuals with focal onset seizures, moderate-quality evidence suggests that oxcarbazepine may be superior to phenytoin in terms of treatment failure for any reason, seizure recurrence and seizure remission. Therefore, oxcarbazepine may be a preferable alternative treatment than phenytoin, particularly for individuals with focal onset seizures. The evidence in this review which relates to individuals with generalised onset seizures is of low quality and does not inform current treatment policy. We recommend that future trials should be designed to the highest quality possible with regards to choice of population, classification of seizure type, duration of follow-up (including continued follow-up after failure or withdrawal of randomised treatment), choice of outcomes and analysis, and presentation of results.

We assessed the evidence from three studies (specifically, randomised controlled trials) comparing oxcarbazepine with phenytoin. We were able to combine information for 480 people from two of the three trials. For the remaining 37 people from one trial, information was not available to use in this review. The evidence is current to 20 August 2018. Results The review found that people taking oxcarbazepine stop taking treatment because of side effects significantly later than people taking phenytoin. Our results also showed that people with focal onset seizures taking phenytoin may stop taking treatment for any reason earlier than people with focal onset seizures taking oxcarbazepine. The results also suggest that people with focal onset seizures taking oxcarbazepine may experience a repeat seizure later, and achieve freedom from seizures earlier, than people with focal onset seizures taking phenytoin. There was no clear difference between the drugs in terms of withdrawal from the treatment, seizure recurrence and seizure remission for individuals with generalised onset seizures. Quality of the evidence The two studies included in analysis were well designed but no information about seizures was recorded after people stopped taking their trial medication, which may have impacted on the results of the study. Most people (70%) included in the studies within this review had focal onset seizures, so the results are mainly relevant to people with this epilepsy type. Also up to 30% of the people in the trials used in our results may have been wrongly classified as having generalised seizures, which may have impacted on the results. For these reasons, we judged the quality of the evidence provided by this review to be of moderate quality for people with focal onset seizures, and low quality for people with generalised onset seizures. Conclusions For people with focal onset seizures, oxcarbazepine may be a preferable treatment to phenytoin, but more information is needed for people with generalised onset seizures to choose between these medications. We recommend that all future trials comparing these medications, or any other antiepileptic medications, should be designed using high-quality methods. Seizure types of people included in trials should also be classified very carefully.

10.1002/14651858.CD003615.pub4

cochrane-simplification-train-530

cochrane-simplification-train-530

No trials comparing hydroxyurea with placebo or standard care were found. However, we included one randomised controlled trial (n = 61) comparing 20 mg/kg/day with 10 mg/kg/day of hydroxyurea for 24 weeks. Both haemoglobin and foetal haemoglobin levels were lower at 24 weeks in the 20 mg group compared with the 10 mg group, mean difference -2.39 (95% confidence interval - 2.8 to -1.98) and mean difference -1.5 (95% confidence interval -1.83 to -1.17), respectively. Major adverse effects were significantly more common in the 20 mg group, for neutropenia risk ratio 9.93 (95% confidence interval 1.34 to 73.97) and for thrombocytopenia risk ratio 3.68 (95% confidence interval 1.13 to 12.07). No difference was reported for minor adverse effects (gastrointestinal disturbances and raised liver enzymes). The effect of hydroxyurea on transfusion frequency was not reported. The overall quality for the outcomes reported was graded as very low mainly because the outcomes were derived from only one small study with an unclear method of allocation concealment. There is no evidence from randomised controlled trials to show whether hydroxyurea has any effect compared with controls on the need for blood transfusion. Administration of 10 mg/kg/day compared to 20 mg/kg/day of hydroxyurea resulted in higher haemoglobin levels and seems safer with fewer adverse effects. It has not been reported whether hydroxyurea is capable of reducing the need for blood transfusion. Large well-designed randomised controlled trials with sufficient duration of follow up are recommended.

We did not find any randomised controlled trials (where people taking part in the trial have equal chances of being in the treatment or the control group) comparing hydroxyurea with a placebo (a dummy drug) or usual care. However, we found one randomised controlled trial comparing two different doses of hydroxyurea (10 mg/kg/day versus 20 mg/kg/day given for 24 weeks) and included it in this review. A total of 61 people took part in this trial. The lower dose of hydroxyurea appeared to increase levels of foetal haemoglobin, but the higher dose did not. We found some evidence that the higher dose was harmful, particularly to the bone marrow. The trial did not look at whether blood transfusions could be given less often or whether the effects of the anaemia were reduced. In the short term, the lower dose does not appear to have any side effects. The trial duration was very short and we need to know what might happen if treatment with hydroxyurea is continued for a longer period of time. We graded the quality of the evidence as very low. This was because our key results are based on only one small trial. In addition we can not be sure whether the trial methods were of high quality because the authors have not completely described them.

10.1002/14651858.CD011579.pub2

cochrane-simplification-train-531

cochrane-simplification-train-531

While five studies addressed the interventions of interest, we did not include them in the review because the investigators of the studies did not report any information specific to people with cystic fibrosis. Our attempts to obtain this information have not yet been successful. We will include any provided data in future updates of the review. The lack of currently available evidence makes it impossible to draw conclusions about the comparative efficacy and safety of the various immunosuppressive drugs among people with cystic fibrosis after lung transplantation. A 2013 Cochrane Review comparing tacrolimus with cyclosporine in all lung transplant recipients (not restricted to those with cystic fibrosis) reported no significant difference in mortality and risk of acute rejection. However, tacrolimus use was associated with lower risk of broncholitis obliterans syndrome and arterial hypertension and higher risk of diabetes mellitus. It should be noted that this wider review contained only a small number of included studies (n = 3) with a high risk of bias. Additional randomised studies are required to provide evidence for the benefit and safety of the use of immunosuppressive therapy among people with cystic fibrosis after lung transplantation.

Although we found five studies which looked at anti-rejection drugs, they included people with a number of chronic conditions and not just cystic fibrosis. The studies we found reported results from all volunteers combined and we were not able to isolate the results that were specific to people with cystic fibrosis. We contacted the researchers who conducted these studies, but they have not yet sent us the specific results we need. If we receive these results, we will include them in the future when we update this systematic review. There is a review of drugs to suppress the immune systems of people who have had lung transplants (not restricted to those with cystic fibrosis) and this only included three studies which the review authors judged to have a high risk of bias. The review did not find that any one drug was better than another for reducing the chances of death or acute rejection; but one drug (tacrolimus) led to a lower risk of long-term rejection and high blood pressure, although there was a higher risk of diabetes. Research is needed on the use of drugs that suppress the immune system in people with cystic fibrosis who have received a lung transplant.

10.1002/14651858.CD009421.pub4

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cochrane-simplification-train-532

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis decreased all-cause mortality during hospital stay (typical RR 0.57, 95% CI 0.35 to 0.93; typical RD -0.08, 95% CI -0.14 to -0.01; NNTB 13, 95% CI 7 to 100; 6 studies, 416 participants, low-quality evidence). Subgroup analyses revealed decrease in mortality in preterm infants, infants with confirmed sepsis, and infants with gram-negative sepsis (low-quality evidence, four studies). Pentoxifylline decreased length of hospital stay (MD -7.59 days, 95% CI -11.65 to -3.52; 2 studies, 148 participants, low-quality evidence). Pentoxifylline did not change the risk of development of NEC, chronic lung disease, severe intraventricular haemorrhage, retinopathy of prematurity, or periventricular leukomalacia in neonates with sepsis (one to two studies, very low-quality evidence). Pentoxifylline therapy compared to pentoxifylline and immunoglobulin M-enriched intravenous immunoglobulin or immunoglobulin M-enriched intravenous immunoglobulin alone did not change mortality or development of NEC in neonates with sepsis (one study, very low-quality evidence). We noted no adverse effects due to pentoxifylline. We identified no trials evaluating pentoxifylline treatment for NEC. Low-quality evidence from six small studies suggests that pentoxifylline therapy as an adjunct to antibiotics in neonatal sepsis decreases mortality without any adverse effects. We encourage researchers to undertake large, well-designed multicentre trials to confirm or refute the effectiveness of pentoxifylline in reducing mortality and morbidity in neonates with sepsis or NEC.

Six randomised controlled trials met our inclusion criteria. We found low-quality evidence that pentoxifylline in combination with antibiotics decreases deaths and duration of hospital stay in newborn sepsis. Pentoxifylline treatment did not affect lung, eye, or brain injury as a result of sepsis (very low-quality evidence). We identified no adverse effects due to pentoxifylline. There were no completed studies looking at pentoxifylline treatment in NEC. We need better-quality evidence on the use of pentoxifylline in the treatment of sepsis or NEC in the newborn.

10.1002/14651858.CD004205.pub3

cochrane-simplification-train-533

cochrane-simplification-train-533

Twelve studies met the inclusion criteria recruiting 350 participants. Trial reporting was poor and trial quality was deemed inadequate to generalise findings. There was variation in the type of active and sham acupuncture, the outcomes measured and time-points presented. The points used in the sham arm of some studies are used for the treatment of asthma according to traditional Chinese medicine. Two studies used individualised treatment strategies and one study used a combination strategy of formula acupuncture with the addition of individualised points. No statistically significant or clinically relevant effects were found for acupuncture compared to sham acupuncture. Data from two small studies were pooled for lung function (post-treatment FEV1): Standardised Mean Difference 0.12, 95% confidence interval -0.31 to 0.55). There is not enough evidence to make recommendations about the value of acupuncture in asthma treatment. Further research needs to consider the complexities and different types of acupuncture.

The objective of this review was to assess whether there is evidence from randomised controlled trials that asthma patients benefit from acupuncture. The studies included in the review were of variable quality and had inconsistent results. Future research should concentrate on establishing whether there is a non-specific component of acupuncture which benefits recipients of treatment. There should be an assessment not merely of placebo treatment, but also of 'no treatment' as well. There is insufficient evidence to make recommendations about the value of acupuncture as a treatment for asthma based on current evidence.

10.1002/14651858.CD000008.pub2

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cochrane-simplification-train-534

Nine RCTs with a total of 320 participants were included. Four SSRIs were evaluated: fluoxetine (three studies), fluvoxamine (two studies), fenfluramine (two studies) and citalopram (two studies). Five studies included only children and four studies included only adults. Varying inclusion criteria were used with regard to diagnostic criteria and intelligence quotient of participants. Eighteen different outcome measures were reported. Although more than one study reported data for Clinical Global Impression (CGI) and obsessive-compulsive behaviour (OCB), different tool types or components of these outcomes were used in each study. As such, data were unsuitable for meta-analysis, except for one outcome (proportion improvement). One large, high-quality study in children showed no evidence of positive effect of citalopram. Three small studies in adults showed positive outcomes for CGI and OCB; one study showed improvements in aggression, and another in anxiety. There is no evidence of effect of SSRIs in children and emerging evidence of harm. There is limited evidence of the effectiveness of SSRIs in adults from small studies in which risk of bias is unclear.

We found nine trials, involving 320 people, which evaluated four SSRIs: fluoxetine, fluvoxamine, fenfluramine and citalopram. Five studies included only children and four studies included only adults. One trial enrolled 149 children, but the other trials were much smaller. We found no trials that evaluated sertraline, paroxetine or escitalopram. There is no evidence to support the use of SSRIs to treat autism in children. There is limited evidence, which is not yet sufficiently robust, to suggest effectiveness of SSRIs in adults with autism. Treatment with an SSRI may cause side effects. Decisions about the use of SSRIs for established clinical indications that may co-occur with autism, such as obsessive-compulsive disorder and depression in adults or children, and anxiety in adults, should be made on a case-by-case basis.

10.1002/14651858.CD004677.pub3

cochrane-simplification-train-535

cochrane-simplification-train-535

A total of three studies including 242 participants met the inclusion criteria for this review. One study reported the diagnostic performance of CRP for two threshold levels (> 200 mg/L and > 279 mg/L) without stating the day on which the CRP was measured. One study reported the diagnostic performance of procalcitonin on day 1 (1 day after admission) using a threshold level of 0.5 ng/mL. One study reported the diagnostic performance of CRP on day 3 (3 days after admission) using a threshold level of 140 mg/L and LDH on day 5 (5 days after admission) using a threshold level of 290 U/L. The sensitivities and specificities varied: the point estimate of the sensitivities ranged from 0.72 to 0.88, while the point estimate of the specificities ranged from 0.75 to 1.00 for the different index tests on different days of hospital admission. However, the confidence intervals were wide: confidence intervals of sensitivities ranged from 0.51 to 0.97, while those of specificities ranged from 0.18 to 1.00 for the different tests on different days of hospital admission. Overall, none of the tests assessed in this review were sufficiently accurate to suggest that they could be useful in clinical practice. The paucity of data and methodological deficiencies in the studies meant that it was not possible to arrive at any conclusions regarding the diagnostic test accuracy of the index test because of the uncertainty of the results. Further well-designed diagnostic test accuracy studies with prespecified index test thresholds of CRP, procalcitonin, LDH; appropriate follow-up (for at least two weeks to ensure that the person does not have pancreatic necrosis, as early scans may not indicate pancreatic necrosis); and clearly defined reference standards (of surgical or radiological confirmation of pancreatic necrosis) are important to reliably determine the diagnostic accuracy of CRP, procalcitonin, and LDH.

We performed a thorough literature search for studies reporting the accuracy of CRP, procalcitonin, or LDH in identifying pancreatic necrosis. We included studies reported until 20 March 2017. We identified three studies reporting information on 242 people with pancreatitis. The studies included pancreatitis due to all causes. Variations in when the studies carried out the blood tests and what level was considered abnormal meant that we were unable to combine the data to provide the overall results. It was not possible to arrive at any firm conclusions about how accurate the tests are for the following reasons. • The studies included few participants. As a result, there was significant uncertainty in the results. • The studies were of poor methodological quality, which introduced additional uncertainty in the results. • For the results to be trusted, they must be reproduced in another group of participants. Since this was not done, there was uncertainty in the results. All of the studies were of unclear or low methodological quality, which may result in arriving at false conclusions.

10.1002/14651858.CD012645

cochrane-simplification-train-536

cochrane-simplification-train-536

Six trials (1078 women) were identified for inclusion in this updated review. All six trials provided data on OS (1071 women) and PFS (1027 women). Data on resection rates and pathological response were only available for five trials (908 to 940 women) and data on recurrence were only available for four trials (737 women). Both OS (HR 0.77, 95% confidence interval (CI) 0.62 to 0.96, P = 0.02) and PFS (HR 0.75, 95% CI 0.61 to 0.93, P = 0.008) were significantly improved with neoadjuvant chemotherapy. The estimate for local recurrence was in favour of neoadjuvant chemotherapy (OR 0.67, 95% CI 0.45 to 0.99, P = 0.04), although heterogeneity was observed. The result was no longer significant when the random-effects model was used (OR 0.60, 95% CI 0.32 to 1.12, P = 0.11). Whilst not significant, estimates for distant recurrence (OR 0.72, 95% CI 0.45 to 1.14, P = 0.16) and rates of resection (OR 1.55, 95% CI 0.96 to 2.50, P = 0.07) tended to favour neoadjuvant chemotherapy, although heterogeneity was observed. Exploratory analyses of pathological response showed a significant decrease in adverse pathological findings with neoadjuvant chemotherapy (OR 0.54, 95% CI 0.40 to 0.73, P = < 0.0001 for lymph node status; OR 0.58, 95% CI 0.41 to 0.82, P = 0.002 for parametrial infiltration) which, despite substantial heterogeneity, was still significant when the random-effects model was used. There were also no differences in the effect of neoadjuvant chemotherapy on survival according to total cisplatin dose, chemotherapy cycle length or by cervical cancer stage. Both OS and PFS were improved with neoadjuvant chemotherapy. Although the effects were less clear on all other pre-specified outcomes, they all tended to be in favour of neoadjuvant chemotherapy. Whilst these results appear to indicate that neoadjuvant chemotherapy may offer a benefit over surgery alone for women with early-stage or locally-advanced cervical cancer, the evidence is based on only a small number of trials, and further research may be warranted.

This review found six trials that included 1078 women. Using information from the trials, we found that giving chemotherapy before surgery helped women to live longer and also to live longer without cancer. It was not clear whether chemotherapy made radical surgery easier or helped to stop the cancer from coming back. The type of drugs used, and how they were given, did not affect the results. Also, results were similar in women with both early stage and more advanced stages of disease. In one trial, all of the women also had radiotherapy after surgery (post-operative radiotherapy). In the other trials, up to two thirds of women got this post-operative radiotherapy. We are not sure how this extra treatment affects the results. It may also give women more side-effects. Although neoadjuvant chemotherapy seems to help women with cervical cancer live for longer and also to live for longer without disease, the results are based on only a small number of trials. If new drugs or new combinations of drugs show promising results, it may be worth doing more trials with these new treatments of neoadjuvant chemotherapy before surgery.

10.1002/14651858.CD007406.pub3

cochrane-simplification-train-537

cochrane-simplification-train-537

We included two interrupted time-series studies conducted in the USA. One study was conducted in five large US transportation companies (N = 115,019) that carried passengers and/or cargo. Monthly injury rates were available from 1983 to 1999. In the study company, two interventions of interest were evaluated: mandatory random drug testing and mandatory random and for-cause alcohol testing programmes. The third study focused only on mandatory random drug testing and was conducted on federal injury data that covered all truck drivers of interstate carriers. We recalculated the results from raw data provided by the study authors. Following reanalysis, we found that in one study mandatory random and for-cause alcohol testing was associated with a significant decrease in the level of injuries immediately following the intervention (-1.25 injuries/100 person years, 95% CI -2.29 to -0.21) but did not significantly affect the existing long-term downward trend (-0.28 injuries/100 person years/year, 95% CI -0.78 to 0.21). Mandatory random drug testing was significantly associated with an immediate change in injury level following the intervention (1.26 injuries/100 person years, 95% CI 0.36 to 2.16) in one study, and in the second study there was no significant effect (-1.36/injuries/100 person years, 95% CI -1.69 to 0.41). In the long term, random drug testing was associated with a significant increase in the downward trend (-0.19 injuries/100 person years/year, 95% CI -0.30 to -0.07) in one study, the other study was also associated with a significant improvement in the long-term downward trend (-0.83 fatal accidents/100 million vehicle miles/year, 95% CI -1.08 to -0.58). There is insufficient evidence to advise for or against the use of drug and alcohol testing of occupational drivers for preventing injuries as a sole, effective, long-term solution in the context of workplace culture, peer interaction and other local factors. Cluster-randomised trials are needed to better address the effects of interventions for injury prevention in this occupational setting.

We conducted a systematic search of the literature on the effects of alcohol and drug screening among occupational drivers for preventing injury. We then appraised the quality of the studies found and assessed their results. We found two time-series studies conducted in the USA. One was conducted in five large transportation companies, and it examined the effects of two interventions of interest: implementation of legislation for mandatory random drug testing and mandatory random and for-cause alcohol testing. The other study was conducted using national injury data. There is limited evidence that in the long term mandatory drug-testing interventions can be more effective than no intervention in reducing injuries in occupational drivers. For mandatory alcohol testing there was evidence of an immediate effect only. Given the widespread practice of alcohol and drug testing and the paucity of evaluation studies found, more evaluation studies are needed. Interrupted time-series is a feasible study design for evaluating interventions that aim at preventing alcohol and drug related injuries. However, time-series studies of higher quality and of long duration are needed to increase the level of evidence. A cluster-randomised trial would be the ideal study design to evaluate the effects of interventions for injury prevention in this occupational setting.

10.1002/14651858.CD006566.pub2

cochrane-simplification-train-538

cochrane-simplification-train-538

Three cohort studies were eligible for analysis, including 3380 patients ; 96 children were diagnosed with CSI. One study evaluated the accuracy of the Canadian C-spine Rule and the NEXUS criteria, and two studies evaluated the accuracy of the NEXUS criteria. The studies were of moderate quality. Due to the small number of included studies and the diverse outcomes of those studies, we could not describe a pooled estimate for the diagnostic test accuracy. The sensitivity of the NEXUS criteria of the individual studies was 0.57 (95% confidence interval (CI) 0.18 to 0.90), 0.98 (95% CI 0.91 to 1.00) and 1.00 (95% CI 0.88 to 1.00). The specificity of the NEXUS criteria was 0.35 (95% CI 0.25 to 0.45), 0.54 (95% CI 0.45 to 0.62) and 0.2 (95% CI 0.18 to 0.21). For the Canadian C-spine Rule the sensitivity was 0.86 (95% CI 0.42 to 1.00) and specificity was 0.15 (95% CI 0.08 to 0.23). Since the quantity of the data was small we were not able to investigate heterogeneity. There are currently few studies assessing the diagnostic test accuracy of the NEXUS criteria and CCR in children. At the moment, there is not enough evidence to determine the accuracy of the Canadian C-spine Rule to detect CSI in pediatric trauma patients following blunt trauma. The confidence interval of the sensitivity of the NEXUS criteria between the individual studies showed a wide range, with a lower limit varying from 0.18 to 0.91 with a total of four false negative test results, meaning that if physicians use the NEXUS criteria in children, there is a chance of missing CSI. Since missing CSI could have severe consequences with the risk of significant morbidity, we consider that the NEXUS criteria are at best a guide to clinical assessment, with current evidence not supporting strict or protocolized adoption of the tool into pediatric trauma care. Moreover, we have to keep in mind that the sensitivity differs among several studies, and individual confidence intervals of these studies show a wide range. Our main conclusion is therefore that additional well-designed studies with large sample sizes are required to better evaluate the accuracy of the NEXUS criteria or the Canadian C-spine Rule, or both, in order to determine whether they are appropriate triage tools for the clearance of the cervical spine in children following blunt trauma.

We searched medical literature databases to identify studies which tested how well both decision tools can establish whether children are at risk for CSI after blunt trauma. We performed the search in February 2015. We identified three studies of moderate to good quality. All studies tested the accuracy of the NEXUS criteria, and one of them also tested the accuracy of the Canadian C-spine Rules. Since only one study looked at the accuracy of the Canadian C-spine Rules, there is not enough evidence at the moment to determine whether the Canadian C-spine Rules can be used safely in children. The sensitivity and specificity of the NEXUS criteria varied among the three studies, meaning that there is a chance of false-negative test results when using the NEXUS criteria, and as a result there is a chance of missing cervical spine injury if doctors only rely on the NEXUS criteria. We therefore consider that the NEXUS criteria are at best a guide to clinical assessment, with current evidence not supporting strict or protocolized adoption of the tool into pediatric trauma care. The conclusion of our review is that we need more research to evaluate the accuracy of the NEXUS criteria and the Canadian C-spine rules for routine use in children.

10.1002/14651858.CD011686.pub2

cochrane-simplification-train-539

cochrane-simplification-train-539

We included seven trials, with a total of 5390 women. The quality of studies was mixed. The CS rate was slightly lower in the active management group compared with the group that received routine care, but this difference did not reach statistical significance (RR 0.88, 95% CI 0.77 to 1.01). However, in one study there was a large number of post-randomisation exclusions. On excluding this study, CS rates in the active management group were statistically significantly lower than in the routine care group (RR 0.77 95% CI 0.63 to 0.94). More women in the active management group had labours lasting less than 12 hours, but there was wide variation in length of labour within and between trials. There were no differences between groups in use of analgesia, rates of assisted vaginal deliveries or maternal or neonatal complications. Only one trial examined maternal satisfaction; the majority of women (over 75%) in both groups were very satisfied with care. Active management is associated with small reductions in the CS rate, but it is highly prescriptive and interventional. It is possible that some components of the active management package are more effective than others. Further work is required to determine the acceptability of active management to women in labour.

The review included seven trials involving 5390 women. These studies show that women who received active management were slightly less likely to have a caesarean section and were more likely to have shorter labours (less than 12 hours). There was no difference in the number of assisted deliveries, nor was there any difference in complications for mothers or their babies when comparing women in the active management group with those receiving routine care.

10.1002/14651858.CD004907.pub3

cochrane-simplification-train-540

cochrane-simplification-train-540

We included 18 RCTs, which were reported in 17 publications (one publication reports on two trials) with 4342 participants (of which 212 were children) suffering from the common cold, both naturally occurring and experimentally induced. The interventions consisted of an antihistamine as monotherapy compared with placebo. In adults there was a short-term beneficial effect of antihistamines on severity of overall symptoms: on day one or two of treatment 45% had a beneficial effect with antihistamines versus 38% with placebo (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.60 to 0.92). However, there was no difference between antihistamines and placebo in the mid term (three to four days) to long term (six to 10 days). When evaluating individual symptoms such as nasal congestion, rhinorrhoea and sneezing, there was some beneficial effect of the sedating antihistamines compared to placebo (e.g. rhinorrhoea on day three: mean difference (MD) -0.23, 95% CI -0.39 to -0.06 on a four- or five-point severity scale; sneezing on day three: MD -0.35, 95% CI -0.49 to -0.20 on a four-point severity scale), but this effect is clinically non-significant. Adverse events such as sedation were more commonly reported with sedating antihistamines although the differences were not statistically significant. Only two trials included children and the results were conflicting. The majority of the trials had a low risk of bias although some lacked sufficient trial quality information. Antihistamines have a limited short-term (days one and two of treatment) beneficial effect on severity of overall symptoms but not in the mid to long term. There is no clinically significant effect on nasal obstruction, rhinorrhoea or sneezing. Although side effects are more common with sedating antihistamines, the difference is not statistically significant. There is no evidence of effectiveness of antihistamines in children.

The evidence is current to August 2015. The participants were adults or children with a common cold. We excluded studies with participants suffering from hay fever, asthma or eczema. The effect of different antihistamines was compared to placebo. A beneficial effect meant a decrease in the severity or duration of the general feeling of illness and/or of specific symptoms such as stuffy nose, runny nose or sneezing. We also investigated whether side effects were more common with antihistamines than placebo. As the common cold usually resolves in seven to 10 days, most studies were of short duration. Where possible we studied the immediate effect and the effect after six to 10 days. Most studies were of good quality although in some studies information to allow us to assess quality was lacking. We considered five out of 16 adults studies and one out of two paediatric studies to be of excellent quality. All trials outlined the financial support received from pharmaceutical companies in the form of grants, supplying the respective intervention drug or having an author currently employed by a pharmaceutical company. In adults, there is a short-term beneficial effect on severity of overall symptoms on the first or second day of treatment (45% felt better versus 38% with placebo), but there was no difference between antihistamines and placebo in the mid to long term. The effect of sedating antihistamines on rhinorrhoea and sneezing is too small to be relevant to the patient and involves a risk of side effects such as sedation (9% versus 5.2% with placebo). Trials in children were smaller and of lower quality and lacked evidence of effectiveness.

10.1002/14651858.CD009345.pub2

cochrane-simplification-train-541

cochrane-simplification-train-541

There were 1415 participants in five neoadjuvant studies and 280 participants in four adjuvant studies involving five treatment comparisons. Four of the five neoadjuvant studies collected data for the primary outcome (overall survival) and two studies had data available; one of the four adjuvant studies collected overall survival data. The neoadjuvant studies suggested that the administration of taxanes first probably resulted in little to no difference in overall survival (HR 0.80, 95% CI 0.60 to 1.08; 947 participants; 2 studies; moderate-certainty evidence) and disease-free survival (HR 0.84, 95% CI 0.65 to 1.09; 828 participants; 1 study; moderate-certainty evidence). Administration of taxanes first also resulted in little to no difference in pathological complete response (absence of cancer in the breast and axilla: RR 1.15, 95% CI 0.96 to 1.38; 1280 participants; 4 studies; high-certainty evidence). However, there appeared to be a trend in favour of taxanes first. Studies reported treatment adherence using a range of measures. Administration of taxanes first probably did not increase the likelihood of requiring dose reductions compared to administration of anthracyclines first (RR 0.81, 95% CI 0.59 to 1.11; 280 participants; 1 study; moderate-certainty evidence). There was probably little to no difference in the risk of grade 3/4 neutropenia (RR 1.25, 95% CI 0.86 to 1.82; 280 participants, 1 study; moderate-certainty evidence) or grade 3/4 neurotoxicity (RR 0.95, 95% CI 0.55 to 1.65; 1108 participants; 2 studies; low-certainty evidence) when taxanes were given first. There were no data on quality of life. Only one adjuvant study collected data on overall survival and disease-free survival but did not report data. Administration of taxanes first reduced the risk of grade 3/4 neutropenia (RR 0.62, 95% CI 0.40 to 0.97; 279 participants; 4 studies, 5 treatment comparisons; high-certainty evidence) and appeared to result in little to no difference in grade 3/4 neurotoxicity (RR 0.78, 95% CI 0.25 to 2.46; 162 participants; 3 studies; low-certainty evidence). There was probably little to no difference in the proportions experiencing dose delays when taxanes are given first compared to anthracyclines given first (RR 0.76, 95% CI 0.52 to 1.12; 238 participants; 3 studies, 4 treatment comparisons; moderate-certainty evidence). One study reported on quality of life and indicated that scores (using the Functional Assessment of Cancer Therapy – Breast Cancer (FACT-B) validated questionnaire) were similar in both groups though did not provide numerical data. In the neoadjuvant setting, there is high- to low-certainty evidence of equivalent outcomes for the sequence in which taxanes are delivered. In the adjuvant setting, none of the studies reported on overall survival or disease-free survival. In most institutions, standard practice would be to deliver anthracycline followed by taxane, and currently available data do not support a change in this practice. We wait for the full-text publication of a relevant neoadjuvant study for women with HER2-negative breast cancer for inclusion in an update of this review.

None of the studies reported data on quality of life. Many of the studies did not report information on important outcomes such as how long people will live or remain free of breast cancer. We await the publication of one relevant study involving 112 participants who receive chemotherapy before breast cancer surgery for inclusion in an update of this review. In summary, the results found no sufficient evidence of benefit or harm due to the order in which taxane and anthracycline chemotherapies are given. In most institutions, standard practice would be to deliver anthracycline followed by taxane. Based on this review of the evidence, the currently available data do not support a change in this practice. What was studied in the review? For women with early breast cancer who have a higher risk of cancer returning, combination chemotherapy with anthracycline and taxane is often offered either before or after surgery to reduce the risk of cancer returning and prolong life. Traditionally, anthracyclines are given first followed by taxanes but there is no strong evidence for this order. We compared the possibility of giving taxanes first followed by anthracyclines compared to the standard treatment with anthracycline first. What are the main results of the review? All participants in the studies were women. We found five studies involving 1415 participants in which chemotherapy was given prior to surgery. The taxane medicine used in three of these studies was paclitaxel, while the other two studies used docetaxel. Two studies used a single agent anthracycline (epirubicin), while three studies used a combination of epirubicin, cyclophosphamide and fluorouracil. There were also four studies involving 280 participants that compared the order of giving taxanes and anthracyclines to participants who were receiving chemotherapy after breast cancer surgery. The taxane used in all four studies was docetaxel, while the anthracyclines used were a combination of epirubicin or adriamycin plus either cyclophosphamide or fluorouracil (or both). The main results were that the order in which taxane chemotherapy is given: – probably resulted in little to no difference in survival or risk of cancer coming back for participants who receive chemotherapy before surgery; – probably resulted in little or no difference in the degree by which the tumour may have shrunk in response to chemotherapy for participants who received chemotherapy before surgery; – may have resulted in little or no difference in having side effects for participants receiving chemotherapy before surgery but giving taxanes first reduced the risk of neutropenia (low white blood cell count) in those who received chemotherapy after surgery. The side effects that were examined were neutropenia and neurotoxicity (damage to the nerves); – probably resulted in little to no difference in the proportion of participants receiving chemotherapy after breast cancer surgery experiencing delays in chemotherapy doses. Many studies did not collect or report data on survival, the risk of cancer coming back or overall well-being (quality of life). In some cases, the studies did not report data that could be used in the review and we wait for responses from the investigators who conducted the trials. How up-to-date is this review? The review authors searched for studies that had been published up to February 2018.

10.1002/14651858.CD012873.pub2

cochrane-simplification-train-542

cochrane-simplification-train-542

We included data from 12 randomised trials with data for more than 11,000 women. The trials were carried out in countries across the world, and in both high- and low-resource settings. In low-resource settings women receiving usual care may have received no additional postnatal care after early hospital discharge. The interventions and control conditions varied considerably across studies with trials focusing on three broad types of comparisons: schedules involving more versus fewer postnatal home visits (five studies), schedules involving different models of care (three studies), and home versus hospital clinic postnatal check-ups (four studies). In all but two of the included studies, postnatal care at home was delivered by healthcare professionals. The aim of all interventions was broadly to assess the wellbeing of mothers and babies, and to provide education and support, although some interventions had more specific aims such as to encourage breastfeeding, or to provide practical support. For most of our outcomes only one or two studies provided data, and overall results were inconsistent. There was no evidence that home visits were associated with improvements in maternal and neonatal mortality, and no consistent evidence that more postnatal visits at home were associated with improvements in maternal health. More intensive schedules of home visits did not appear to improve maternal psychological health and results from two studies suggested that women receiving more visits had higher mean depression scores. The reason for this finding was not clear. In a cluster randomised trial comparing usual care with individualised care by midwives extended up to three months after the birth, the proportions of women with Edinburgh postnatal depression scale (EPDS) scores ≥ 13 at four months was reduced in the individualised care group (RR 0.68, 95% CI 0.53 to 0.86). There was some evidence that postnatal care at home may reduce infant health service utilisation in the weeks following the birth, and that more home visits may encourage more women to exclusively breastfeed their babies. There was some evidence that home visits are associated with increased maternal satisfaction with postnatal care. Increasing the number of postnatal home visits may promote infant health and maternal satisfaction and more individualised care may improve outcomes for women, although overall findings in different studies were not consistent. The frequency, timing, duration and intensity of such postnatal care visits should be based upon local and individual needs. Further well designed RCTs evaluating this complex intervention will be required to formulate the optimal package.

We included 12 randomised trials with data for more than 11,000 women. Some trials focused on physical checks of the mother and newborn, while others provided support for breastfeeding, and one included the provision of practical support with housework and childcare. They were carried out in both high-resource countries and low-resource settings where women receiving usual care may not have received additional postnatal care after early hospital discharge. The trials focused on three broad types of comparisons: schedules involving more versus less postnatal home visits (five studies), schedules involving different models of care (three studies), and home versus hospital clinic postnatal check-ups (four studies). In all but two of the included studies postnatal care at home was delivered by healthcare professionals. For most of our outcomes only one or two studies provided data and overall results were inconsistent. There was no evidence that home visits were associated with reduced newborn deaths or serious health problems for the mothers. Women's physical and psychological health were not improved with more intensive schedules of home visits although more individualised care improved women's mental health in one study. Overall, babies were less likely to have emergency medical care if their mothers received more postnatal home visits. More home visits may have encouraged more women to exclusively breastfeed their babies. The different outcomes reported in different studies, how the outcomes were measured, and the considerable variation in the interventions and control conditions across studies were limitations of this review. The studies were of mixed quality as regards risk of bias. More research is needed before any particular schedule of postnatal care can be recommended

10.1002/14651858.CD009326.pub3

cochrane-simplification-train-543

cochrane-simplification-train-543

Nine randomised clinical trials were included in this review. Eight trials compared alpha blockers versus placebo (five trials tested alfuzosin and two trials tested tamsulosin, one trial tested both alfuzosin and tamsulosin, one trial tested silodosin) and one trial compared an alpha blocker (doxazosin) versus no treatment. Trial without catheter was performed after treatment with the drug for one to three days in seven trials and for eight and 32 days in two other trials respectively. There was moderate quality evidence to suggest that the rate of successful trial without catheter favoured alpha blockers over placebo ( 366/608, 60.2%, of men using an alpha blocker were able to void spontaneously after catheter removal compared with 185/486, 38.1%, using placebo, risk ratio (RR) 1.55, 95% confidence interval (CI) 1.36 to 1.76). The incidence of recurrent acute urinary retention was lower in groups treated with an alpha blocker (RR 0.69, 95% CI 0.60 to 0.79). This evidence was of moderate quality and was statistically significant for alfuzosin, tamsulosin and silodosin, though not for doxazosin. Of the trials mentioning adverse effects (for example, postural hypotension, dizziness), there was not enough information to detect statistically significant differences between the groups (RR 1.19, 95% CI 0.75 to 1.89) and the evidence was of low quality. Overall, adverse effect rates were low for both placebo and alpha blockers and, for example, vasodilatation-related adverse effects did not often result in discontinuation. However, the data in this review are limited due to the large amount of unpublished data that was not available to us. There was some evidence to suggest that alpha blockers increase the success rates of trial without catheter, and the incidence of adverse effects was low. There was some evidence of a decreased incidence of acute urinary retention. The need for further surgery, cost effectiveness and recommended duration of alpha blocker treatment after successful trial without catheter remain unknown as these were not reported by any trial. There is a lack of internationally agreed outcome measures for what constitutes successful trial without catheter. This makes meta-analysis difficult. Large, well-designed controlled trials, which use the recommendations set out in the CONSORT statement, and include clinically important outcome measures, are required.

In nine clinical trials men were either given a dummy tablet (placebo, inactive drug), an alpha blocker for one to three days (in one study up to a maximum of eight days and in another for 32 days) or no treatment before the catheter was removed. In ideal circumstances, neither patients nor doctors knew which type of tablet was given, to prevent the bias in reporting the results. The results suggested that alpha blocker treatment increased the chances of successful catheter removal and return to urination although the overall scientific evidence available to support this was limited. Four different alpha blockers were tested (alfuzosin, tamsulosin, doxazosin and silodosin). Their results were similar except for doxazosin which did not seem to make a significant difference. Side effects caused by alpha blockers were few and comparable to placebo or no treatment, though this evidence was limited. They included retrograde ejaculation, dizziness, low blood pressure, fainting, sleepiness, feeling unwell and headache. There was some evidence to say that alpha blockers also reduce the risk of suffering another (recurrent) episode of urinary retention after successful catheter removal, though it remains unclear whether they reduce the need for future surgery on the prostate. It is therefore unclear whether, or for how long, alpha blocker treatment should be continued after successful catheter removal and whether the costs of alpha blocker treatment in such situations are justified. Further research is needed to answer these questions.

10.1002/14651858.CD006744.pub3

cochrane-simplification-train-544

cochrane-simplification-train-544

Three RCTs met our inclusion criteria. The studies enrolled 151 participants with CAP or immunosuppressed patients with pulmonary infiltrates. Overall, we found that non-invasive ventilation can reduce the risk of death in the ICU, odd ratio (OR) 0.28, 95% confidence interval (CI) 0.09 to 0.88; endotracheal intubation, OR 0.26, 95% CI 0.11 to 0.61; complications, OR 0.23, 95% CI 0.08 to 0.70; and shorten ICU length of stay, mean duration (MD) -3.28, 95% CI -5.41 to -1.61. Non-invasive ventilation and standard oxygen supplementation via a Venturi mask were similar when measuring mortality in hospital, OR 0.54, 95% CI 0.11 to 2.68; two-month survival, OR 1.67, 95% CI 0.53 to 5.28; duration of hospital stay, MD -1.00, 95% CI -2.05 to 0.05; and duration of mechanical ventilation, standard MD -0.26, 95% CI -0.66 to 0.14. Some outcomes and complications of non-invasive ventilation were varied according to different participant populations. We also found that some subgroups had a high level of heterogeneity when conducting pooled analyses. Non-invasive ventilation can reduce the risk of death in the ICU, endotracheal intubation, shorten ICU stay and length of intubation. Some outcomes and complications of non-invasive ventilation were varied according to different participant populations. Other than the oxygen therapy, we must mention the importance of standard treatment by physicians. The evidence is weak and we did not include participants with pulmonary tuberculosis and cystic fibrosis. More RCTs are required to answer these clinical questions. However, the review indicates that non-invasive ventilation may be more beneficial than standard oxygen supplementation via a Venturi mask for pneumonia.

We searched the related literature and included three randomised controlled trials involving 151 adults with pneumonia aged around 60 years. We did not include patients with pulmonary tuberculosis or cystic fibrosis. We found that NIV can reduce the risk of death in the intensive care unit (ICU) and the need for endotracheal intubation, shorten ICU stay and length of intubation. Some outcomes and complications of oxygen therapy depended upon the delivery system and primary diseases. The most common complications of invasive ventilation are ventilator-associated pneumonia. However, we must be aware that oxygen therapy is just one of the treatments for pneumonia and the other standard treatments used by physicians are of equal importance. The evidence is weak and it is limited by the small number of studies and the small number of study participants.

10.1002/14651858.CD006607.pub4

cochrane-simplification-train-545

cochrane-simplification-train-545

We included five studies involving 1140 women with asymptomatic bacteriuria. We did not perform meta-analysis; each trial examined different antibiotic regimens and so we were not able to pool results. In a study comparing a single dose of fosfomycin trometamol 3 g with a five-day course of cefuroxime, there was no significant difference in persistent infection (risk ratio (RR) 1.36, 95% confidence interval (CI) 0.24 to 7.75), shift to other antibiotics (RR 0.08, 95% CI 0.00 to 1.45), or in allergy or pruritus (RR 2.73, 95% CI 0.11 to 65.24). A comparison of seven-day courses of 400 mg pivmecillinam versus 500 mg ampicillin, both given four times daily, showed no significant difference in persistent infection at two weeks or recurrent infection, but there was an increase in vomiting (RR 4.57, 95% CI 1.40 to 14.90) and women were more likely to stop treatment early with pivmecillinam (RR 8.82, 95% CI 1.16 to 66.95). When cephalexin 1 g versus Miraxid® (pivmecillinam 200 mg and pivampicillin 250 mg) were given twice-daily for three days, there was no significant difference in persistent or recurrent infection. A one- versus seven-day course of nitrofurantoin resulted in more persistent infection with the shorter course (RR 1.76, 95% CI 1.29 to 2.40), but no significant difference in symptomatic infection at two weeks, nausea, or preterm birth. Comparing cycloserine with sulphadimidine, no significant differences in symptomatic, persistent, or recurrent infections were noted. We cannot draw any definite conclusion on the most effective and safest antibiotic regimen for the initial treatment of asymptomatic bacteriuria in pregnancy. One study showed advantages with a longer course of nitrofurantoin, and another showed better tolerability with ampicillin compared with pivmecillinam; otherwise, there was no significant difference demonstrated between groups treated with different antibiotics. Given this lack of conclusive evidence, it may be useful for clinicians to consider factors such as cost, local availability and side effects in the selection of the best treatment option.

We included five randomized controlled trials involving 1140 women with urine test results showing asymptomatic bacteriuria. Each of the five studies looked at different antibiotics; thus, we have not pooled the results. Four of the comparisons (fosfomycin versus cefuroxime; pivmecillinam versus ampicillin; cephalexin versus Miraxid® (pivmecillinam 200 mg and pivampicillin 250 mg); and cycloserine versus sulphadimidine) showed no definite advantage of one antibiotic over another for treating infection, side effects, or safety. Ampicillin compared with pivmecillinam resulted in less vomiting and was thus better tolerated by the women in one study. There was however no difference in curing present infection and preventing recurring infection in women who took ampicillin compared with those who took pivmecillinam. In another study comparing a one-day versus a seven-day course of nitrofurantoin, the longer course was better in treating bacteria in urine during pregnancy. Women receiving the shorter course had more persistent infection but no clear difference in symptomatic infection at two weeks, nausea or preterm birth.

10.1002/14651858.CD007855.pub2

cochrane-simplification-train-546

cochrane-simplification-train-546

Twenty-two trials with a total of 3529 patients are included (14 in the original review and a further eight in this update). For the majority of comparisons, only one trial was available so results were rarely combined in meta-analyses. Individual trials were generally small and risk of bias was often unclear due to limitations in reporting. Three trials reported on drug versus placebo/control; results were consistently available for a maximum follow-up of only six months. At six months post intervention, a statistically significant reduction in reocclusion was found for high-dose acetylsalicylic acid (ASA) combined with dipyridamole (DIP) (OR 0.40, 95% CI 0.19 to 0.84), but not for low-dose ASA combined with DIP (OR 0.69, 95% CI 0.44 to 1.10; P = 0.12) nor in major amputations for lipo-ecraprost (OR 0.89, 95% CI 0.44 to 1.80). The remaining trials compared different drugs; results were more consistently available for a longer period of 12 months. At 12 months post intervention, no statistically significant difference in reocclusion/restenosis was detected for any of the following comparisons: high-dose ASA versus low-dose ASA (OR 0.98, 95% CI 0.64 to 1.48; P = 0.91), ASA/DIP versus vitamin K antagonists (VKA) (OR 0.65, 95% CI 0.40 to 1.06; P = 0.08), clopidogrel and aspirin versus low molecular weight heparin (LMWH) plus warfarin (OR 0.31, 95% CI 0.06 to 1.68; P = 0.18), suloctidil versus VKA: reocclusion (OR 0.59, 95% CI 0.20 to 1.76; P = 0.34), restenosis (OR 1.87, 95% CI 0.66 to 5.31; P = 0.24) and ticlopidine versus VKA (OR 0.71, 95% CI 0.37 to 1.36; P = 0.30). Treatment with cilostazol resulted in statistically significantly fewer reocclusions than ticlopidine (OR 0.32, 95% CI 0.13 to 0.76; P = 0.01). Compared with aspirin alone, LMWH plus aspirin significantly decreased occlusion/restenosis (by up to 85%) in patients with critical limb ischaemia (OR 0.15, 95% CI 0.06 to 0.42; P = 0.0003) but not in patients with intermittent claudication (OR 1.73, 95% CI 0.97 to 3.08; P = 0.06) and batroxobin plus aspirin reduced restenosis in diabetic patients (OR 0.28, 95% CI 0.13 to 0.60). Data on bleeding and other potential gastrointestinal side effects were not consistently reported, although there was some evidence that high-dose ASA increased gastrointestinal side effects compared with low-dose ASA, that clopidogrel and aspirin resulted in fewer major bleeding episodes compared with LMWH plus warfarin, and that abciximab resulted in more severe bleeding episodes. There is limited evidence suggesting that restenosis/reocclusion at six months following peripheral endovascular treatment is reduced by use of antiplatelet drugs compared with placebo/control, but associated information on bleeding and gastrointestinal side effects is lacking. There is also some evidence of variation in effect according to different drugs with cilostazol reducing reocclusion/restenosis at 12 months compared with ticlopidine and both LMWH and batroxobin combined with aspirin appearing beneficial compared with aspirin alone. However, available trials are generally small and of variable quality and side effects of drugs are not consistently addressed. Further good quality, large-scale RCTs, stratified by severity of disease, are required.

This review of 22 randomised clinical trials, with a combined total of 3529 patients, set out to determine if any drug was more effective than another in preventing occlusion or restenosis of the artery after the blood vessels have been surgically widened. For the majority of comparisons, only one study was available. Evidence suggests that some drugs which reduce platelet aggregation, such as higher-dose aspirin, can reduce the rate of reocclusion six months after surgery, but evidence on associated side effects and for longer-term restenosis rates is scarce. There is also some evidence of variation in effect according to different drugs, with reocclusion/restenosis rates lower in people taking cilostazol compared with ticlopidine 12 months after surgery and, in patients with more severe disease, those taking low molecular weight heparin in addition to aspirin compared with aspirin alone. Batroxobin plus aspirin compared with aspirin alone may be an effective treatment in diabetic patients. However, available trials are generally small and of variable quality and side effects of drugs are not consistently addressed. Further good quality, large-scale randomised controlled trials, grouped by severity of disease, are required.

10.1002/14651858.CD002071.pub3

cochrane-simplification-train-547

cochrane-simplification-train-547

No new trials were found for inclusion in this update. We included 24 studies; 19 including 2531 randomised participants and five including 4354 cluster-randomised participants. There were no cases of meningococcal disease during follow-up in the trials, thus effectiveness regarding prevention of future disease cannot be directly assessed. Mortality that was reported in one study was not related to meningococcal disease or treatment. Ciprofloxacin (RR 0.04; 95% CI 0.01 to 0.12), rifampin (rifampicin) (RR 0.17; 95% CI 0.13 to 0.24), minocycline (RR 0.28; 95% CI 0.21 to 0.37) and penicillin (RR 0.47; 95% CI 0.24 to 0.94) proved effective at eradicating N meningitidis one week after treatment when compared with placebo. Rifampin (RR 0.20; 95% CI 0.14 to 0.29), ciprofloxacin (RR 0.03; 95% CI 0.00 to 0.42) and penicillin (RR 0.63; 95% CI 0.51 to 0.79) still proved effective at one to two weeks. Rifampin was effective compared to placebo up to four weeks after treatment but resistant isolates were seen following prophylactic treatment. No trials evaluated ceftriaxone against placebo but rifampin was less effective than ceftriaxone after one to two weeks of follow-up (RR 5.93; 95% CI 1.22 to 28.68). Mild adverse events associated with treatment were observed. Using rifampin during an outbreak may lead to the circulation of resistant isolates. Use of ciprofloxacin, ceftriaxone or penicillin should be considered. All four agents were effective for up to two weeks follow-up, though more trials comparing the effectiveness of these agents for eradicating N. meningitidis would provide important insights.

Data from 24 studies, most of high quality, including 6885 participants found that rifampin (also known as rifampicin), ciprofloxacin, ceftriaxone and penicillin are effective agents for eradicating carriage of N meningitidis. However, the use of rifampin may have a disadvantage as development of resistance to the antibiotic has been noted following treatment. Mild adverse events are associated with the different antibiotics used. Disease prevention could not be evaluated directly in this review as only data for eradication of the bacteria were available. Different follow-up periods were reported in the studies. Evidence in this review is current as of June 2013.

10.1002/14651858.CD004785.pub5

cochrane-simplification-train-548

cochrane-simplification-train-548

One study (4155 women at less than 20 weeks' gestation) met the inclusion criteria. The intervention group (2058 women) received infection screening and treatment for bacterial vaginosis, trichomonas vaginalis and candidiasis; the control group (2097 women) also received screening, but the results of the screening program were not revealed and women received routine antenatal care. The rate of preterm birth before 37 weeks' gestation was significantly lower in the intervention group (3% versus 5% in the control group) with a risk ratio (RR) of 0.55 (95% confidence interval (CI) 0.41 to 0.75; the evidence for this outcome was graded as of moderate quality). The incidence of preterm birth for infants with a weight equal to or below 2500 g (low birthweight) and infants with a weight equal to or below 1500 g (very low birthweight) were significantly lower in the intervention group than in the control group (RR 0.48, 95% CI 0.34 to 0.66 and RR 0.34; 95% CI 0.15 to 0.75, respectively; both graded as moderate quality evidence). Based on a subset of costs for preterm births of < 1900 g, the authors reported that for each of those preterm births averted, EUR 60,262 would be saved. There is evidence from one trial that infection screening and treatment programs for pregnant women before 20 weeks' gestation reduce preterm birth and preterm low birthweight. Infection screening and treatment programs are associated with cost savings when used for the prevention of preterm birth. Future trials should evaluate the effects of different types of infection screening programs.

In this review, only one study of moderate quality evidence was included. The study reported on 4155 women randomly assigned either to an intervention group (2058 women received infection screening and treatment for bacterial vaginosis, trichomonas vaginalis and candidiasis) or a control group (2097 women received screening, but the results of the screening program were not revealed). The present systematic review found that a simple infection screening and treatment program during routine antenatal care may reduce preterm births and preterm low (below 2500 g) and very low (below 1500 g) birthweight. The simple infection screening reduced preterm births from 5% of women in the control group to 3% in the intervention group. The number of low birthweight preterm infants and very low birthweight preterm infants were significantly lower in the intervention group than in the control group. Moreover, an infection screening and treatment program during routine antenatal care is likely to save over EUR 60,000 for each preterm birth averted.

10.1002/14651858.CD006178.pub3

cochrane-simplification-train-549

cochrane-simplification-train-549

We found no randomised controlled trials for inclusion in this review. As we did not identify any randomised controlled trials for inclusion in this review, we are unable to comment on implications for practice. Although evidence from animal studies has supported a fetal neuroprotective role for creatine when administered to the mother during pregnancy, no trials assessing creatine in pregnant women for fetal neuroprotection have been published to date. If creatine is established as safe for the mother and her fetus, research efforts should first be directed towards randomised trials comparing creatine with either no intervention (ideally using a placebo), or with alternative agents aimed at providing fetal neuroprotection (including magnesium sulphate for the very preterm infant). If appropriate, these trials should then be followed by studies comparing different creatine regimens (dosage and duration of exposure). Such trials should be high quality and adequately powered to evaluate maternal and infant short and longer-term outcomes (including neurodevelopmental disabilities such as cerebral palsy), and should consider utilisation/costs of health care.

We found no completed (or ongoing) randomised controlled trials that assessed whether creatine given to the mother at times of known, suspected, or potential fetal compromise during pregnancy helps to protect the baby's brain. Randomised controlled trials are needed to establish whether creatine can protect against brain injury for the baby in the womb. The babies in these trials need to be followed up over a long period so that we can monitor the effects of creatine on their development into childhood and adulthood.

10.1002/14651858.CD010846.pub2

cochrane-simplification-train-550

cochrane-simplification-train-550

Fourteen trials were identified, of which 10 trials (792 patients) were included. Four trials are awaiting assessment. In the 10 included trials follow up was performed at 14 to 35 days after stroke. In all studies neurological outcome was assessed but none of them reported on disability (activities of daily living function) or quality of life. Only three trials reported adverse events. In nine trials, all of them assessed to be of inferior quality, significant improvement in neurological deficit at the end of the treatment was used as the outcome measure. When analysing these trials together, Ginkgo biloba extract was associated with a significant increase in the number of improved patients (Peto odds ratio (OR) 2.66; 95% confidence interval (CI) 1.79 to 3.94). One placebo-controlled trial, assessed to be of good quality, reported neurological outcome as a continuous variable. It failed to show an improvement of neurological deficit at the end of treatment (weighted mean difference (fixed) 0.81; 95% CI -8.9 to 10.52). No deaths or major adverse events were reported during the follow-up period. There was no convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High-quality and large-scale randomised controlled trials are needed to test its efficacy.

This review identified all randomised or quasi-randomised trials of Ginkgo biloba extract in patients with acute ischaemic stroke. There was no convincing evidence, from trials of sufficient methodological quality, to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High-quality and large-scale randomised controlled trials are needed to test its efficacy.

10.1002/14651858.CD003691.pub2

cochrane-simplification-train-551

cochrane-simplification-train-551

We identified 11 trials (800 participants) and two ongoing studies. Style and duration of yoga differed between trials. Half of the participants recruited to the studies were at high risk of CVD. Most of studies were at risk of performance bias, with inadequate details reported in many of them to judge the risk of selection bias. No study reported cardiovascular mortality, all-cause mortality or non-fatal events, and most studies were small and short-term. There was substantial heterogeneity between studies making it impossible to combine studies statistically for systolic blood pressure and total cholesterol. Yoga was found to produce reductions in diastolic blood pressure (mean difference (MD) -2.90 mmHg, 95% confidence interval (CI) -4.52 to -1.28), which was stable on sensitivity analysis, triglycerides (MD -0.27 mmol/l, 95% CI -0.44 to -0.11) and high-density lipoprotein (HDL) cholesterol (MD 0.08 mmol/l, 95% CI 0.02 to 0.14). However, the contributing studies were small, short-term and at unclear or high risk of bias. There was no clear evidence of a difference between groups for low-density lipoprotein (LDL) cholesterol (MD -0.09 mmol/l, 95% CI -0.48 to 0.30), although there was moderate statistical heterogeneity. Adverse events, occurrence of type 2 diabetes and costs were not reported in any of the included studies. Quality of life was measured in three trials but the results were inconclusive. The limited evidence comes from small, short-term, low-quality studies. There is some evidence that yoga has favourable effects on diastolic blood pressure, HDL cholesterol and triglycerides, and uncertain effects on LDL cholesterol. These results should be considered as exploratory and interpreted with caution.

We searched scientific databases for randomised controlled trials (clinical trials where people are allocated at random to one of two or more treatments) looking at the effects of yoga on adults at high risk of developing CVD. We did not included people who had already had CVD (e.g. heart attacks and strokes). The evidence is current to December 2013. We found 11 trials (800 participants), none of them were large enough or of long enough duration to examine the effects of yoga on decreasing death or non-fatal endpoints.There were variations in the style and duration of yoga and the follow-up of the interventions ranged from three to eight months.The results showed that yoga has favourable effects on diastolic blood pressure, high-density lipoprotein (HDL) cholesterol and triglycerides (a blood lipid), and uncertain effects on low-density lipoprotein (LDL) cholesterol. None of the included trials reported adverse events, the occurrence of type 2 diabetes or costs. Longer-term, high-quality trials are needed in order to determine the effectiveness of yoga for CVD prevention. These results should be considered as exploratory and interpreted with caution. This is because the included studies were of short duration, small and at risk of bias (where there was a risk of arriving at the wrong conclusions because of favouritism by the participants or researchers).

10.1002/14651858.CD010072.pub2

cochrane-simplification-train-552

cochrane-simplification-train-552

We included 18 studies, although we were only able to extract participant data from 14 studies that included a total of 511 participants; 419 participants were managed by intralesional treatment and 92 underwent a wide resection. We were not able to extract participant data from four studies, including 270 participants, and so we included them as a narrative summary only. The evidence was at high risk of performance, detection and reporting bias. Meta-analysis of data from 238 participants across seven studies demonstrated little or no difference in recurrence-free survival after intralesional treatment versus wide resection for central LGCS in the long bones (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.92 to 1.04; very low-certainty evidence). MSTS scores were probably better after intralesional surgery (mean score 93%) versus resection (mean score 78%) with a mean difference of 12.69 (95% CI 2.82 to 22.55; P value < 0.001; 3 studies; 72 participants; low-certainty evidence). Major complications across six studies (203 participants) were lower in cases treated by intralesional treatment (5/125 cases) compared to those treated by wide resection (18/78 cases), with RR 0.23 (95% CI 0.10 to 0.55; low-certainty evidence). In four people (0.5% of total participants) a high-grade (grade 2 or dedifferentiated) tumour was found after a local recurrence. Two participants were treated with second surgery with no evidence of disease at their final follow-up and two participants (0.26% of total participants) died due to disease. Kaplan-Meier analysis of data from 115 individual participants across four studies demonstrated 96% recurrence-free survival after a maximum follow-up of 300 months after resection versus 94% recurrence-free survival after a maximum follow-up of 251 months after intralesional treatment (P value = 0.58; very low-certainty evidence). Local recurrence or metastases were not reported after 41 months in either treatment group. Only evidence of low- and very low-certainty was available for this review according to the GRADE system. Included studies were all retrospective in nature and at high risk of selection and attrition bias. Therefore, we could not determine whether wide resection is superior to intralesional treatment in terms of event-free survival and recurrence rates. However, functional outcome and complication rates are probably better after intralesional surgery compared to wide resection, although this is low-certainty evidence, considering the large effect size. Nevertheless, recurrence-free survival was excellent in both groups and a prospective RCT comparing intralesional treatment versus wide resection may be challenging for both practical and ethical reasons. Future research could instead focus on less invasive treatment strategies for these tumours by identifying predictors that help to stratify participants for surgical intervention or close observation.

We identified 14 studies that were suitable for analysis with a total of 511 participants; 92 were treated by wide resection compared to 419 by intralesional treatment. Age of the participants varied from 13 to 82 years with a mean age of 48 years. Women outnumbered men in the studies by just over one and a half times, which reflects that LGCS are more common in women. People were followed-up for between 24 to 300 months after surgery. In addition, there were four studies including 270 participants, from which we could not extract the exact data, but were used to confirm the statistical analysis. We found that there was little or no difference in rates of local recurrence between treatment types. In 94% to 96% of the cases, the tumour was successfully removed after a single operation. In the few cases where disease recurred, a second operation was needed. People with LGCS probably have better functionality after less aggressive intralesional treatment, and complication rates were probably lower compare to wide surgical resection. Less than 0.3% of all people with LGCS died due to their disease, irrespective of the surgical technique. Overall certainty of the studies was very low, as all studies only described the results of the treatment in hindsight and none of the studies randomly selected patients between treatment groups.

10.1002/14651858.CD010778.pub2

cochrane-simplification-train-553

cochrane-simplification-train-553

In this update we identified 14 additional trials resulting in the inclusion of 18 small trials in 813 patients. Eleven trials used TENS, four interferential current stimulation, one both TENS and interferential current stimulation, and two pulsed electrostimulation. The methodological quality and the quality of reporting was poor and a high degree of heterogeneity among the trials (I2 = 80%) was revealed. The funnel plot for pain was asymmetrical (P < 0.001). The predicted SMD of pain intensity in trials as large as the largest trial was -0.07 (95% CI -0.46 to 0.32), corresponding to a difference in pain scores between electrostimulation and control of 0.2 cm on a 10 cm visual analogue scale. There was little evidence that SMDs differed on the type of electrostimulation (P = 0.94). The relative risk of being withdrawn or dropping out due to adverse events was 0.97 (95% CI 0.2 to 6.0). In this update, we could not confirm that transcutaneous electrostimulation is effective for pain relief. The current systematic review is inconclusive, hampered by the inclusion of only small trials of questionable quality. Appropriately designed trials of adequate power are warranted.

- There was no difference in the number of people who dropped out of the trial because of side effects (difference of 0%). This could be the result of chance. Side effects - 15 people out of 100 who used electrostimulation experienced side effects (15%). - 15 people out of 100 who used a fake electrostimulation machine or just took their usual treatments experienced side effects (15%). - There was no difference in the number of people who experience side effects (difference of 0%). This could be the result of chance.

10.1002/14651858.CD002823.pub2

cochrane-simplification-train-554

cochrane-simplification-train-554

We included 13 studies enrolling a total of 468 participants. We identified two ongoing studies. All studies included adults, and two studies included both teenagers and adults. The 13 studies took place in high altitude areas, mostly in the European Alps. Twelve studies included participants with acute mountain sickness, and one study included participants with high altitude pulmonary oedema. Follow-up was usually less than one day. We downgraded the quality of the evidence in most cases due to risk of bias and imprecision. We report results for the main comparisons as follows. Non-pharmacological interventions (3 studies, 124 participants) All-cause mortality and complete relief of AMS symptoms were not reported in the three included trials. One study in 64 participants found that a simulated descent of 193 millibars versus 20 millibars may reduce the average of symptoms to 2.5 vs 3.1 units after 12 hours of treatment (clinical score ranged from 0 to 11 ‒ worse; reduction of 0.6 points on average with the intervention; low quality of evidence). In addition, no complications were found with use of hyperbaric chambers versus supplementary oxygen (one study; 29 participants; low-quality evidence). Pharmacological interventions (11 trials, 375 participants) All-cause mortality was not reported in the 11 included trials. One trial found a greater proportion of participants with complete relief of AMS symptoms after 12 and 16 hours when dexamethasone was administered in comparison with placebo (47.1% versus 0%, respectively; one study; 35 participants; low quality of evidence). Likewise, when acetazolamide was compared with placebo, the effects on symptom severity was uncertain (standardized mean difference (SMD) −1.15, 95% CI −2.56 to 0.27; 2 studies, 25 participants; low-quality evidence). One trial of dexamethasone in comparison with placebo in 35 participants found a reduction in symptom severity (difference on change in the AMS score: 3.7 units reported by authors; moderate quality of evidence). The effects from two additional trials comparing gabapentin with placebo and magnesium with placebo on symptom severity at the end of treatment were uncertain. For gabapentin versus placebo: mean visual analogue scale (VAS) score of 2.92 versus 4.75, respectively; 24 participants; low quality of evidence. For magnesium versus placebo: mean scores of 9 and 10.3 units, respectively; 25 participants; low quality of evidence). The trials did not find adverse events from either treatment (low quality of evidence). One trial comparing magnesium sulphate versus placebo found that flushing was a frequent event in the magnesium sulphate arm (percentage of flushing: 75% versus 7.7%, respectively; one study; 25 participants; low quality of evidence). There is limited available evidence to determine the effects of non-pharmacological and pharmacological interventions in treating acute high altitude illness. Low-quality evidence suggests that dexamethasone and acetazolamide might reduce AMS score compared to placebo. However, the clinical benefits and harms related to these potential interventions remain unclear. Overall, the evidence is of limited practical significance in the clinical field. High-quality research in this field is needed, since most trials were poorly conducted and reported.

We included 13 studies with a total of 468 participants. Most studies included participants with mild or moderate forms of mountain sickness, and only one study included the severe neurological (disorder of the nervous system) form. Follow-up was usually less than one day. We also identified two ongoing studies. We found studies evaluating the following interventions: simulated descent with a hyperbaric chamber (medical use of oxygen in a special chamber at greater than atmospheric pressure to increase the availability of oxygen in the body); oxygen; medicines: acetazolamide, dexamethasone, ibuprofen, paracetamol, gabapentin, sumatriptan, nitric oxide, and magnesium sulphate. None of the studies reported the effects of these interventions on all-cause mortality. The report of complete relief from acute mountain sickness symptoms, and adverse events was infrequent. Studies related to simulated descent with the use of a hyperbaric chamber did not find additional benefits or harms related to this intervention (3 studies, 124 participants). In addition, studies related to administration of medicines found some benefits in terms of reduction of symptoms with the use of acetazolamide (2 studies, 25 participants), and dexamethasone (1 study, 35 participants), without an increase in side effects. The quality of the evidence we found was low, and thus our certainty in the findings is limited. There was insufficient information on how the studies were conducted, and in some cases there was evidence of tampering at some stages of the trials. Furthermore, the number of persons in each study was very small (< 30 participants), and therefore the results were not clear (imprecise). Some studies were not blinded (that is, participants knew what experimental treatment they were receiving), and this could have affected how the participants evaluated their own symptoms.

10.1002/14651858.CD009567.pub2

cochrane-simplification-train-555

cochrane-simplification-train-555

A total of 54 randomised controlled trials (n = 5122) were included. No strong evidence was found to indicate that fluvoxamine was either superior or inferior to other antidepressants regarding response, remission and tolerability. However, differing side effect profiles were evident, especially with regard to gastrointestinal side effects of fluvoxamine when compared to other antidepressants. For example, fluvoxamine was generally associated with a higher incidence of vomiting/nausea (versus imipramine, OR 2.23, CI 1.59 to 3.14; versus clomipramine, OR 2.13, CI 1.06 to 4.27; versus amitriptyline, OR 2.86, CI 1.31 to 2.63). We found no strong evidence that fluvoxamine was either superior or inferior to any other antidepressants in terms of efficacy and tolerability in the acute phase treatment of depression. However, differing side effect profiles were evident. Based on these findings, we conclude that clinicians should focus on practical or clinically relevant considerations, including these differences in side effect profiles.

This review reports trials comparing fluvoxamine with other antidepressants for treatment of major depression. We found no strong evidence that fluvoxamine was either superior or inferior to any other antidepressants in terms of efficacy and tolerability in the acute phase treatment of depression. However, there is evidence of differing side-effect profiles, especially when comparing gastrointestinal side effects between fluvoxamine and tricyclic antidepressants (TCAs). Based on these findings, we conclude that clinicians should focus on practical or clinically relevant considerations including these differences in side effect profiles.

10.1002/14651858.CD006114.pub2

cochrane-simplification-train-556

cochrane-simplification-train-556

We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy was associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but did not significantly improve overall survival (OS). The median progression-free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P < 0.0001; 311 participants; 1 trial; low-quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P = 0.872; 311 participants; 1 trial; low-quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P = 0.0329, respectively). Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who underwent early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remained unclear whether there were differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated.

From the literature search in September 2014, we included one randomised controlled trial, involving 311 participants, that looked at early or delayed radiotherapy given at the time of disease progression in people with LGG. This study was well-designed and reported useful data on survival, but did not include other clinically important information, such as functional independent survival (functional, or neurological impairment, or both) and quality of life. Therefore, we felt that the trial was of unclear quality. People who received early (soon after surgery) radiotherapy had a longer time until their disease progressed than people who only had radiotherapy once the disease had progressed. However, the people that were initially observed had similar survival to the people who had early radiotherapy. Quality of life measures such as memory, executive function, and cognitive deterioration differences were not evaluated in either group. The findings did not suggest that people who received early radiotherapy lived longer than those had delayed radiotherapy. However, people who had early radiotherapy had better control over their seizures than those who had delayed radiotherapy. The toxic effects of radiotherapy were rated as minimal in both groups using a grading system which measured severity and included skin reactions, ear inflammation, mild headache, nausea, and vomiting. Update searches in November 2019 found no new articles which met the inclusion criteria. No articles were considered eligible for inclusion in this review update. Based on the current evidence, the results should be interpreted with caution. It is unclear whether or not early radiotherapy is better than delayed radiotherapy because survival was the same in both groups. People who had early radiotherapy experienced longer periods of tumour remission compared with patients who had delayed radiotherapy. However, it is unclear if these people suffered increased rates of cognitive impairment, neuroendocrine dysfunction, or radiation necrosis compared with people who had delayed radiotherapy. Toxic effects of radiation were minimal in both groups and there were no cases of second malignancies.

10.1002/14651858.CD009229.pub3

cochrane-simplification-train-557

cochrane-simplification-train-557

A total of 26 trials involving 2997 people were included, with a follow-up ranging from 3 to 24 months. Studies were conducted in 11 different countries. The mean age of the included participants was 68 years, 68% were male and the mean forced expiratory volume in one second (FEV1)% predicted value was 44.3% (range 28% to 66%). Participants were treated in all types of healthcare settings: primary (n = 8), secondary (n = 12), tertiary care (n = 1), and in both primary and secondary care (n = 5). Overall, the studies were of high to moderate methodological quality. Compared with controls, IDM showed a statistically and clinically significant improvement in disease-specific QoL on all domains of the Chronic Respiratory Questionnaire after 12 months: dyspnea (mean difference (MD) 1.02; 95% confidence interval (CI) 0.67 to 1.36); fatigue (MD 0.82; 95% CI 0.46 to 1.17); emotional (MD 0.61; 95% CI 0.26 to 0.95) and mastery (MD 0.75; 95% CI 0.38 to 1.12). The St. George's Respiratory Questionnaire (SGRQ) for QoL reached the clinically relevant difference of four units only for the impact domain (MD -4.04; 95% CI -5.96 to -2.11, P < 0.0001). IDM showed a significantly improved disease-specific QoL on the activity domain of the SGRQ: MD -2.70 (95% CI -4.84 to -0.55, P = 0.01). There was no significant difference on the symptom domain of the SGRQ: MD -2.39 (95% CI -5.31 to 0.53, P = 0.11). According to the GRADE approach, quality of evidence on the SGRQ was scored as high quality, and on the CRQ as moderate quality evidence. Participants treated with an IDM program had a clinically relevant improvement in six-minute walking distance of 43.86 meters compared with controls after 12 months (95% CI 21.83 to 65.89; P < 0.001, moderate quality). There was a reduction in the number of participants with one or more hospital admissions over three to 12 months from 27 per 100 participants in the control group to 20 (95% CI 15 to 27) per 100 participants in the IDM group (OR 0.68; 95% CI 0.47 to 0.99, P = 0.04; number needed to treat = 15). Hospitalization days were significantly lower in the IDM group compared with controls after 12 months (MD -3.78 days; 95% CI -5.90 to -1.67, P < 0.001). Admissions and hospital days were graded as high quality evidence. No adverse effects were reported in the intervention group. No difference between groups was found on mortality (OR 0.96; 95%CI 0.52 to 1.74). There was insufficient evidence to refute or confirm the long term effectiveness of IDM. In these COPD participants, IDM not only improved disease-specific QoL and exercise capacity, but also reduced hospital admissions and hospital days per person.

We evaluated 26 studies in 2997 people with COPD. Overall the evidence found was of high to moderate quality. The trials were conducted in 11 different countries. The average age of participants was 68 years, 68% of participants were men and the severity of COPD on average was severe (according to lung function measures). Some of the trials took place in GP clinics and some in hospitals. Overall, the studies were of good to moderate methodological quality. People who participated in an IDM program had better quality of life and improved their exercise tolerance after 12 months. Furthermore, in participants treated with such a program, the number of hospital admissions related to exacerbations decreased and the total number of hospital days was reduced by three days. We found no evidence of an effect on mortality. The results support an IDM program for people with COPD to optimize quality of life and exercise tolerance. This plain language summary is up-to-date as of April 2012.

10.1002/14651858.CD009437.pub2

cochrane-simplification-train-558

cochrane-simplification-train-558

Analyses were based on 491 patients from six trials, representing 90% of all patients randomised in cisplatin-based combination chemotherapy trials and 66% of patients from all eligible trials. The power of this meta-analysis is clearly limited. The overall hazard ratio for survival of 0.75 (95% CI 0.60 to 0.96, P = 0.019) suggests a 25% relative reduction in the risk of death for chemotherapy compared to that on control. Cox regression suggests that small imbalances in patient characteristics do not bias the results in favour of chemotherapy. However, the impact of trials that stopped early, of patients not receiving allocated treatments or not receiving salvage chemotherapy is less clear. This IPD meta-analysis provides the best evidence currently available on the role of adjuvant chemotherapy for invasive bladder cancer. However, at present there is insufficient evidence on which to reliably base treatment decisions. These results highlight the urgent need for further research into the use of adjuvant chemotherapy. The results of appropriately sized randomised trials, such as the ongoing EORTC-30994 trial are needed before any definitive conclusions can be drawn.

This review suggested that 54 out of every 100 patients who had chemotherapy after surgery were alive after three years, compared to 45 out of every 100 patients who received only surgery. Although these results are encouraging, there are not enough trials or patients for these results to be completely reliable. More randomised trials are needed. This review should encourage greater participation in ongoing randomised trials.

10.1002/14651858.CD006018

cochrane-simplification-train-559

cochrane-simplification-train-559

We included one trial of 526 women with a twin pregnancy of two viable twins, with no known morphological abnormality, in this review. The trial compared women receiving fetal growth and Doppler ultrasounds at 25, 30 and 35 weeks' gestation to fetal growth alone. We judged the included study to be at low risk of bias however the risk of performance and detection bias were unclear. The primary outcome was the perinatal mortality rate (after randomisation), for which there was no evidence of a clear difference between the fetal growth + Doppler and the fetal growth alone groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.32 to 2.41, low-quality evidence) with similar rates in both groups (seven events in the Dopper + fetal growth group and eight in the fetal growth alone group). No clear differences were seen between the two regimens for the other outcomes in this review: stillbirth (RR 0.67, 95% CI 0.11 to 3.99), neonatal death (RR 1.01, 95% CI 0.29 to 3.46, low-quality evidence), gestational age at birth (weeks) (mean difference 0.10, 95% CI -0.39 to 0.59, moderate-quality evidence), infant requiring ventilation (RR 0.86, 95% CI 0.59 to 1.25), admission to special care or intensive care units (RR 0.96, 95% CI 0.88 to 1.05), caesarean section (any) (RR 1.00, 95% CI 0.81 to 1.23, high-quality evidence), elective caesarean section (RR 1.06, 95% CI 0.77 to 1.47), emergency caesarean section (RR 0.93, 95% CI 0.66 to 1.32), induction of labour (RR 1.10, 95% CI 0.80 to 1.50, moderate-quality evidence) or antenatal hospital admission (RR 0.96, 95% CI 0.80 to 1.15, high-quality evidence). The number of preterm births before 28 weeks' gestation was not reported in the included study. For the mortality-related outcomes, event numbers were small. The included study did not report the majority of our maternal and infant secondary outcomes. Infant outcomes not reported included fetal acidosis, Apgar scores less than 7 at five minutes and preterm birth before 37 and 34 weeks' gestation. The maternal outcomes; length of antenatal hospital stay, timely diagnosis of significant complications, rate of preterm, prelabour rupture of membranes and women's level of satisfaction with their care were not reported. The study did not classify twin pregnancies according to their chorionicity. An awareness of the chorionicity may have improved applicability of this data set. We downgraded outcomes assessed using GRADE for imprecision of effect estimates. This review is based on one small study which was underpowered for detection of rare outcomes such as perinatal mortality, stillbirth and neonatal death. There is insufficient evidence from randomised controlled trials to inform best practice for fetal ultrasound surveillance regimens when caring for women with a twin pregnancy. More studies are needed to evaluate the effects of currently used ultrasound surveillance regimens in twin pregnancies. Future research could report on the important maternal and infant outcomes as listed in this review.

We searched for evidence from randomised controlled trials in August 2017. We found one multicentre study that was at low risk of bias. The study involved 526 women with healthy twin pregnancies that appeared to be normally formed on ultrasound. The women were randomised to have scans to measure either just the growth of the babies or both growth and blood flow to the babies, at 25, 30 and 35 weeks of pregnancy. Findings were similar with the different tests. The study found that having scans to measure growth alone or growth with blood flow made no clear difference to the number of babies that died in the third trimester, at birth, or in the 28 days following birth. There were also no clear differences in the number of babies who were admitted to special care units or needed help breathing (ventilation). We found no difference in numbers of women who had an elective or emergency caesarean section or who were admitted to hospital during their pregnancy (both high-quality evidence). Having different types of scans made no difference to whether women gave birth early or had to have their labour induced (moderate-quality evidence). No information was available on the diagnosis of significant complications during the pregnancy, early preterm births before 28 week's gestation, or women's level of satisfaction with their care. The study did not group the pregnancies by whether the twins shared the same outermost membrane that surrounds them, or not (their chorionicity). If they do, the two babies also share the same placenta and have an intermingled blood circulation, which increases the possibility of twin-related complications. From this one study, we still do not know if the different scanning tests and how often they are done improves outcomes for women with a twin pregnancy. Future studies could find that there are differences in the number of infant deaths with the different ways of scanning. More research is needed to find out how often scans should be done and how detailed they should be in order to see whether the twins are growing normally and to pick up any problems quickly.

10.1002/14651858.CD011371.pub2

cochrane-simplification-train-560

cochrane-simplification-train-560

There were minimal differences identified between multi-session psychosocial interventions and standard educational interventions for both injection and sexual risk behaviour. Although it should be noted there were large pre-post changes for both groups suggesting both were effective in reducing risk behaviours. In addition, there was some evidence of benefit for multi-session psychosocial interventions when compared with minimal controls. Subgroup analyses suggest that people in formal treatment are likely to respond to multi-session psychosocial interventions. It also appears single-gender groups may be associated with greater benefit. There is limited support for the widespread use of formal multi-session psychosocial interventions for reducing injection and sexual risk behaviour. Brief standard education interventions appear to be a more cost-effective option. Further research is required to assess if there are particular groups of drug users more likely to respond to such interventions.

There were 35 trials on 11,867 participants that examined whether these interventions are effective in reducing sexual and injection behaviour associated with greater risk of developing HIV. There are not large differences in effectiveness between multi-session psychosocial interventions and briefer interventions. This suggests brief educational interventions are more likely to be cost-effective and may be more readily implemented in a variety of different contexts.

10.1002/14651858.CD007192.pub2

cochrane-simplification-train-561

cochrane-simplification-train-561

We included five trials from 14 reports, with a total of 494 participants. All included trials were individual RCTs that examined the effect of TNF-α blockers for KD. Five trials (with 494 participants) reported the incidence of treatment resistance. TNF-α blockers reduced the incidence of treatment resistance (TNF-α blocker intervention group 30/237, control group 58/257; risk ratio (RR) 0.57, 95% confidence interval (CI) 0.38 to 0.86; low-certainty evidence). Four trials reported the incidence of coronary artery abnormalities (CAAs). Three trials (with 270 participants) contributed data to the meta-analysis, since we could not get the data needed for the analysis from the fourth trial. There was no clear difference between groups in the incidence of CAAs (TNF-α blocker intervention group 8/125, control group 9/145; RR 1.18, 95% CI 0.45 to 3.12; low-certainty evidence). Three trials with 250 participants reported the adverse effect 'infusion reactions' after treatment initiation. The TNF-α blocker intervention decreased infusion reactions (TNF-α blocker intervention group 0/126, control group 15/124; RR 0.06, 95% CI 0.01 to 0.45; low-certainty evidence). Two trials with 227 participants reported the adverse effect 'infections' after treatment initiation. There was no clear difference between groups (TNF-α blocker intervention group 7/114, control group 10/113; RR 0.68, 95% CI 0.33 to 1.37; low-certainty evidence). One trial (with 31 participants) reported the adverse effect 'cutaneous reactions' (rash and contact dermatitis). There was no clear difference between the groups for incidence of rash (TNF-α blocker intervention group 2/16, control group 0/15; RR 4.71, 95% CI 0.24 to 90.69; very low-certainty evidence) or for incidence of contact dermatitis (TNF-α blocker intervention group 1/16, control group 3/15; RR 0.31, 95% CI 0.04 to 2.68; very low-certainty evidence). No trials reported other adverse effects such as injection site reactions, neutropenia, infections, demyelinating disease, heart failure, malignancy, and induction of autoimmunity. We found a limited number of RCTs examining the effect of TNF-α blockers for KD. In summary, low-certainty evidence indicates that TNF-α blockers have beneficial effects on treatment resistance and the adverse effect 'infusion reaction' after treatment initiation for KD when compared with no treatment or additional treatment with IVIG. Further research will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution. Further large high quality trials with timing and type of TNF-α blockers used are needed to determine the effects of TNF-α blockers for KD.

We included trials that used TNF-α blockers as a treatment for children with KD and measured treatment resistance, cardiovascular events and side effects, such as infusion reactions and infections, or other symptoms. We found five completed studies with a total of 494 participants (most recent search for studies September 2018). Four studies used TNF-α blockers as the additional treatment after IVIG treatment and one used TNF-α blockers as the first treatment for children with KD. Key results The analyses showed that TNF-α blockers might reduce treatment resistance by 14% to 62% (low-certainty evidence) and infusion reactions by 55% to 99% (low-certainty evidence). It was not clear whether or not TNF-α blockers were effective in reducing serious heart diseases such as coronary artery abnormalities. There was also no clear difference in the incidence of infections between children who did or didn't receive TNF-α blockers. Certainty of evidence It is important to note that the certainty of evidence is low because the studies only included a small number of participants. Therefore, a large scale clinical trial is needed.

10.1002/14651858.CD012448.pub2

cochrane-simplification-train-562

cochrane-simplification-train-562

The 18 included trials tested seven comparisons in a total of 2615 mainly female and older participants with a total of 2619 fractures. All trials had methodological flaws that may affect the validity of their results. Three trials of 355 participants comparing a fixed nail plate (Jewett or McLaughlin) with the sliding hip screw (SHS) found an increased risk of fixation failure for fixed nail plates. The two trials of 433 participants comparing the Resistance Augmented Bateaux (RAB) plate with the SHS had contrasting results, notably in terms of operative complications, fixation failure and anatomical restoration. One trial of 100 participants comparing the Pugh nail and the SHS found no significant difference between implants. Three trials of 458 participants compared the Medoff plate with the SHS. There was a trend to higher blood losses and longer operation times for the Medoff plate along with a trend to a lower risk of fixation failure with the Medoff plate for unstable trochanteric fractures. Two trials of 676 participants compared the Medoff plate with three different screw-plate systems. There were no statistically significant differences in outcome for trochanteric fractures. For subtrochanteric fractures, there was a lower fixation failure rate for the Medoff plate but no evidence for differences in longer-term outcomes. Four trials of 396 participants comparing the Gotfried percutaneous compression plate (PCCP) with a SHS found a trend to lower blood loss and transfusion requirements for the PCCP but no other confirmed differences in outcomes between implants. Three of the trials reported intra-operative problems with the PCCP, some of which precluded its use. Three trials of 200 participants comparing external fixation with a SHS found less operative trauma for the external fixation. Final outcome appeared similar. The markedly increased fixation failure rate of fixed nail plates compared with the SHS is a major consideration and thus the SHS appears preferable. There was insufficient evidence from other comparisons of extramedullary implants or on the use of external fixators to draw definite conclusions.

The 18 randomised controlled trials included in this review tested seven comparisons in a total of 2615 mainly female and older participants. All trials had methodological flaws that may affect the validity of their results and there was a general lack of evidence on long-term effects and functional recovery. Some extramedullary implants appeared to be associated with an increased risk of fixation complications and reoperation. In particular, three trials comparing a fixed nail plate (Jewett or McLaughlin) with the sliding hip screw (the 'standard' extramedullary device for these fractures) found an increased risk of fixation failure for fixed nail plates. Less invasive implants, such as the external fixator, which require smaller incisions resulted in less blood loss and often quicker operations than the sliding hip screw. We concluded that the sliding hip screw seems preferable to older types of fixed nail plates given their high rate of implant and fixation failure. However, there was not enough evidence to draw conclusions for other comparisons of extramedullary implants or on the use of external fixators.

10.1002/14651858.CD000339.pub3

cochrane-simplification-train-563

cochrane-simplification-train-563

There were 12 randomised controlled trials with 14 comparisons included in the review, with a total sample of 500 participants across all comparisons. Included studies were typically very small (n = 20 to 72), all except one were assessed as being at high risk of bias, and all reported short-term outcomes. For the purposes of pooling, studies were divided into seven clinically homogenous comparisons according to the patient population (acute or chronic LBP) and the nature of the control intervention. Most of the comparisons (five out of seven) included only one study, one comparison had two studies, and one comparison included seven studies. The meta-analyses provided low-quality evidence that MET provided no additional benefit when added to other therapies on the outcomes of chronic pain and disability in the short-term (weighted mean difference (WMD) for pain 0.00, 95% CI -2.97 to 2.98 on a 100-point scale; standardised mean difference (SMD) for disability -0.18, 95% CI -0.43 to 0.08, 7 studies, 232 participants). There was low-quality evidence that MET produced no clinically relevant differences in pain compared to sham MET (mean difference (MD) 14.20, 95% CI -10.14 to 38.54, 1 study, 20 participants). For the comparison of MET to other conservative therapies for acute non-specific LBP, there was very low-quality evidence of no clinically relevant difference for the outcomes of pain (MD -10.72, 95% CI -32.57 to 11.13, 2 studies, 88 participants) and functional status (MD 0.87, 95% CI -6.31 to 8.05, 1 study, 60 participants). For the comparison of MET to other conservative therapies for chronic non-specific LBP, there was low-quality evidence of no clinically relevant difference for the outcomes of pain (MD -9.70, 95% CI -20.20 to 0.80, 1 study, 30 participants) and functional status (MD -4.10, 95% CI -9.53 to 1.33, 1 study, 30 participants). There was low-quality evidence of no clinically relevant difference for the addition of MET to other interventions for acute non-specific LBP for the outcome of pain (MD -3, 95% CI -11.37 to 5.37, 1 study, 40 participants) and low-quality evidence of an effect in favour of MET for functional status (MD -17.6, 95% CI -27.05 to -8.15, 1 study, 40 participants). For chronic non-specific LBP, there was low-quality evidence of an effect in favour of MET for the addition of MET to other interventions for the outcomes of pain (MD -34.1, 95% CI -38.43 to -29.77, 1 study, 30 participants) and functional status (MD -22, 95% CI -27.41 to -16.59, 1 study, 30 participants). Lastly, there was low-quality evidence of no difference for the addition of MET to another manual intervention compared to the same intervention with other conservative therapies for the outcomes of pain (MD 5.20, 95% CI -3.03 to 13.43, 1 study, 20 participants) and functional status (MD 6.0, 95% CI -0.49 to 12.49, 1 study, 20 participants). No study reported on our other primary outcome of general well-being. Seven studies reported that no adverse events were observed, whereas the other five studies did not report any information on adverse events. The quality of research related to testing the effectiveness of MET is poor. Studies are generally small and at high risk of bias due to methodological deficiencies. Studies conducted to date generally provide low-quality evidence that MET is not effective for patients with LBP. There is not sufficient evidence to reliably determine whether MET is likely to be effective in practice. Large, methodologically-sound studies are necessary to investigate this question.

The people in these studies ranged in age from 18 to 65 years and had pain ranging in severity from mild to substantial. They usually had about five sessions of MET, or the comparison treatment(s), over a period of about 10 days. The review authors aimed to determine if MET helped to relieve pain or increase a person's ability to do normal activities of daily living, or both. Background Low-back pain (LBP) is a common symptom from adolescence into old age. About 50% of the general population experiences back pain over the course of a year and up to 80% of people report LBP over the course of their lifetimes. The vast majority of people have acute (short-term) back pain and recover within a few weeks, with or without treatment. Longer lasting LBP, subacute (for 6 to 12 weeks) and chronic (> 12 weeks) pain, generally has less favourable outcomes. A small proportion of people with acute LBP go on to have chronic disabling LBP, which can interfere with every aspect of normal living, cause significant pain and suffering, and create huge costs in terms of medical care, work disability, and workers’ compensation claims. There are many therapies claimed to be useful for the treatment of LBP. Most of these treatments have not been well investigated or have been found to have modest effects in terms of pain relief and improving disability. For many people with LBP, however, even modestly effective treatments can help in coping with symptoms and returning to normal living. It is therefore useful to explore the effectiveness of treatments that may assist people with LBP, particularly those treatments such as MET which are non-invasive and are likely to be safe and inexpensive. Study characteristics The Cochrane Collaboration researchers looked for studies (randomised controlled trials) published through to May and June 2014. They included studies where MET was delivered by osteopathic physicians, chiropractors, or physical therapists. Twelve randomised controlled trials were found that included a total of 500 patients. All patients in these studies had 'non-specific LBP', meaning that there was no identifiable cause for their back symptoms. After looking at the evidence, The Cochrane Collaboration review authors included four types of comparison treatments, each divided into acute and chronic pain: •MET plus any intervention versus that same intervention alone; •MET versus no treatment; •MET versus sham MET; •MET versus all other therapies. Key results The review authors could not find adequate evidence to make any definitive judgements about the safety or effectiveness of MET. Studies were generally too small and had a high risk of bias, producing unreliable answers about this therapy. There is a need for larger, high-quality studies to determine the effectiveness and safety of MET. At present there is no convincing evidence that MET is effective as a stand-alone therapy or improves the effectiveness as an accompaniment to other therapies. Quality of the evidence The quality of the evidence was poor. The available studies were small and reported only short term outcomes. Most studies were determined to have a high risk of bias because of the way they were designed and conducted.

10.1002/14651858.CD009852.pub2

cochrane-simplification-train-564

cochrane-simplification-train-564

The studies analysed were in two groups: those comparing anticholinergics with placebo and those comparing the combination of anticholinergics with short acting ß2 -agonists versus short acting ß2 -agonists alone. The former group had 13 studies involving 205 participants included in this review, and the latter 9 studies involving 440 patients. Generally methodological quality was poorly reported, and there were some reservations with respect to the quality of the studies. Despite the limited number of studies that could be combined, anticholinergic agents in comparison with placebo resulted in more favourable symptom scores particularly in respect of daytime dyspnoea (WMD -0.09 (95%CI -0.14, -0.04, 3 studies, 59 patients). Daily peak flow measurements also showed a statistically significant improvement for the anticholinergic (e.g. morning PEF: WMD =14.38 litres/min (95%CI 7.69, 21.08; 3 studies, 59 patients). However the clinical significance is small and in terms of peak flow measurements equates to approximately a 7% increase over placebo. The more clinically relevant comparison of a combination of anticholinergic plus short acting ß2 -agonist versus short acting ß2 -agonist alone gave no evidence in respect of symptom scores or peak flow rates of any significant differences between the two regimes. Again there are reservations with respect to the quality of the information from which these conclusions are drawn. An update search in August 2004 did not identify any new studies. Overall this review provides no justification for routinely introducing anticholinergics as part of add-on treatment for patients whose asthma is not well controlled on standard therapies. This does not exclude the possibility that there may be a sub-group of patients who derive some benefit and a trial of treatment in individual patients may still be justified. The role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with asthma and any future trials might draw on the messages derived from this review.

This review found that although this treatment was better than placebo, the size of the effect was rather small. When the drug was used in combination with more widely used bronchodilators (beta-agonists such as fenoterol), it did not appear to add much benefit. However, there are concerns about the quality of the studies that have been analysed. It could be that there are some adults with chronic asthma who respond to treatment with anticholinergic drugs, but the review has not been able to identify their common characteristics.

10.1002/14651858.CD003269.pub2

cochrane-simplification-train-565

cochrane-simplification-train-565

We identified 13 eligible cohort studies including 2837 participants with a hearing test after treatment with a platinum analogue for different types of childhood cancers. All studies had methodological limitations, with regard to both internal (risk of bias) and external validity. Participants were treated with cisplatin, carboplatin or both, in varying doses. The reported prevalence of hearing loss varied considerably between 0% and 90.1%; none of the studies provided data on tinnitus. Three studies reported a prevalence of 0%, but none of these studies provided a definition for hearing loss and there might be substantial or even complete overlap in included participants between these three studies. When only studies that did provide a definition for hearing loss were included, the prevalence of hearing loss still varied widely between 1.7% and 90.1%. All studies were very heterogeneous with regard to, for example, definitions of hearing loss, used diagnostic tests, participant characteristics, (prior) anti-tumour treatment, other ototoxic drugs and length of follow-up. Therefore, pooling of results was not possible. Only two studies included a control group of people who had not received platinum treatment. In one study, the prevalence of hearing loss was 67.1% (95% confidence interval (CI) 59.3% to 74.1%) in platinum-treated participants, while in the control participants it was 7.4% (95% CI 6.2% to 8.8%). However, hearing loss was detected by screening in survivors treated with platinum analogues and by clinical presentation in control participants. It is uncertain what the effect of this difference in follow-up/diagnostic testing was. In the other study, the prevalence of hearing loss was 20.1% (95% CI 17.4% to 23.2%) in platinum-treated participants and 0.4% (95% CI 0.12% to 1.6%) in control participants. As neither study was a randomized controlled trial or controlled clinical trial, the calculation of a risk ratio was not feasible as it is very likely that both groups differed more than only the platinum treatment. Only two studies evaluated possible risk factors using multivariable analysis. One study identified a significantly higher risk of hearing loss in people treated with cisplatin 400 mg/m2 plus carboplatin 1700 mg/m2 as compared to treatment with cisplatin 400 mg/m2 or less, irrespective of the definition of hearing loss. They also identified a significantly higher risk of hearing loss in people treated with non-anthracycline aminoglycosides antibiotics (using a surrogate marker) as compared to people not treated with them, for three out of four definitions of hearing loss. The other study reported that age at treatment (odds ratio less than 1 for each single-unit increase) and single maximum cisplatin dose (odds ratio greater than 1 for each single-unit increase) were significant predictors for hearing loss, while gender was not. This systematic review shows that children treated with platinum analogues are at risk for developing hearing loss, but the exact prevalence and risk factors remain unclear. There were no data available for tinnitus. Based on the currently available evidence we can only advise that children treated with platinum analogues are screened for ototoxicity in order to make it possible to diagnose hearing loss early and to take appropriate measures. However, we are unable to give recommendations for specific follow-up protocols including frequency of testing. Counselling regarding the prevention of noise pollution can be considered, such as the use of noise-limiting equipment, avoiding careers with excess noise and ototoxic medication. Before definitive conclusions on the prevalence and associated risk factors of platinum-induced ototoxicity can be made, more high-quality research is needed. Accurate and transparent reporting of findings will make it possible for readers to appraise the results of these studies critically.

The evidence is current to September 2015. We found 13 studies including 2837 participants with a hearing test after platinum-based therapy for different types of childhood cancers. Participants were treated with cisplatin, carboplatin or both, in varying doses. All studies were very different with regard to definitions of hearing loss, used diagnostic tests, participant characteristics, (prior) anti-cancer treatment, other ototoxic drugs and length of follow-up. The reported frequency of hearing loss varied between 0% and 90.1%; none of the studies provided data on tinnitus (that is, ringing in the ears). Three studies reported a frequency of 0%, but none of these studies provided a definition for hearing loss and there might be substantial or even complete overlap in included participants between these three studies. When only studies that did provide a definition for hearing loss were included, the frequency of hearing loss still varied between 1.7% and 90.1%. Only two studies included people who had not received platinum treatment (called control group). In one study, the frequency of hearing loss was 67.1% in people treated with platinum, while in the control group it was 7.4%. In the other study, the frequency of hearing loss was 20.1% in people treated with platinum and 0.44% in the control group. But due to methodological problems of these studies, it is unclear how reliable these results are. Only two studies evaluated possible risk factors. One study found a higher risk of hearing loss in people treated with cisplatin 400 mg/m2 plus carboplatin 1700 mg/m2 compared to treatment with cisplatin 400 mg/m2 or less, irrespective of the definition of hearing loss. They also found a higher risk of hearing loss in people treated with non-anthracycline aminoglycosides antibiotics (that is, a certain type of antibiotics) as compared to people not treated with these antibiotics, for three out of four definitions of hearing loss. The other study reported that age at treatment (lower risk in older children) and single maximum cisplatin dose (higher risk with an increasing dose) were significant predictors for hearing loss, while gender was not. Based on the currently available evidence, we can only advise that children treated with platinum analogues are screened for ototoxicity in order to make it possible to diagnose hearing loss early and to take appropriate measures. However, we are unable to give recommendations for specific follow-up methods including how often hearing is tested. Counselling regarding the prevention of noise pollution can be considered, like the use of noise-limiting equipment, avoiding careers with excess noise and ototoxic medicines. Before definitive conclusions on how often hearing loss happens (called prevalence) and associated risk factors of platinum-induced ototoxicity can be made, more high-quality research is needed. All studies had problems relating to quality of the evidence.

10.1002/14651858.CD010181.pub2

cochrane-simplification-train-566

cochrane-simplification-train-566

We included two studies, involving a total of 94 participants, in the review. Continuous veno-venous hemofiltration versus no intervention We included one study in which 64 participants with severe acute pancreatitis were randomized to undergo CVVH (32 participants) or no intervention (32 participants). There were no deaths in either group (very low-quality evidence). Adverse events, length of stay in the intensive care unit (ICU), length of hospital stay, total hospital cost, and quality of life were not reported in the study. One type of continuous veno-venous hemofiltration versus a different type of continuous veno-venous hemofiltration We included one study in which 30 participants with severe acute pancreatitis were randomized to undergo high-volume CVVH (15 participants) or standard CVVH (15 participants). High-volume CVVH may lead to little or no difference in in-hospital mortality rates (20.0% in the high-volume CVVH group versus 33.3% in the standard CVVH group; risk ratio (RR) 0.60, 95% confidence interval (CI) 0.17 to 2.07; 30 participants; 1 study; low-quality evidence). We are uncertain whether high-volume hemofiltration reduces rates of adverse events (13.3% in both groups; RR 1.00, 95% CI 0.16 to 6.20; 30 participants; 1 study; very low-quality evidence). Length of ICU stay, length of hospital stay, total hospital cost, and quality of life were not reported in the study. The quality of the current evidence is very low or low. For both comparisons addressed in this review, data are sparse. It is unclear whether CVVH has any effect on mortality or complications in patients with severe acute pancreatitis. It is also unclear whether high-volume CVVH is superior, equivalent or inferior to standard CVVH in patients with severe acute pancreatitis.

We searched for all relevant, well-conducted studies conducted up to September 2019. We included two randomized controlled trials (experiments in which participants are randomly allocated to two or more interventions, possibly including a control intervention or no intervention, and the results are compared). One study randomized 64 people with severe acute pancreatitis to receive either CVVH (32 people) or no intervention (32 people). The other study randomized 30 people with severe acute pancreatitis to receive either high-volume (high-speed) CVVH (15 people) or standard CVVH (15 people). There were no in-hospital deaths in either group. We cannot tell from our results whether CVVH has an important effect on death or complications for people with severe acute pancreatitis because the sample size was small. High-volume CVVH may have little to no difference on numbers of in-hospital deaths (20.0% with high-volume CVVH versus 33.3% with standard CVVH). We are uncertain whether high-volume CVVH reduces numbers of adverse events (13.3% in both groups). We cannot tell from our results whether high-volume CVVH is superior, equivalent or inferior to standard CVVH for people with severe acute pancreatitis because the sample size was small and the results were imprecise. Most of the included studies had some limitations in terms of how they were conducted or reported. Overall, the quality of the evidence varied from very low to low.

10.1002/14651858.CD012959.pub2

cochrane-simplification-train-567

cochrane-simplification-train-567

Five studies involving 3,070 individuals met the criteria for inclusion in the meta-analysis. All interventions for promoting use of booster seats among 4 to 8 year olds demonstrated a positive effect (relative risk (RR) 1.43; 95% confidence intervals (CI) 1.05 to 1.96). Incentives combined with education demonstrated a beneficial effect (RR 1.32, 95% CI 1.12 to 1.55; n = 1,898). Distribution of free booster seats combined with education also had a beneficial effect (RR 2.34; 95% CI 1.50 to 3.63; n = 380) as did education-only interventions (RR 1.32; 95% CI 1.16 to 1.49; n = 563). One study which evaluated enforcement of booster seat law met the criteria for inclusion in the meta-analysis, but demonstrated no marked beneficial effect. Available evidence suggests that interventions to increase use of booster seats among children age four to eight years are effective. Combining incentives (booster seat discount coupons or gift certificates) or distribution of free booster seats with education demonstrated marked beneficial outcomes for acquisition and use of booster seats for four to eight year olds. There is some evidence of beneficial effect of legislation on acquisition and use of booster seats but this was mainly from uncontrolled before-and-after studies, which did not meet the criteria for inclusion in the meta-analysis.

The authors found five studies involving a total of 3,070 participants. All interventions investigated by the studies were found to increase the use of booster seats, compared to the group receiving no intervention. The distribution of free booster seats combined with education on their use, had a marked beneficial effect, as did incentives (for example, booster seat discount coupons or gift certificates) combined with education. Education-only interventions also produced beneficial outcomes. One of the studies evaluated the effectiveness of the enforcement of a booster seat law, but did not detect an effect on usage. The authors concluded that the current evidence suggests that several types of interventions aimed at increasing the use of booster seats among children aged four to eight years, are effective. However, there is still a need for further high quality trials, especially those conducted outside of the USA and Australia, where current research dominates.

10.1002/14651858.CD004334.pub2

cochrane-simplification-train-568

cochrane-simplification-train-568

Sixteen trials were identified, including 558 participants. Eleven trials were of cross-over design. Eleven trials included only people with faecal incontinence related to liquid stool (either chronic diarrhoea, following ileoanal pouch or rectal surgery, or due to use of a weight-reducing drug). Two trials were amongst people with weak anal sphincters, one in participants with faecal impaction and bypass leakage, and one in geriatric patients. In one trial there was no specific cause for faecal incontinence. Seven trials tested anti-diarrhoeal drugs to reduce faecal incontinence and other bowel symptoms (loperamide, diphenoxylate plus atropine, and codeine). Six trials tested drugs that enhance anal sphincter function (phenylepinephrine gel and sodium valproate). Two trials evaluated osmotic laxatives (lactulose) for the treatment of faecal incontinence associated with constipation in geriatric patients. One trial assessed the use of zinc-aluminium ointment for faecal incontinence. No studies comparing drugs with other treatment modalities were identified. There was limited evidence that antidiarrhoeal drugs and drugs that enhance anal sphincter tone may reduce faecal incontinence in patients with liquid stools. Loperamide was associated with more adverse effects (such as constipation, abdominal pain, diarrhoea, headache and nausea) than placebo. However, the dose may be titrated to the patient's symptoms to minimise side effects while achieving continence. The drugs acting on the sphincter sometimes resulted in local dermatitis, abdominal pain or nausea. Laxative use in geriatric patients reduced faecal soiling and the need for help from nurses. Zinc-aluminium ointment was associated with improved quality of life, with no reported adverse effects. However, the observed improvement in quality of life was seen in the placebo group as well as the treatment group. It should be noted that all the included trials in this review had small sample sizes and short duration of follow-up. 'Risk of bias' assessment was unclear for most of the domains as there was insufficient information. There were no data suitable for meta-analysis. The small number of trials identified for this review assessed several different drugs in a variety of patient populations. The focus of most of the included trials was on the treatment of diarrhoea, rather than faecal incontinence. There is little evidence to guide clinicians in the selection of drug therapies for faecal incontinence. Larger, well-designed controlled trials, which use the recommendations and principles set out in the CONSORT statement, and include clinically important outcome measures, are required.

This review looked at drugs for the treatment of faecal incontinence. These included anti-diarrhoea drugs or laxatives to regulate stools, and drugs to try to enhance the tone of muscle around the anus which help to keep it closed. Sixteen small trials were found, including 558 participants. The review of these trials found some evidence that anti-diarrhoea drugs may reduce faecal incontinence for people having liquid stools. However, these drugs were associated with some side effects. There was some evidence that drugs to enhance the tone of the muscle around the anus may help, but more research is needed.

10.1002/14651858.CD002116.pub2

cochrane-simplification-train-569

cochrane-simplification-train-569

We included six studies: five small, cross-over studies with 174 participants, and one parallel group study with 170 participants. Participants were treated with levetiracetam (2000 mg to 3000 mg daily) or placebo for between four and 14 weeks. Each study included participants with a different type of neuropathic pain; central pain due to multiple sclerosis, pain following spinal cord injury, painful polyneuropathy, central post-stroke pain, postherpetic neuralgia, and post-mastectomy pain. None of the included studies provided first or second tier evidence. The evidence was very low quality, downgraded because of the small size of the treatment arms, and because studies reported results using last observation carried forward (LOCF) imputation for withdrawals or using only participants who completed the study according to the protocol, where there were greater than 10% withdrawals. There were insufficient data for a pooled efficacy analysis in particular neuropathic pain conditions, but individual studies did not show any analgesic effect of levetiracetam compared with placebo. We did pool results for any outcome considered substantial pain relief (≥ 50% pain intensity reduction or ‘complete’ or ‘good’ responses on the verbal rating scale) for four studies with dichotomous data; response rates across different types of neuropathic pain was similar with levetiracetam (10%) and placebo (12%), with no statistical difference (risk ratio 0.9; 95% confidence interval (CI) 0.4 to1.7). We pooled data across different conditions for adverse events and withdrawals. Based on very limited data, significantly more participants experienced an adverse event with levetiracetam than with placebo (number needed to treat for an additional harmful event (NNH) 8.0 (95% CI 4.6 to 32)). There were significantly more adverse event withdrawals with levetiracetam (NNH 9.7 (6.7 to 18)). The amount of evidence for levetiracetam in neuropathic pain conditions was very small and potentially biased because of the methods of analysis used in the studies. There was no indication that levetiracetam was effective in reducing neuropathic pain, but it was associated with an increase in participants who experienced adverse events and who withdrew due to adverse events.

Levetiracetam is one of a type of medicine normally used to treat epilepsy. Some of these medicines are also useful for treating neuropathic pain. We looked for clinical trials in which levetiracetam was used to treat neuropathic pain. We found six studies in 344 adult participants with six different neuropathic pain conditions published up to July 2014. These studies were randomised and double blind, which usually means we can trust them. But all had one or more problems that could make the results look better than found in practice. There was no benefit from levetiracetam in any of the six conditions. More participants experienced adverse events with levetiracetam (67 in 100) than with placebo (54 in 100), and stopped taking levetiracetam because of adverse events (13 in 100) than stopped taking placebo (2 in 100). Adverse events included tiredness, dizziness, headache, constipation, and nausea. There was too little information, which was of inadequate quality, to be sure that levetiracetam works as a pain medicine in any of the neuropathic pain conditions investigated. Other medicines have been shown to be effective in some of these conditions.

10.1002/14651858.CD010943.pub2

cochrane-simplification-train-570

cochrane-simplification-train-570

We included in the review seven studies with a total of 852 participants. The methodological quality of the included studies was generally ranked as showing low risk of bias in most domains, with the exception of one study, which did not mask participants. We were able to include data from 838 participants in the meta-analysis. We found no statistically significant differences between participants receiving air and those given saline in any of the outcomes evaluated: inability to locate the epidural space (three trials, 619 participants) (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.33 to 2.31, low-quality evidence); accidental intravascular catheter placement (two trials, 223 participants) (RR 0.90, 95% CI 0.33 to 2.45, low-quality evidence); accidental subarachnoid catheter placement (four trials, 682 participants) (RR 2.95, 95% CI 0.12 to 71.90, low-quality evidence); combined spinal epidural failure (two trials, 400 participants) (RR 0.98, 95% CI 0.44 to 2.18, low-quality evidence); unblocked segments (five studies, 423 participants) (RR 1.66, 95% CI 0.72 to 3.85); and pain measured by VAS (two studies, 395 participants) (mean difference (MD) -0.09, 95% CI -0.37 to 0.18). With regard to adverse effects, we found no statistically significant differences between participants receiving air and those given saline in the occurrence of paraesthesias (three trials, 572 participants) (RR 0.89, 95% CI 0.69 to 1.15); difficulty in advancing the catheter (two trials, 227 participants) (RR 0.91, 95% CI 0.32 to 2.56); catheter replacement (two trials, 501 participants) (RR 0.69, 95% CI 0.26 to 1.83); and postdural puncture headache (one trial, 110 participants) (RR 0.83, 95% CI 0.12 to 5.71). Low-quality evidence shows that results do not differ between air and saline in terms of the loss of resistance technique for identification of the epidural space and reduction of complications. Applicability might be compromised, as most of the results described in this review were obtained from parturient patients. This review underlines the need to conduct well-designed trials in this field.

Adults (18 years of age and older) undergoing surgical procedures, pregnant women in obstetrical labour and patients receiving postoperative pain relief. The evidence is current to September 2013. We found seven studies with a total of 852 participants. The maximum time that a participant was followed by the doctor was 24 hours after giving birth. The quality of the included studies was considered reasonable. The following results were examined: inability to locate the epidural space; accidental catheter placement (mis-insertion of the catheter); combined spinal epidural failure (cases of failed regional anaesthetic technique, which combines the benefits of spinal and epidural anaesthesia); unblocked segments (patchy block); and pain. We found no convincing evidence that results differed when air or saline was used. Because conducted studies were only reasonably well conducted (results very similar across studies; minor issues with study design; and not enough data), we ranked the overall quality of the evidence as low. The applicability of findings might be compromised, as most of the results described in this review were obtained from parturient patients. Low-quality evidence shows that results do not differ between air and saline in using loss of resistance technique for identification of the epidural space and in reducing complications.

10.1002/14651858.CD008938.pub2

cochrane-simplification-train-571

cochrane-simplification-train-571

Eleven studies with 818 infants met the criteria for inclusion in this review. Four trials with 329 infants assessed the use of an H2 receptor antagonist for prevention of upper gastrointestinal bleeding in high-risk newborn infants. Meta-analysis of these four trials identified a reduction in any upper gastrointestinal bleeding when using an H2 receptor antagonist (typical risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.58; typical risk difference (RD) −0.20, 95% CI −0.28 to −0.11; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 4 to 9). The quality of evidence was moderate. A single trial with 53 infants assessing prevention of upper gastrointestinal bleeding reported no difference in mortality in infants assigned H2 receptor antagonist versus no treatment; however the quality of evidence was very low. Seven trials with 489 infants assessed an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) for treatment of gastrointestinal bleeding in newborn infants. Meta-analysis of two trials (131 infants) showed no difference in mortality from use of a H2 receptor antagonist compared to no treatment. The quality of evidence was low. Meta-analysis of two trials (104 infants) showed a reduction in duration of upper gastrointestinal bleeding from use of an inhibitor of gastric acid compared to no treatment (mean difference −1.06 days, 95% CI −1.28 to −0.84). The quality of evidence was very low. Meta-analysis of six trials (451 infants) showed a reduction in continued upper gastrointestinal bleeding from use of any inhibitor of gastric acid compared to no treatment (typical RR 0.36, 95% CI 0.26 to 0.49; typical RD −0.26, 95% CI −0.33, −0.19; NNTB 4, 95% CI 3 to 5). The quality of evidence was low. There were no significant subgroup differences in duration of upper gastrointestinal bleeding or of continued upper gastrointestinal bleeding according to type of inhibitor of gastric acid. A single trial (38 infants) reported no difference in anaemia requiring blood transfusion from use of a H2 receptor antagonist compared to no treatment. Although no serious adverse events were reported from the use of a H2 receptor antagonist or proton pump inhibitor, some neonatal morbidities — including necrotising enterocolitis, ventilator-associated pneumonia, duration of ventilation and respiratory support, and duration of hospital stay — were not reported. Long-term outcome was not reported. There is moderate-quality evidence that use of an H2 receptor antagonist reduces the risk of gastrointestinal bleeding in newborn infants at high risk of gastrointestinal bleeding. There is low-quality evidence that use of an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) reduces the duration of upper gastrointestinal bleeding and the incidence of continued gastric bleeding in newborn infants with gastrointestinal bleeding. However, there is no evidence that use of an inhibitor of gastric acid in newborn infants affects mortality or the need for blood transfusion. As no study reported the incidence of necrotising enterocolitis, ventilator- or hospital-associated pneumonia, sepsis, or long-term outcome, the safety of inhibitors of gastric acid secretion is unclear.

We included randomised controlled trials (RCTs). The search is up to date as of 12 July 2018. We found 11 trials with 818 infants. We considered no trial to be at low risk of bias. Four trials included 329 infants in neonatal intensive care units and used a histamine 2 receptor antagonist for prevention of upper gastrointestinal bleeding. These four trials demonstrated a reduction in the incidence of upper gastrointestinal bleeding with a histamine 2 receptor antagonist, but no change in mortality. Outcomes such as serious gastrointestinal problems (e.g. necrotising enterocolitis) and infections were not reported. Seven trials with 489 infants enrolled sick newborn infants with upper gastrointestinal bleeding and used either a histamine 2 receptor antagonist or a proton pump inhibitor for treatment. Use of a histamine 2 receptor antagonist or proton pump inhibitor in a treatment context was associated with a reduction of both duration of upper gastrointestinal bleeding and continued upper gastrointestinal bleeding; however it did not affect mortality or requirement for blood transfusion. No long-term follow-up was reported. Although there is moderate-quality evidence that use of an inhibitor of gastric acid reduces the incidence and duration of upper gastrointestinal bleeding in newborn infants, there is insufficient safety data in this population. The implication of this is that caution should be applied when deciding whether to use an inhibitor of gastric acid in sick newborn infants until additional studies are performed. We graded the quality of evidence for prevention of upper gastrointestinal bleeding as low and moderate. We graded the quality of evidence for the treatment of upper gastrointestinal bleeding as low and very low.

10.1002/14651858.CD011785.pub2

cochrane-simplification-train-572

cochrane-simplification-train-572

The database search identified 3,253 references. Sixteen trials fulfilled the inclusion criteria. Psychological interventions show a small beneficial effect on depression compared to usual care (range of SMD of depression scores across trials and time frames: -0.81;0.12). Based on one trial per outcome, no beneficial effects on mortality rates, cardiac events, cardiovascular hospitalizations and QoL were found, except for the psychosocial dimension of QoL. Furthermore, no differences on treatment outcomes were found between the varying psychological approaches. The review provides evidence of a small beneficial effect of pharmacological interventions with selective serotonin reuptake inhibitors (SSRIs) compared to placebo on depression outcomes (pooled SMD of short term depression change scores: -0.24 [-0.38,-0.09]; pooled OR of short term depression remission: 1.80 [1.18,2.74]). Based on one to three trials per outcome, no beneficial effects regarding mortality, cardiac events and QoL were found. Hospitalization rates (pooled OR of three trials: 0.58 [0.39,0.85] and emergency room visits (OR of one trial: 0.58 [0.34,1.00]) were reduced in trials of pharmacological interventions compared to placebo. No evidence of a superior effect of Paroxetine (SSRI) versus Nortriptyline (TCA) regarding depression outcomes was found in one trial. Psychological interventions and pharmacological interventions with SSRIs may have a small yet clinically meaningful effect on depression outcomes in CAD patients. No beneficial effects on the reduction of mortality rates and cardiac events were found. Overall, however, the evidence is sparse due to the low number of high quality trials per outcome and the heterogeneity of examined populations and interventions.

This review examined clinical trials on psychological treatments and antidepressant drugs in depressed patients with coronary artery disease. The objective was to determine the effects of these treatments on depression, death rates, cardiac events such as another heart attack or surgeries, healthcare costs and quality of life. Sixteen trials were identified as relevant for the review. Seven trials investigated psychological treatments, eight trials antidepressant medications and one trial comprised both psychological and drug treatments. Psychological treatments and antidepressant drugs proved to be slightly superior to usual care or placebo (inactive drug) with regard to depressive symptoms. Furthermore, antidepressant drugs might be superior to placebo in reducing subsequent hospitalization rates and emergency room visits. In contrast, there seems to be no positive effect on death rates and cardiac events. Results regarding quality of life are inconclusive. In summary, psychological treatments and antidepressant medications may have a small yet positive effect on depression outcomes in CAD patients. However, the evidence is sparse due to the low number of trials.

10.1002/14651858.CD008012.pub3

cochrane-simplification-train-573

cochrane-simplification-train-573

One trial assessing smoking cessation advice for 94 infertile women smokers fulfilled the criteria for this review, but the trial did not report on the review's primary outcome of live birth or any other fertility-related outcomes. This trial of women attending a fertility clinic showed that smoking cessation advice tailored to a woman's "stage-of-change" (readiness to stop smoking) did not show significant evidence of a difference in stage (including smoking cessation rates) compared with standard clinical advice. No RCTs were located that assessed the effects of preconception advice on the chance of a live birth or other fertility outcomes in people who perceived that they may be infertile and were investigating the possibility of medical treatment to address subfertility. Given the lack of RCTs evaluating the effectiveness of preconception lifestyle advice for people in the afore-mentioned population, this review cannot provide guidance for clinical practice in this area. However, it does highlight the need for further research into this important subject.

There is no evidence from randomised controlled trials regarding the effects of preconception advice on the chances of a live birth in subfertile people. Infertility is a prevalent problem and has significant consequences for individuals, families and the wider community. People's chance of having a healthy, live birth may be impacted upon by factors such as weight, diet, smoking, other substance abuse, environmental pollutants, infections, medical conditions, medications and family medical history. However, there is no current guideline about what preconception advice should be offered to people presenting for infertility treatment. It is important to determine what preconception advice should be given about these types of factors to people presenting for fertility treatment in order to help them to make positive changes and hopefully improve their chances of conception and having a healthy baby. This review found no evidence from controlled clinical trials about the effect of preconception advice on the chance of a live birth in subfertile people.

10.1002/14651858.CD008189.pub2

cochrane-simplification-train-574

cochrane-simplification-train-574

This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies. Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourse Live birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) −0.00, 95% CI −0.01 to 0.00; 2536 participants; 12 studies; I2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing. Letrozole compared to laparoscopic ovarian drilling There is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI −0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I2 = 0%; low-quality evidence). Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary. Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.

The review includes clinical studies where participants were randomly assigned to the intervention or to the comparison group (randomised controlled trials, RCTs). Our review includes 42 RCTs with 7935 women. In all trials the aromatase inhibitor used was letrozole. Comparators included CC, which was used in 25 of the RCTs, and laparoscopic ovarian drilling (a surgical technique to puncture the membrane surrounding the ovary), which was used in five RCTs. Several studies included other treatments in one or both arms. Letrozole appears to improve live birth and pregnancy rates compared to CC when used to cause ovulation and timed intercourse. The quality of this evidence was moderate and seems to be reliable. There appeared to be no difference for miscarriage rate or multiple pregnancy rate. There appeared to be no difference between letrozole and laparoscopic ovarian drilling for any observed outcomes, although there were few relevant studies. Ovarian hyperstimulation syndrome (OHSS), a serious adverse event of hormonal stimulation, was a very rare event and in most studies it did not occur. The evidence is current to January 2018. The overall quality of the evidence ranged from moderate to high. Some studies in favour of clomiphene citrate may never have been published. It appears that studies that reported live births report higher clinical pregnancy rates in the letrozole group than studies that failed to report live births. This suggests that results might be somewhat less favourable to letrozole if all studies reported live births.

10.1002/14651858.CD010287.pub3

cochrane-simplification-train-575

cochrane-simplification-train-575

Two trials (involving 59 mothers) that examined the use of domperidone in a total of 59 mother-infant pairs met the inclusion criteria. Meta-analysis of these trials showed a modest increase in expressed breastmilk (EBM) of 99.49 mL/day (95% confidence intervals -1.94 to 200.92; random-effects, T² 3511.62, I² 63%) in mothers given domperidone. Both trials gave the same dose of domperidone (10 mg three times per day) with a duration of seven days in the smaller trial and 14 days in the larger. Neither trial showed significant improvements in longer-term outcomes of breastfeeding in a preterm population and no adverse effects were reported. Two studies with a total of 59 mothers suggest modest improvements in short-term EBM volumes when a medication is used after insufficient EBM occurs in mothers following preterm delivery. In both studies, the medication was commenced ≧14 days post delivery and following insufficient EBM supply with other lactation supports. Currently, no studies support prophylactic use of a galactagogue medication at any gestation. Use of any galactagogue medication has only been examined at more than 14 days post delivery and after full lactation support has been given. Further trials should examine larger groups of preterm mothers and consider breastfeeding outcomes over a longer period.

Trials of medications used to improve the breastmilk supply in mothers who have insufficient milk for their hospitalised preterm infants' needs have been reported in two randomised controlled studies involving 59 mothers. These two studies gave the women domperidone 10 mg three times a day when mothers had insufficient EBM, two to three weeks after delivery. These studies showed a modest improvement in EBM volume over the following one to two weeks. No side effects to mothers or infants were noted in these studies. These medications should only be considered in mothers who have received full lactation support and are more than 14 days post delivery but have insufficient EBM for their infants' needs.

10.1002/14651858.CD005544.pub2

cochrane-simplification-train-576

cochrane-simplification-train-576

We included 11 studies that looked at diagnostic accuracy of one or two index tests: four studies (277 suspected fractures) looked at CT, five studies (221 suspected fractures) looked at MRI and six studies (543 suspected fractures) looked at BS. Four of the studies made direct comparisons: two studies compared CT and MRI, one study compared CT and BS, and one study compared MRI and BS. Overall, the studies were of moderate to good quality, but relevant clinical information during evaluation of CT, MRI or BS was mostly unclear or unavailable. As few studies made direct comparisons between tests with the same participants, our results are based on data from indirect comparisons, which means that these results are more susceptible to bias due to confounding. Nonetheless, the direct comparisons showed similar patterns of differences in sensitivity and specificity as for the pooled indirect comparisons. Summary sensitivity and specificity of CT were 0.72 (95% confidence interval (CI) 0.36 to 0.92) and 0.99 (95% CI 0.71 to 1.00); for MRI, these were 0.88 (95% CI 0.64 to 0.97) and 1.00 (95% CI 0.38 to 1.00); for BS, these were 0.99 (95% CI 0.69 to 1.00) and 0.86 (95% CI 0.73 to 0.94). Indirect comparisons suggest that diagnostic accuracy of BS was significantly higher than CT and MRI; and CT and MRI have comparable diagnostic accuracy. The low prevalence of a true fracture among suspected fractures (median = 20%) means the lower specificity for BS is problematic. For example, in a cohort of 1000 patients, 112 will be over-treated when BS is used for diagnosis. If CT is used, only 8 will receive unnecessary treatment. In terms of missed fractures, BS will miss 2 fractures and CT will miss 56 fractures. Although quality of the included studies is moderate to good, findings are based on only 11 studies and the confidence intervals for the summary estimates are wide for all three tests. Well-designed direct comparison studies including CT, MRI and BS could give valuable additional information. Bone scintigraphy is statistically the best diagnostic modality to establish a definitive diagnosis in clinically suspected fractures when radiographs appear normal. However, physicians must keep in mind that BS is more invasive than the other modalities, with safety issues due to level of radiation exposure, as well as diagnostic delay of at least 72 hours. The number of overtreated patients is substantially lower with CT and MRI. Prior to performing comparative studies, there is a need to raise the initially detected prevalence of true fractures in order to reduce the effect of the relatively low specificity in daily practice. This can be achieved by improving clinical evaluation and initial radiographical assessment.

We conducted a thorough search of electronic databases, trial registers and conference proceedings up to July 2012. We included 11 studies in our analysis. The studies were moderate to good quality. Four studies (277 suspected fractures) looked at CT, five studies (221 suspected fractures) looked at MRI and six studies (543 suspected fractures) looked at BS. Four of these studies directly compared two modalities, such as both CT and MRI. When we compared the pooled data for the different imaging tests from all studies, we found that BS has the highest sensitivity, but specificity was lower than CT and MRI. All three imaging tests were found to be highly accurate for definitive diagnosis. CT and MRI were comparable in diagnostic accuracy (the correct diagnosis is made). Although BS had significantly better accuracy than CT and MRI, it could lead to more people receiving unnecessary treatment. Moreover, BS is an invasive technique and is believed to be inappropriate for use in some populations, especially children. Future studies should focus on improving clinical evaluation to raise the prevalence of true fractures. In addition, more direct comparison studies could add valuable data to determine which modality is superior in diagnosis of suspected scaphoid fractures.

10.1002/14651858.CD010023.pub2

cochrane-simplification-train-577

cochrane-simplification-train-577

For this update we added 14 new included studies (3489 participants), and excluded four studies. We also identified 20 additional reports of completed or ongoing studies that have not been published in full. The earlier review included 47 studies. This update included 61 studies. Most compared topical NSAIDs in the form of a gel, spray, or cream with a similar topical placebo; 5311 participants were treated with a topical NSAID, 3470 with placebo, and 220 with an oral NSAID. This was a 63% increase in the number of included participants over the previous version of this review. We also identified a number of studies in clinical trial registries with unavailable results amounting to about 5900 participants for efficacy and 5300 for adverse events. Formulations of topical diclofenac, ibuprofen, ketoprofen, piroxicam, and indomethacin demonstrated significantly higher rates of clinical success (more participants with at least 50% pain relief) than matching topical placebo (moderate or high quality data). Benzydamine did not. Three drug and formulation combinations had NNTs for clinical success below 4. For diclofenac, the Emulgel® formulation had the lowest NNT of 1.8 (95% CI 1.5 to 2.1) in two studies using at least 50% pain intensity reduction as the outcome. Diclofenac plasters other than Flector® also had a low NNT of 3.2 (2.6 to 4.2) based on good or excellent responses in some studies. Ketoprofen gel had an NNT of 2.5 (2.0 to 3.4), from five studies in the 1980s, some with less well defined outcomes. Ibuprofen gel had an NNT of 3.9 (2.7 to 6.7) from two studies with outcomes of marked improvement or complete remission. All other drug and formulation combinations had NNT values above 4, indicating lesser efficacy. There were insufficient data to compare reliably individual topical NSAIDs with each other or the same oral NSAID. Local skin reactions were generally mild and transient, and did not differ from placebo (high quality data). There were very few systemic adverse events (high quality data) or withdrawals due to adverse events (low quality data). Topical NSAIDs provided good levels of pain relief in acute conditions such as sprains, strains and overuse injuries, probably similar to that provided by oral NSAIDs. Gel formulations of diclofenac (as Emugel®), ibuprofen, and ketoprofen, and some diclofenac patches, provided the best effects. Adverse events were usually minimal. Since the last version of this review, the new included studies have provided additional information. In particular, information on topical diclofenac is greatly expanded. The present review supports the previous review in concluding that topical NSAIDs are effective in providing pain relief, and goes further to demonstrate that certain formulations, mainly gel formulations of diclofenac, ibuprofen, and ketoprofen, provide the best results. Large amounts of unpublished data have been identified, and this could influence results in updates of this review.

We searched medical databases for clinical trials comparing topical NSAIDs with placebo (creams or gels that do not contain a medicine) or other medicines in adults aged 16 years or older with musculoskeletal pain (typically sports injuries). The evidence is current to February 2015. This review is an update of 'Topical NSAIDs for acute pain in adults' originally published in Issue 6, 2010. We identified 14 new studies to add to the 47 studies included in the earlier review. We also identified 14 studies in a clinical trial registry that are completed and three short reports from meetings, for which we could not find full details (about 4500 participants). Three more studies are ongoing (almost 900 participants). The 61 included studies, involving 8386 participants, were generally of high-quality. They tested a number of different topical drugs, mostly against a topical placebo (carrier without the NSAID), with application at least once a day. We were interested in participants having good pain reduction (by about half) around seven days after treatment started. At later times, most people are expected to get better even without treatment. We looked at particular formulations of individual drugs. Gel formulations of diclofenac and ketoprofen were among the most effective, along with ibuprofen gel and diclofenac plaster. For diclofenac and ketoprofen gels, 7 or 8 people out of 10 with a painful strain, sprain, or muscle pull had much reduced pain after seven days, compared with only 2 or 3 out of 10 with placebo (high quality data). Other NSAIDs and formulations were better than placebo, but not by as much. Because both topical NSAIDs and topical placebo are rubbed into the skin in these studies, we know that any effect is not just from rubbing. About 1 in 20 people experienced a mild and short-lived side effect like redness at the application site. This was the same for topical NSAID and topical placebo (high quality data). Side effects like a stomach upset or feeling sick were uncommon, with no difference between topical NSAID and topical placebo (high quality data). There were no serious side effects.

10.1002/14651858.CD007402.pub3

cochrane-simplification-train-578

cochrane-simplification-train-578

We found no randomised clinical trials comparing PAIR versus no or sham intervention. We identified only two randomised clinical trials, one comparing PAIR versus surgical treatment (n = 50 participants) and the other comparing PAIR (with or without albendazole) versus albendazole alone (n = 30 participants). Both trials were graded as 'adequate' for allocation concealment; however, generation of allocation sequence and blinding methods were 'unclear' in both. Compared to surgery, PAIR plus albendazole obtained similar cyst disappearance and mean cyst diameter with fewer adverse events (32% versus 84%, P < 0.001) and fewer days in hospital (mean + SD) ( 4.2 + 1.5 versus 12.7 + 6.5 days, P < 0.001). Compared to albendazole, PAIR with or without albendazole obtained significantly more (P < 0.01) cyst reduction and symptomatic relief. PAIR seems promising, but there is insufficient evidence to support or refute PAIR with or without benzimidazole coverage for treating patients with uncomplicated hepatic hydatid cyst. Further well-designed randomised clinical trials are necessary to address the topic.

Two randomised clinical trials on the puncture, aspiration, injection, and re-aspiration method for patients with uncomplicated hepatic hydatid cyst were identified. One trial compared puncture, aspiration, injection, and re-aspiration with surgical treatment. The other trial compared puncture, aspiration, injection, and re-aspiration with or without albendazole with albendazole alone. Both trials had high risk of bias. The number of participants enrolled and the follow-up duration are insufficient for a definite conclusion to be drawn. In general, there is insufficient evidence to support or refute the puncture, aspiration, injection, and re-aspiration method with or without benzimidazole coverage for patients with uncomplicated hepatic hydatid cyst.

10.1002/14651858.CD003623.pub3

cochrane-simplification-train-579

cochrane-simplification-train-579

We included four RCTs with 167 participants. Risk of bias of the included studies was high, as none of them reported method of randomization, allocation concealment or blinding. Only one trial mentioned our primary outcome of duration of anaesthesia. The mean difference in duration of anaesthesia with use of adrenaline with lidocaine was 3.20 hours (95% confidence interval (CI) 2.48 to 3.92 hours; one RCT, 20 participants; low-quality evidence). No trial reported adverse events such as ischaemia distal to the injection site, and no trial reported cost analysis. One trial mentioned the secondary outcome of duration of postoperative pain relief, but available data were insufficient for analysis of the findings. Two trials reported the secondary outcome of reduced bleeding during surgery. Bleeding during surgery was observed in nine out of 52 participants as compared with 25 out of 51 participants in the adrenaline with lidocaine and plain lidocaine groups, respectively. The risk ratio for bleeding in the adrenaline with lidocaine group was 0.35 (95% CI 0.19 to 0.65; two RCTs, 103 participants; low-quality evidence). From the limited data available, evidence is insufficient to recommend use or avoidance of adrenaline in digital nerve blocks. The evidence provided in this review indicates that addition of adrenaline to lidocaine may prolong the duration of anaesthesia and reduce the risk of bleeding during surgery, although the quality of the evidence is low. We have identified the need for researchers to conduct large trials that focus on other important outcomes such as adverse events, cost analysis and duration of postoperative pain relief.

Evidence is current to November 2014. We included studies in children (aged older than 28 days and younger than 18 years) and adult patients (aged 18 years or older) of either gender undergoing surgery on digits (fingers and toes) under nerve blocks using adrenaline with lidocaine. We found four eligible studies with 167 participants. One small study reported the duration of anaesthesia and found that adrenaline prolonged the duration of anaesthesia, but the quality of the evidence was low. No study reported on adverse events such as ischaemia distal to the injection site or cost analysis with use of adrenaline with lidocaine. Duration of postoperative pain relief was reported by one study, but available data were insufficient for analysis of the findings. Two studies reported reduced bleeding during surgery with use of adrenaline with lidocaine. In the light of our results, we would expect that 17.2 out of 100 patients who received adrenaline with lidocaine (between 8.7 and 29.8 patients) would have bleeding during surgery compared with 49 patients who would have received plain lidocaine; however, the quality of the evidence was low, and further research is very likely to impact our confidence in this estimate. The quality of evidence is low for both duration of anaesthesia and bleeding during surgery with use of adrenaline with lidocaine. Further research is needed to prove the benefits of adding adrenaline to lidocaine.

10.1002/14651858.CD010645.pub2

cochrane-simplification-train-580

cochrane-simplification-train-580

Out of 173 articles screened, three studies were included. There were two comparisons: chlorhexidine dressing following alcohol cleansing versus polyurethane dressing following povidone-iodine cleansing (one study); and silver-alginate patch versus control (two studies). A total of 855 infants from level III neonatal intensive care units (NICUs) were evaluated, 705 of whom were from a single study. All studies were at high risk of bias for blinding of care personnel or unclear risk of bias for blinding of outcome assessors. There was moderate-quality evidence for all major outcomes. The single study comparing chlorhexidine dressing/alcohol cleansing against polyurethane dressing/povidone-iodine cleansing showed no significant difference in the risk of CRBSI (RR 1.18, 95% CI 0.53 to 2.65; RD 0.01, 95% CI −0.02 to 0.03; 655 infants, moderate-quality evidence) and sepsis without a source (RR 1.06, 95% CI 0.75 to 1.52; RD 0.01, 95% CI −0.04 to 0.06; 705 infants, moderate-quality evidence). There was a significant reduction in the risk of catheter colonisation favouring chlorhexidine dressing/alcohol cleansing group (RR 0.62, 95% CI 0.45 to 0.86; RD −0.09, 95% CI −0.15 to −0.03; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 7 to 33; 655 infants, moderate-quality evidence). However, infants in the chlorhexidine dressing/alcohol cleansing group were significantly more likely to develop contact dermatitis, with 19 infants in the chlorhexidine dressing/alcohol cleansing group having developed contact dermatitis compared to none in the polyurethane dressing/povidone-iodine cleansing group (RR 43.06, 95% CI 2.61 to 710.44; RD 0.06, 95% CI 0.03 to 0.08; number needed to treat for an additional harmful outcome (NNTH) 17, 95% CI 13 to 33; 705 infants, moderate-quality evidence). The roles of chlorhexidine dressing in the outcomes reported were unclear, as the two assigned groups received different co-interventions in the form of different skin cleansing agents prior to catheter insertion and during each dressing change. In the other comparison, silver-alginate patch versus control, the data for CRBSI were analysed separately in two subgroups as the two included studies reported the outcome using different denominators: one using infants and another using catheters. There were no significant differences between infants who received silver-alginate patch against infants who received standard line dressing in CRBSI, whether expressed as the number of infants (RR 0.50, 95% CI 0.14 to 1.78; RD −0.12, 95% CI −0.33 to 0.09; 1 study, 50 participants, moderate-quality evidence) or as the number of catheters (RR 0.72, 95% CI 0.27 to 1.89; RD −0.05, 95% CI −0.20 to 0.10; 1 study, 118 participants, moderate-quality evidence). There was also no significant difference between the two groups in mortality (RR 0.55, 95% CI 0.15 to 2.05; RD −0.04, 95% CI −0.13 to 0.05; two studies, 150 infants, I² = 0%, moderate-quality evidence). No adverse skin reaction was recorded in either group. Based on moderate-quality evidence, chlorhexidine dressing/alcohol skin cleansing reduced catheter colonisation, but made no significant difference in major outcomes like sepsis and CRBSI compared to polyurethane dressing/povidone-iodine cleansing. Chlorhexidine dressing/alcohol cleansing posed a substantial risk of contact dermatitis in preterm infants, although it was unclear whether this was contributed mainly by the dressing material or the cleansing agent. While silver-alginate patch appeared safe, evidence is still insufficient for a recommendation in practice. Future research that evaluates antimicrobial dressing should ensure blinding of caregivers and outcome assessors and ensure that all participants receive the same co-interventions, such as the skin cleansing agent. Major outcomes like sepsis, CRBSI and mortality should be assessed in infants of different gestation and birth weight.

Three studies (total participants: 855) fit our inclusion criteria. There were two main comparisons: i) chlorhexidine dressing and alcohol skin cleansing against standard polyurethane dressing and povidone-iodine skin cleansing (from one large study), and ii) silver-alginate patch against a control group without patch (from two smaller studies). The quality of the included studies are high, except that the people closely involved in the trials such as the care personnel were not masked from knowing whether or not the infants in the study were given antiseptic or antibiotic dressing, which might have affected their recording or interpretation of the results. One of the studies was funded in part by Johnson and Johnson Medical; Children's Foundation; Children's Hospital, Milwaukee and National Institutes of Health. Another study was funded by the Vanderbilt NICU Research Fund. Funding source was not stated in the third study. In our main findings, chlorhexidine dressing/alcohol skin cleansing made no difference to catheter-related blood stream infection (CRBSI) and blood stream infection ("sepsis") without an identifiable source, although it significantly reduced the chance of micro-organisms lodging in the CVCs ("catheter colonisation"), with an average of 9% reduction in risk among newborn infants with a baseline risk of 24% (1 study, 655 infants). However, infants who received chlorhexidine dressing/alcohol skin cleansing were more likely to develop skin irritation ("contact dermatitis"), as 19 out of 335 infants (5.7%) in the chlorhexidine group developed this complication compared to none in the group that received standard dressing/povidone-iodine cleansing. However, it was unclear whether the dressing or the alcohol solution was mainly responsible for the skin irritation, as the other group did not use alcohol solution for skin cleansing. In the other comparison, silver-alginate patch made no overall differences in CRBSI and mortality compared to no dressing, neither did it cause any adverse reaction. There was moderate-quality evidence for all the major outcomes. The major factor that affected the quality of evidence was the lack of precision in the result estimates, as the calculated plausible range of the effects (the 95% confidence intervals) were wide. Chlorhexidine CVC dressing with alcohol skin cleansing posed a high risk of skin irritation against a modest reduction in catheter colonisation. For silver-alginate patch, evidence is still insufficient for a clear picture of benefit an harm. We have made recommendations for future research that evaluate these interventions.

10.1002/14651858.CD011082.pub2

cochrane-simplification-train-581

cochrane-simplification-train-581

Three eligible studies were identified, all comparing the use of an FIS with a VLS. All studies were small, with only 131 participants in total across all trials. It was impossible for the intubators to be unaware of the device used, so all studies were at high risk of performance and detection bias for outcomes related to intubation. Because of substantial differences in design between the studies, we did not combine their results in meta-analyses. The results for all outcomes were inconclusive, with no differences noted between FIS and VLS. Two studies with experienced intubators reported first attempt success rates greater than 70% in both groups and less than 5% of participants requiring a change of intubation device. No evidence was found of any difference in difficulty or time taken between FIS and VLS intubation. No serious complications or airway trauma was reported, so we were unable to address these outcomes. Bleeding was uncommon, occurring in less than 5% of participants, and we found no evidence that it was more likely in the FIS group. One small study with a novice intubator reported no successful intubations using an FIS and compared with the use of an intubating SAD and stylet, as well as with a VLS. With only five participants in each group, no conclusions can be drawn from these additional comparisons. The evidence base is sparse, and the existing literature does not address the clinical questions of patient safety posed by this review. We are therefore unable to draw any conclusions on safety or effectiveness. More primary research is needed to investigate optimal intubation techniques in obese patients, and new studies should be powered to detect differences in complications and in success rates rather than process measures such as speed, which are of limited clinical importance.

These scopes allow the intubator to see the airway via a camera, but no reviews have examined the use of an FIS in this situation. Intubation with an FIS is considered an advanced method, requiring training and experience; therefore it may be underused in clinical practice. We aimed to compare the safety and effectiveness of an FIS used for tracheal intubation in obese patients with direct laryngoscopy and other intubation methods that give the intubator an indirect view of the larynx. These other methods include videolaryngoscopes (VLSs)—metal laryngoscopes that contain a camera. We found three small studies, with a total of 131 patients, that compared an FIS with a VLS. The results for all patient safety outcomes were inconclusive, and no differences were noted between intubation with a flexible scope and intubation with a videolaryngoscope. We are unable to make any recommendations for practice based on this review. More research is needed to identify the technique for intubating obese people that would offer the best success rate with the fewest complications.

10.1002/14651858.CD010320.pub2

cochrane-simplification-train-582

cochrane-simplification-train-582

We included four trials (4608 women), but only two studies contributed data to the review's analyses (n = 4472). The studies contributing data were assessed as of high risk of bias overall. One of these studies was cluster-randomised and conducted in a low-income country and the other study was carried out in a high-income country. All four included studies assessed blood loss in the third stage of labour. Birth attendants estimated blood loss in two trials. The third trial assessed the hematocrit level on the second day postpartum to determine the effect of the bleeding. The fourth study measured PPH ≥ 500 mL. Nipple stimulation versus no treatment One study (4385 women) compared the effect of suckling versus no treatment. Blood loss was not measured in 114 women (59 in control group and 55 in suckling group). After excluding twin pregnancies, stillbirths and neonatal deaths, the main analyses for this trial were performed on 4227 vaginal deliveries. In terms of maternal death or severe morbidity, one maternal death occurred in the suckling group due to retained placenta (risk ratio (RR) 3.03, 95% confidence interval (CI) 0.12 to 74.26; one study, participants = 4227; very low quality evidence); severe morbidity was not mentioned. Severe PPH (≥ 1000 mL) was not reported in this study. The incidence of PPH (≥ 500 mL) was similar in the suckling and no treatment groups (RR 0.95, 95% CI 0.77 to 1.16; one study, participants = 4227; moderate quality). There were no group differences between nipple stimulation and no treatment regarding blood loss in the third stage of labour (mean difference (MD) 2.00, 95% CI -7.39 to 11.39; one study, participants = 4227; low quality). The rates of retained placenta were similar (RR 1.01, 95% CI 0.14 to 7.16; one study, participants = 4227; very low quality evidence), as were perinatal deaths (RR 1.06, 95% CI 0.57 to 1.98; one study, participants = 4271; low quality), and maternal readmission to hospital (RR 1.01, 95% CI 0.14 to 7.16; one study, participants = 4227; very low quality). We downgraded the evidence for this comparison for risk of bias concerns in the one included trial (inappropriate analyses for cluster design) and for imprecision (wide CIs crossing the line of no difference and, for some outcomes, few events). Many maternal secondary outcomes (including side effects) were not reported. Similarly, most neonatal secondary outcomes were not reported. Nipple stimulation versus oxytocin Another study compared the effect of nipple stimulation (via a breast pump) with oxytocin. Eighty-seven women were recruited but only 85 women were analysed. Severe PPH ≥ 1000 mL and maternal death or severe morbidity were not reported. There was no clear effect of nipple stimulation on blood loss (MD 15.00, 95% CI -24.50 to 54.50; one study, participants = 85; low quality evidence), or on postnatal anaemia compared to the oxytocin group (MD -0.40, 95% CI -2.22 to 1.42; one study, participants = 85; low quality evidence). We downgraded evidence for this comparison due to risk of bias concerns in the one included trial (alternate allocation) and for imprecision (wide CIs crossing the line of no difference and small sample size). Many maternal secondary outcomes (including side effects) were not reported, and none of this review's neonatal secondary outcomes were reported. None of the included studies reported one of this review's primary outcomes: severe PPH ≥ 1000 mL. Only one study reported on maternal death or severe morbidity. There were limited secondary outcome data for maternal outcomes and very few secondary outcome data for neonatal outcomes. There was no clear differences between nipple stimulation (suckling) versus no treatment in relation to maternal death, the incidence of PPH (≥ 500 mL), blood loss in the third stage of labour, retained placenta, perinatal deaths or maternal readmission to hospital. Whilst these data are based on a single study with a reasonable sample size, the quality of these data are mostly low or very low. There is insufficient evidence to evaluate the effect of nipple stimulation for reducing postpartum haemorrhage during the third stage of labour and more evidence from high-quality studies is needed. Further high-quality studies should recruit adequate sample sizes, assess the impact of nipple stimulation compared to uterotonic agents such as syntometrine and oxytocin, and report on important outcomes such as those listed in this review.

We searched for evidence on 15 July 2015 and included four randomised controlled studies with 4608, women but only two of the studies had useable data. We assessed both studies contributing outcome data as being at a high risk of bias. One study compared the effect of the baby suckling immediately after birth with no intervention. Another study compared nipple stimulation (with a breast pump) versus oxytocin injection. Neither study reported postpartum haemorrhage. Side effects of the treatments were not reported. Similarly, there was limited information on other consequences for women and their babies. When comparing nipple stimulation (suckling) with no breastfeeding, there were no clear differences in terms of the number of maternal deaths. The incidence of severe maternal illness was not reported. One woman in the suckling group died as a result of a retained placenta. Blood loss greater than or equal to 500 mL, retained placenta, perinatal deaths and maternal readmission to hospital were not clearly different between those who breast fed and those who did not. While these data were based on a single study with a reasonable sample size (4227 women), the results were mostly of low or very low quality due to concerns related to data analysis and study methodology. Our comparison of nipple stimulation (using a breast pump) versus oxytocin included one small study involving 85 women only. There was no clear difference between the groups in relation to blood loss or postnatal anaemia. These results were of low quality due to our concerns about the way the trial was conducted and its small size. There is insufficient evidence to evaluate the effectiveness of nipple stimulation for reducing bleeding during the third stage of labour and more evidence from high-quality studies is warranted. Future randomised clinical trials, with sufficient sample sizes should assess the impact of nipple stimulation in comparison to agents that stimulate the uterus such as syntometrine or oxytocin alone and report on important outcomes such as those listed in this review.

10.1002/14651858.CD010845.pub2

cochrane-simplification-train-583

cochrane-simplification-train-583

Only one trial with an unclear risk of bias in the majority of domains was included in the study; the overall study quality was judged to be low. This factorial trial of 256 women compared three types of postal reminder strategies (in a total of 213 women) with usual care (no postal reminder, 43 women) and reported on the uptake of four possible types of glucose tests. The three strategies investigated were: reminders sent to both the woman and the physician; reminder sent to the woman only; and reminder sent to the physician only, all issued approximately three months after the woman had given birth. There was low-quality evidence that all three reminder interventions increased uptake of oral glucose tolerance tests compared with usual care (no reminder system): reminders to the woman and the physician (uptake 60% versus 14%): risk ratio 4.23 (95% confidence interval (CI) 1.85 to 9.71); 116 participants); reminder to the woman only (uptake 55% versus 14%): RR 3.87 (95% CI 1.68 to 8.93); 111 participants); reminder to the physician only (uptake 52% versus 14%): RR 3.61 (95% CI 1.50 to 8.71); 66 participants). This represented an increase in uptake from 14% in the no reminder group to 57% across the three reminder groups. There was also an increase in uptake of fasting glucose tests in the reminder group compared with the usual care group: reminders to the woman and the physician versus no reminder (uptake 63% versus 40%): RR 1.57 (95% CI 1.01 to 2.44); reminder to the woman only (uptake 71% versus 40%): RR 1.78 (95% CI 1.16 to 2.73); reminder to the physician only (uptake 68% versus 40%): RR 1.69 (95% CI 1.06 to 2.72). Uptake of random glucose and glycated haemoglobin A1c tests was low, and no statistically significant differences were seen between the reminder and no reminder groups for these tests. Uptake of any test was higher in each of the reminder groups compared with the no reminder group (RR 1.65 (95% CI 1.12 to 2.41); 1.73 (95% CI 1.18 to 2.52); and 1.55 (95% CI 1.01 to 2.38) in the respective reminder groups. The trial did not report this review's other primary outcomes (proportion of women diagnosed with type 2 diabetes or showing impaired glucose tolerance or impaired fasting glucose after giving birth; or health-related quality of life). Nor did it report any secondary review outcomes such as diabetes-associated morbidity, lifestyle changes, need for insulin, recurrence of GDM or women's and/or health professionals' views of the intervention. No adverse events of the intervention were reported. Subgroup interaction tests gave no indication that dual reminders (to both women and physicians) were more successful than single reminders to either women or physicians alone. It was also not clear if test uptakes between women in the reminder and no reminder groups differed by type of glucose test undertaken. Results from the only trial that fulfilled our inclusion criteria showed low-quality evidence for a marked increase in the uptake of testing for type 2 diabetes in women with previous GDM following the issue of postal reminders. The effects of other forms of reminder systems need to be assessed to see whether test uptake also increases when email and telephone reminders are deployed. We also need a better understanding of why some women fail to take opportunities to be screened postpartum. As the ultimate aim of increasing postpartum testing is to prevent the subsequent development of type 2 diabetes, it is important to determine whether increased test uptake rates also increase women's use of preventive strategies such as lifestyle modifications.

A single study of 256 women who had experienced GDM whether posting reminder letters to 213 women or their doctors, three months after the birth of a baby, would help to increase the number of women taking a blood glucose test compared with 43 women sent no reminder. This study showed that, compared with no reminder, a postal reminder was around two to four times (depending on the blood glucose test concerned) more likely to encourage women who had experienced GDM to take a blood glucose test three months after having their baby. It did not seem to make a difference if the reminder was sent to the woman only, the physician only or to both the woman and the physician. The trial did not assess women's quality of life, or how many women were subsequently diagnosed with type 2 diabetes or impaired glucose results after giving birth. Other kinds of reminders such as email and telephone need to be assessed in studies as they might be easier and more convenient for women than posted reminders. We need to know more about women's preferences and attitudes, and also to find out whether increasing the chances of a woman being tested helps to reduce her risk of developing type 2 diabetes in the future, for example by encouraging a healthier diet and more exercise. The overall quality of evidence was considered low as the only included study involved few numbers of participants and provided imprecise results. This evidence is up to date as of June 2013.

10.1002/14651858.CD009578.pub2

cochrane-simplification-train-584

cochrane-simplification-train-584

Six randomised, double-blind studies between 12 and 24 weeks' long met the inclusion criteria. Five studies contributed data to the meta-analysis, assigning 2781 people with stable asthma to the comparison of interest. The definition of stable asthma and inclusion criteria varied across studies, and Global Initiative for Asthma (GINA) criteria were not used. Risk of bias across studies was generally low, and most evidence was rated as moderate quality. Stopping LABA might increase the number of people having exacerbations and requiring oral corticosteroids (odds ratio (OR) 1.74, 95% confidence interval (CI) 0.83 to 3.65; participants = 1257; studies = 4), although the confidence intervals did not exclude the possibility that stopping LABA was beneficial; over 17 weeks, 19 people per 1000 who continued their LABA had an exacerbation, compared with 32 per 1000 when LABA were stopped (13 more per 1000, 95% CI 3 fewer to 46 more). People who stopped LABA had worse scores on the Asthma Control Questionnaire (mean difference (MD) 0.24, 95% CI 0.13 to 0.35; participants = 645; studies = 3) and on measures of asthma-related quality of life (standardised mean difference (SMD) 0.36, 95% CI 0.15 to 0.57; participants = 359; studies = 2) than those who continued LABA, but the effects were not clinically relevant. Too few events occurred for investigators to tell whether stopping LABA has a greater effect on serious adverse events compared with continuing LABA+ICS (OR 0.82, 95% CI 0.28 to 2.42; participants = 1342; studies = 5), and no study reported exacerbations requiring an emergency department visit or hospitalisation as a separate outcome. Stopping LABA may result in fewer adverse events of any kind compared with continuing, although the effect was not statistically significant (OR 0.83, 95% CI 0.66 to 1.05; participants = 1339; studies = 5), and stopping LABA made people more likely to withdraw from participation in research studies (OR 1.95, 95% CI 1.47 to 2.58; participants = 1352; studies = 5). This review suggests that stopping LABA in adults who have stable asthma while they are taking a combination of LABA and ICS inhalers may increase the likelihood of asthma exacerbations that require treatment with oral corticosteroids, but this is not certain. Stopping LABA may slightly reduce asthma control and quality of life, but evidence was insufficient to show whether this had an effect on important outcomes such as serious adverse events and exacerbations requiring hospital admission, and longer trials are warranted. Trialists should include patient-important outcomes such as asthma control and quality of life and should use validated measurement tools. Definitions of exacerbations should be provided.

We looked for studies at least 8 weeks' long that compared a group of people with stable asthma who stopped taking LABA versus a group who continued taking ICS+LABA together. We were mainly interested in determining whether stopping LABA had an effect on asthma attacks, asthma control or side effects. What did we find out? We included in the data analyses five studies of people with stable asthma. We rated the overall quality of evidence as moderate for most outcomes, meaning that additional studies are likely to change our confidence in what we found. It looked as though people who stopped LABA might be more likely to have asthma attacks needing treatment with oral steroids, but this is uncertain. Over 17 weeks, 19 of 1000 people continuing their LABA had an attack, compared with 32 of 1000 who stopped taking LABA. This means that 13 more people in 1000 would have an attack if they stopped their LABA, but the uncertainty meant that between 3 fewer and 46 more could be affected. Asthma control and asthma-related quality of life were a bit worse among people who stopped taking LABA, and we could not tell whether stopping LABA increased serious side effects or admission to the hospital.

10.1002/14651858.CD011306.pub2

cochrane-simplification-train-585

cochrane-simplification-train-585

We identified six trials, involving 479 subjects, comparing incision and drainage of perianal abscess alone versus incision and drainage with fistula treatment. Metaanalysis showed a significant reduction in recurrence, persistent abscess/fistula or repeat surgery in favour of fistula surgery at the time of abscess incision and drainage (RR=0.13, 95% Confidence Interval of RR = 0.07-0.24). Transient manometric reduction in anal sphincter pressures, without clinical incontinence, may occur after treatment of low fistulae with abscess drainage. Incontinence at one year following drainage with fistula surgery was not statistically significant (pooled RR 3.06, 95% Confidence Interval 0.7-13.45) with heterogeneity demonstrable between the trials (Chi2 =5.39,df=3, p=0.14, I2 =44.4%). The published evidence shows fistula surgery with abscess drainage significantly reduces recurrence or persistence of abscess/fistula, or the need for repeat surgery. There was no statistically significant evidence of incontinence following fistula surgery with abscess drainage. This intervention may be recommended in carefully selected patients.

This systematic review assesses randomised trials that have addressed the benefits and risks of combined treatment of perianal abscesses and fistulae. Six studies have been published on this topic. The analyses show that combined treatment reduces the risk of persistent abscess or fistula, or repeat surgery without a statistically significant increase in postoperative incontinence.

10.1002/14651858.CD006827.pub2

cochrane-simplification-train-586

cochrane-simplification-train-586

This review included 12 multicentre RCTs randomly assigning 9547 participants with stable COPD. All the studies were industry-sponsored and had similar inclusion criteria with relatively good methodological quality. All but one study included in the meta-analysis were double-blind and scored low risk of bias. The study duration ranged from four weeks to 52 weeks. Participants were more often males, mainly Caucasians, mean age ranging from 61.7 to 65.6 years, and with a smoking history of 10 or more pack years. They had moderate to severe symptoms at randomisation; the mean post-bronchodilator forced expiratory volume in one second (FEV1) was between 46% and 57.6% of the predicted normal value, and the mean St George's Respiratory Questionnaire score (SGRQ) ranged from 45.1 to 50.4 when reported. There was no difference between aclidinium and placebo in all-cause mortality (low quality) and number of patients with exacerbations requiring a short course of oral steroids or antibiotics, or both (moderate quality). Aclidinium improved quality of life by lowering the SGRQ total score with a mean difference of -2.34 (95% CI -3.18 to -1.51; I2 = 48%, 7 trials, 4442 participants) when compared to placebo. More patients on aclidinium achieved a clinically meaningful improvement of at least four units decrease in SGRQ total score (OR 1.49; 95% CI 1.31 to 1.70; I2 = 34%; number needed to treat (NNT) = 10, 95% CI 8 to 15, high quality evidence) over 12 to 52 weeks than on placebo. Aclidinium also resulted in a significantly greater improvement in pre-dose FEV1 than placebo with a mean difference of 0.09 L (95% CI 0.08 to 0.10; I2 = 39%, 9 trials, 4963 participants). No trials assessed functional capacity. Aclidinium reduced the number of patients with exacerbations requiring hospitalisation by 4 to 20 fewer per 1000 over 4 to 52 weeks (OR 0.64; 95% CI 0.46 to 0.88; I2 = 0%, 10 trials, 5624 people; NNT = 77, 95% CI 51 to 233, high quality evidence) compared to placebo. There was no difference in non-fatal serious adverse events (moderate quality evidence) between aclidinium and placebo. Compared to tiotropium, aclidinium did not demonstrate significant differences for exacerbations requiring oral steroids or antibiotics, or both, exacerbation-related hospitalisations and non-fatal serious adverse events (very low quality evidence). Inadequate data prevented the comparison of aclidinium to formoterol or other LABAs. Aclidinium is associated with improved quality of life and reduced hospitalisations due to severe exacerbations in patients with moderate to severe stable COPD compared to placebo. Overall, aclidinium did not significantly reduce mortality, serious adverse events or exacerbations requiring oral steroids or antibiotics, or both. Currently, the available data are insufficient and of very low quality in comparisons of the efficacy of aclidinium versus tiotropium. The efficacy of aclidinium versus LABAs cannot be assessed due to inaccurate data. Thus additional trials are recommended to assess the efficacy and safety of aclidinium compared to other LAMAs or LABAs.

The evidence was current to 7 April 2014. We included 12 studies involving 9547 COPD patients over a period of four to 52 weeks. These studies were sponsored by drug companies and were well designed. Both patients and the people doing the research did not know which treatment the patients were getting; although in one study one treatment was known to both parties. More men than women took part, and they were mostly Caucasians. They were in their 60s and had smoked a lot in their lives. These people had moderate to severe symptoms when they started treatment. Aclidinium did not reduce the number of people with flare-ups that need additional drugs. There was little or no difference in deaths or serious side effects between aclidinium and a dummy inhaler. Aclidinium inhalers improved quality of life more than the dummy inhalers. People who took aclidinium had fewer hospital admissions due to serious flare-ups. Based on our results, among 1000 COPD patients using a dummy inhaler over four weeks to one year 37 would have severe flare-ups needing hospital admission. Only 17 to 33 patients out of 1000 would require hospital admission if they were using aclidinium inhalers. We also set out to compare this new medication with tiotropium, which is already used to treat COPD. There were only two studies for this comparison thus we could not be sure how aclidinium compared to tiotropium. We also could not compare aclidinium with another well known inhaler that contains the drug formoterol because of unreliable data. For the comparison of aclidinium inhalers and dummy inhalers, we are confident that there are benefits in terms of the number of hospitalisations and patients' quality of life; we are less certain about the numbers of flare-ups needing additional drugs and serious side effects. We do not have enough information to assess any effect on the number of deaths. We did not have enough information to reliably compare aclidinium with tiotropium or formoterol.

10.1002/14651858.CD010509.pub2

cochrane-simplification-train-587

cochrane-simplification-train-587

A total of 43 randomised controlled trials (4,364 participants) were included in this review. Very few trials provided data suitable for inclusion in a meta-analysis. Among the five trials that yielded data assessing the daily frequency of hot flushes suitable for pooling, no significant difference overall was noted in the incidence of hot flushes between participants taking Promensil (a red clover extract) and those given placebo (mean difference (MD) -0.93, 95% confidence interval (CI) -1.95 to 0.10, I2 = 31%). No evidence indicated a difference in percentage reduction in hot flushes in two trials between Promensil and placebo (MD 20.15, 95% CI -12.08 to 52.38, I2 = 82%). Four trials that were not combined in meta-analyses suggested that extracts with high (> 30 mg/d) levels of genistein consistently reduced the frequency of hot flushes. Individual results from the remaining trials were compared in broad subgroups such as dietary soy, soy extracts and other types of phytoestrogens that could not be combined. Some of these trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared with placebo, but many trials were small and were determined to be at high risk of bias. A strong placebo effect was noted in most trials, with a reduction in frequency ranging from 1% to 59% with placebo. No indication suggested that discrepant results were due to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms or trial quality factors. Also, no evidence indicated that these treatments caused oestrogenic stimulation of the endometrium or the vagina or other adverse effects when used for up to two years. No conclusive evidence shows that phytoestrogen supplements effectively reduce the frequency or severity of hot flushes and night sweats in perimenopausal or postmenopausal women, although benefits derived from concentrates of genistein should be further investigated.

This review found 43 RCTs conducted up to July 2013 that included 4,084 participants with hot flushes who were close to the menopause or were menopausal. Evidence obtained is current to July 2013. Some trials reported a slight reduction in hot flushes and night sweats with phytoestrogen-based treatment. Extracts containing high levels of genistein (a substance derived from soy) appeared to reduce the number of daily hot flushes and need to be investigated further. Overall no indication suggested that other types of phytoestrogens work any better than no treatment. No evidence was found of harmful effects on the lining of the womb, stimulation of the vagina or other adverse effects with short-term use. Many of the trials in this review were small, of short duration and of poor quality, and the types of phytoestrogens used varied substantially.

10.1002/14651858.CD001395.pub4

cochrane-simplification-train-588

cochrane-simplification-train-588

Twenty-eight trials involving 107,362 women in seven countries are included in this updated review. Five studies involving 3,124 women did not contribute outcome data and we excluded them from the analyses. The methodological quality of the included trials was mixed, with significant numbers of studies at high or unclear risk of bias due to: inadequate allocation concealment (N = 20); lack of blinding of outcome assessment (N = 20); incomplete outcome data (N = 19); selective reporting (N = 22) and bias from other potential sources (N = 17). Healthcare professional-led breastfeeding education and support versus standard care The studies pooled here compare professional health workers delivering breastfeeding education and support during the prenatal and postpartum periods with standard care. Interventions included promotion campaigns and counselling, and all took place in a formal setting. There was evidence from five trials involving 564 women for improved rates ofbreastfeeding initiation among women who received healthcare professional-led breastfeeding education and support (average risk ratio (RR) 1.43, 95% confidence interval (CI) 1.07 to 1.92; Tau² = 0.07, I² = 62%, low-quality evidence) compared to those women who received standard care. We downgraded evidence due to design limitations and heterogeneity. The outcome of early initiation of breastfeeding was not reported in the studies under this comparison. Non-healthcare professional-led breastfeeding education and support versus standard care There was evidence from eight trials of 5712 women for improved rates of breastfeeding initiation among women who received interventions from non-healthcare professional counsellors and support groups (average RR 1.22, 95% CI 1.06 to 1.40; Tau² = 0.02, I² = 86%, low-quality evidence) compared to women who received standard care. In three trials of 76,373 women, there was no clear difference between groups in terms of the number of women practicing early initiation of breastfeeding (average RR 1.70, 95% CI 0.98 to 2.95; Tau² = 0.18, I² = 78%, very low-quality evidence). We downgraded the evidence for a combination of design limitations, heterogeneity and imprecision (wide confidence intervals crossing the line of no effect). Other comparisons Other comparisons in this review also looked at the rates of initiation of breastfeeding and there were no clear differences between groups for the following comparisons of combined healthcare professional-led education with peer support or community educator versus standard care (2 studies, 1371 women) or attention control (1 study, 237 women), breastfeeding education using multimedia (a self-help manual or a video) versus routine care (2 studies, 497 women); early mother-infant contact versus standard care (2 studies, 309 women); and community-based breastfeeding groups versus no breastfeeding groups (1 study, 18,603 women). None of these comparisons reported data on early initiation of breastfeeding. This review found low-quality evidence that healthcare professional-led breastfeeding education and non-healthcare professional-led counselling and peer support interventions can result in some improvements in the number of women beginning to breastfeed. The majority of the trials were conducted in the USA, among women on low incomes and who varied in ethnicity and feeding intention, thus limiting the generalisability of these results to other settings. Future studies would ideally be conducted in a range of low- and high-income settings, with data on breastfeeding rates over various timeframes, and explore the effectiveness of interventions that are initiated prior to conception or during pregnancy. These might include well-described interventions, including health education, early and continuing mother-infant contact, and initiatives to help mothers overcome societal barriers to breastfeeding, all with clearly defined outcome measures.

We searched for evidence on 29 February 2016. This updated review now includes 28 randomised controlled studies involving 107,362 women. Twenty studies involving 27,865 women looked at interventions to increase the number of women who started breastfeeding, in three high-income countries (Australia, 1 study; UK, 4 studies; and USA, 14 studies) and one lower middle-income country (Nicaragua, 1 study). Three studies investigated the effect of an intervention to increase the number of women who started breastfeeding early, within one hour after birth. These involved 76,373 women from Malawi, Nigeria and Ghana. The study from Malawi was large, with 55,931 participants. Health education delivered by doctors and nurses and counselling and peer support by trained volunteers improved the number of women who began breastfeeding their babies. Five studies involving 564 women reported that women who received breastfeeding education and support from doctors or nurses were more likely to start breastfeeding compared to women who received standard care. Four of these studies were conducted in low-income or amongst minority ethnic women in the USA, where baseline breastfeeding rates are typically low. Eight studies involving 5712 women showed improved rates of starting breastfeeding with trained volunteer-delivered interventions and support groups compared to the women who received standard care. Breastfeeding education provided by trained volunteers could also improve the rates of early initiation of breastfeeding, within one hour of giving birth, in low-income countries. We assessed all the evidence in this review to be low-quality because of limitations in study design and variations in the interventions, to whom, when, where, and how an intervention was delivered. Standard care also differed and could include some breastfeeding support, for example, in the UK. We found too little evidence to say whether strategies with multimedia, early mother-infant contact, or community-based breastfeeding groups were able to improve breastfeeding initiation. Health professionals with training in breastfeeding including midwives, nurses, and doctors, and trained volunteers can deliver education sessions and provide counselling and peer support to increase the number of women who start breastfeeding their babies. High-quality research is needed to understand which interventions are likely to be effective in different population groups. More studies are needed in low- and middle-income countries to find out which strategies will encourage women to start breastfeeding just after giving birth.

10.1002/14651858.CD001688.pub3

cochrane-simplification-train-589

cochrane-simplification-train-589

We found 41 trials (>33,000 participants) which met our inclusion criteria. Four trials, which directly compared the same intervention in stage-based and standard versions, found no clear advantage for the staging component. Stage-based versus standard self-help materials (two trials) gave a relative risk (RR) of 0.93 (95% CI 0.62 to 1.39). Stage-based versus standard counselling (two trials) gave a relative risk of 1.00 (95% CI 0.82 to 1.22). Six trials of stage-based self-help systems versus any standard self-help support demonstrated a benefit for the staged groups, with an RR of 1.27 (95% CI 1.01 to 1.59). Twelve trials comparing stage-based self help with 'usual care' or assessment-only gave an RR of 1.32 (95% CI 1.17 to 1.48). Thirteen trials of stage-based individual counselling versus any control condition gave an RR of 1.24 (95% CI 1.08 to 1.42). These findings are consistent with the proven effectiveness of these interventions in their non-stage-based versions. The evidence was unclear for telephone counselling, interactive computer programmes or training of doctors or lay supporters. This uncertainty may be due in part to smaller numbers of trials. Based on four trials using direct comparisons, stage-based self-help interventions (expert systems and/or tailored materials) and individual counselling were neither more nor less effective than their non-stage-based equivalents. Thirty-one trials of stage-based self help or counselling interventions versus any control condition demonstrated levels of effectiveness which were comparable with their non-stage-based counterparts. Providing these forms of practical support to those trying to quit appears to be more productive than not intervening. However, the additional value of adapting the intervention to the smoker's stage of change is uncertain. The evidence is not clear for other types of staged intervention, including telephone counselling, interactive computer programmes and training of physicians or lay supporters. The evidence does not support the restriction of quitting advice and encouragement only to those smokers perceived to be in the preparation and action stages.

In this review, we have compared stage-based programmes of smoking cessation with standard (unstaged) programmes, or with 'usual care', or with assessment only. We found 41 stage-based trials, covering more than 33,000 smokers, which measured quit rates at least six months after treatment. Only four of the 41 trials directly compared the same intervention in a standard and a stage-based version. This showed that the stage-based version was neither more nor less effective than the standard one. Eighteen trials which compared stage-based self-help programmes with any control condition showed better success rates for the intervention groups. Thirteen trials of stage-based individual counselling versus any control condition showed a similar benefit for the intervention groups. These findings confirm the known effectiveness of these interventions, whether staged or unstaged. The evidence was less clear on the effects of stage-based telephone counselling, interactive computer programmes or training of doctors and helpers. This uncertainty may be due in part to smaller numbers of trials. We find on the evidence from this review that providing self-help or counselling support to smokers trying to quit is more effective than 'usual care' or simple observation. However, the extra value of fitting that support to the smoker's stage of change is currently unclear.

10.1002/14651858.CD004492.pub4

cochrane-simplification-train-590

cochrane-simplification-train-590

We identified 24 eligible trials with a total of 7279 adult participants randomised. Two studies focused on relapse prevention among smokers who had recently stopped smoking, and the remaining 22 studies were concerned with smoking cessation for smokers who wished to quit. Eleven studies were with women only and one with men only. Most studies recruited fairly inactive people. Most of the trials employed supervised, group-based cardiovascular-type exercise supplemented by a home-based exercise programme and combined with a multi-session cognitive behavioural smoking cessation programme. The comparator in most cases was a multi-session cognitive behavioural smoking cessation programme alone. Overall, we judged two studies to be at low risk of bias, 11 at high risk of bias, and 11 at unclear risk of bias. Among the 21 studies analysed, we found low-certainty evidence, limited by potential publication bias and by imprecision, comparing the effect of exercise plus smoking cessation support with smoking cessation support alone on smoking cessation outcomes (RR 1.08, 95% CI 0.96 to 1.22; I2 = 0%; 6607 participants). We excluded one study from this analysis as smoking abstinence rates for the study groups were not reported. There was no evidence of subgroup differences according to the type of exercise promoted; the subgroups considered were: cardiovascular-type exercise alone (17 studies), resistance training alone (one study), combined cardiovascular-type and resistance exercise (one study) and type of exercise not specified (two studies). The results were not significantly altered when we excluded trials with high risk of bias, or those with special populations, or those where smoking cessation intervention support was not matched between the intervention and control arms. Among the two relapse prevention studies, we found very low-certainty evidence, limited by risk of bias and imprecision, that adding exercise to relapse prevention did not improve long-term abstinence compared with relapse prevention alone (RR 0.98, 95% CI 0.65 to 1.47; I2 = 0%; 453 participants). There is no evidence that adding exercise to smoking cessation support improves abstinence compared with support alone, but the evidence is insufficient to assess whether there is a modest benefit. Estimates of treatment effect were of low or very low certainty, because of concerns about bias in the trials, imprecision and publication bias. Consequently, future trials may change these conclusions.

We found 24 studies with a total of 7279 people. Two studies focused on helping those who had recently stopped smoking and the rest of the studies included current smokers who wished to quit. All the studies were conducted with adults. Eleven studies were with women only and one with men only. Most studies recruited fairly inactive people. Most studies offered supervised and group-based, aerobic-type exercise. The evidence is up-to-date to May 2019. When we combined the results of 21 studies (6607 participants) which compared exercise and smoking-cessation programmes to smoking cessation programmes alone, there was no evidence that exercise increased quit rates at six months or longer. There was no evidence that the effect was different for different types of exercise. When we combined results from two studies (453 participants), there was no evidence that exercise helped people who had recently quit to stay quit. We judged the quality of evidence for whether exercise programmes help people quit smoking as low certainty, suggesting that future research could change these results. The low certainty is because we cannot rule out chance as an explanation for the suggested slight benefit. It could be that exercise may not help at all, or it could be that supporting people to do exercise modestly increases quit rates. We do not know which of these is true. We also consider that a good number of the trials may be biased. We have concerns that small studies which found smaller effects were less likely to be published than small studies which found bigger effects, making the average result misleading. We judged the evidence from two studies examining whether exercise helps people to avoid relapse to smoking to be of very low certainty, again suggesting that more research is needed. This is due to imprecision of the estimated effects and a high risk of bias in the methods used by one of the studies.

10.1002/14651858.CD002295.pub6

cochrane-simplification-train-591

cochrane-simplification-train-591

Ten randomised controlled trials were available for analysis. The quality of included studies was adequate, though in some trials the numbers were small and they were inadequately powered for equivalence or to detect significant differences. Comparisons were made between various modalities of treatments. There were no significant difference in recurrence rates or incontinence rates in any of the studied comparisons except in the case of advancement flaps. There were more recurrences in the glue plus flap group, a significant difference that favoured the flap only technique. It was also noted that Fibrin glue and advancement flap procedures report low incontinence rates.In the review of literature of non-randomised trials, most trials on fibrin glue indicate good healing in simple fistulae with low incontinence rates. There are very few randomized controlled trials comparing the various modalities of surgery for fistula in ano. While post operative pain, time to healing and discharge from hospital affect quality of life, recurrence and incontinence are the most important. As it turns out, there seems to be no major difference between the various techniques used as far as recurrence rates are concerned. The use of Fibrin glue and advancement flaps are associated with low incontinence rates. There is a crying need for well powered, well conducted randomised controlled trials comparing various modes of treatment of fistula in ano. Newer operations like the anal fistula plug and the LIFT procedure need to be evaluated by randomised clinical trials.

The reviewers identified 10 trials that compare various fistula treatments against one another. There are various parameters that these procedures can be compared on, but we looked at the two most important ones, recurrence (the numbers who got the disease again) and incontinence (a worsening in the ability to control rectal content). In the trials that were compared, there was no significant difference between the various comparisons for the disease to recur. However the trials on fibrin glue, as well as data from non randomised trials show that incontinence is less, probably as there is no surgical disruption of the anal muscle. There is a paucity of good quality data that compares various types of operative treatment for anorectal fistula and there is scope for further trials in the area.

10.1002/14651858.CD006319.pub2

cochrane-simplification-train-592

cochrane-simplification-train-592

We included 141 studies that involved 15,141 participants and evaluated 122 blood biomarkers. All the studies were of poor methodological quality. Studies evaluated the blood biomarkers either in a specific phase of the menstrual cycle or irrespective of the cycle phase, and they tested for them in serum, plasma or whole blood. Included women were a selected population with a high frequency of endometriosis (10% to 85%), in which surgery was indicated for endometriosis, infertility work-up or ovarian mass. Seventy studies evaluated the diagnostic performance of 47 blood biomarkers for endometriosis (44 single-marker tests and 30 combined tests of two to six blood biomarkers). These were angiogenesis/growth factors, apoptosis markers, cell adhesion molecules, high-throughput markers, hormonal markers, immune system/inflammatory markers, oxidative stress markers, microRNAs, tumour markers and other proteins. Most of these biomarkers were assessed in small individual studies, often using different cut-off thresholds, and we could only perform meta-analyses on the data sets for anti-endometrial antibodies, interleukin-6 (IL-6), cancer antigen-19.9 (CA-19.9) and CA-125. Diagnostic estimates varied significantly between studies for each of these biomarkers, and CA-125 was the only marker with sufficient data to reliably assess sources of heterogeneity. The mean sensitivities and specificities of anti-endometrial antibodies (4 studies, 759 women) were 0.81 (95% confidence interval (CI) 0.76 to 0.87) and 0.75 (95% CI 0.46 to 1.00). For IL-6, with a cut-off value of > 1.90 to 2.00 pg/ml (3 studies, 309 women), sensitivity was 0.63 (95% CI 0.52 to 0.75) and specificity was 0.69 (95% CI 0.57 to 0.82). For CA-19.9, with a cut-off value of > 37.0 IU/ml (3 studies, 330 women), sensitivity was 0.36 (95% CI 0.26 to 0.45) and specificity was 0.87 (95% CI 0.75 to 0.99). Studies assessed CA-125 at different thresholds, demonstrating the following mean sensitivities and specificities: for cut-off > 10.0 to 14.7 U/ml: 0.70 (95% CI 0.63 to 0.77) and 0.64 (95% CI 0.47 to 0.82); for cut-off > 16.0 to 17.6 U/ml: 0.56 (95% CI 0.24, 0.88) and 0.91 (95% CI 0.75, 1.00); for cut-off > 20.0 U/ml: 0.67 (95% CI 0.50 to 0.85) and 0.69 (95% CI 0.58 to 0.80); for cut-off > 25.0 to 26.0 U/ml: 0.73 (95% CI 0.67 to 0.79) and 0.70 (95% CI 0.63 to 0.77); for cut-off > 30.0 to 33.0 U/ml: 0.62 (95% CI 0.45 to 0.79) and 0.76 (95% CI 0.53 to 1.00); and for cut-off > 35.0 to 36.0 U/ml: 0.40 (95% CI 0.32 to 0.49) and 0.91 (95% CI 0.88 to 0.94). We could not statistically evaluate other biomarkers meaningfully, including biomarkers that were assessed for their ability to differentiate endometrioma from other benign ovarian cysts. Eighty-two studies evaluated 97 biomarkers that did not differentiate women with endometriosis from disease-free controls. Of these, 22 biomarkers demonstrated conflicting results, with some studies showing differential expression and others no evidence of a difference between the endometriosis and control groups. Of the biomarkers that were subjected to meta-analysis, none consistently met the criteria for a replacement or triage diagnostic test. A subset of blood biomarkers could prove useful either for detecting pelvic endometriosis or for differentiating ovarian endometrioma from other benign ovarian masses, but there was insufficient evidence to draw meaningful conclusions. Overall, none of the biomarkers displayed enough accuracy to be used clinically outside a research setting. We also identified blood biomarkers that demonstrated no diagnostic value in endometriosis and recommend focusing research resources on evaluating other more clinically useful biomarkers.

The evidence included in this review is current to July 2015. We included 141 studies involving 15,141 participants. All studies evaluated reproductive-aged women who were undertaking diagnostic surgery because they were suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). Cancer antigen-125 (CA-125) was the most common blood biomarker studied. Seventy studies evaluated 47 blood biomarkers that were expressed differently in women with and without endometriosis, and 82 studies identified 97 biomarkers that did not distinguish between the two groups. Twenty-two biomarkers were in both categories. Only four of the assessed biomarkers (anti-endometrial Abs (anti-endometrial autoantibodies), interleukin-6 (IL-6), CA-19.9 and CA-125) were evaluated by enough studies to provide a meaningful assessment of test accuracy. None of these tests was accurate enough to replace diagnostic surgery. Several studies identified biomarkers that might be of value in diagnosing endometriosis, but there are too few reports to be sure of their diagnostic benefit. Overall, there is not enough evidence to recommend testing for any blood biomarker in clinical practice to diagnose endometriosis. Generally, the reports were of low methodological quality, and most blood tests were only assessed by a single or a small number of studies. When the same biomarker was studied, there were significant differences in how studies were conducted, the group of women studied and the cut-offs used to determine a positive result. More high quality research trials are necessary to accurately assess the diagnostic potential of certain blood biomarkers, whose diagnostic value for endometriosis was suggested by a limited number of studies.

10.1002/14651858.CD012179

cochrane-simplification-train-593

cochrane-simplification-train-593

A total of 24 studies met our inclusion criteria. Seventeen studies provided data for the primary analysis: six studies (434 children) included data on procalcitonin, 13 studies (1638 children) included data on CRP, and six studies (1737 children) included data on ESR (some studies had data on more than one test). The summary sensitivity estimates (95% CI) for the procalcitonin, CRP, ESR tests at the aforementioned cutoffs were 0.86 (0.72 to 0.93), 0.94 (0.85 to 0.97), and 0.87 (0.77 to 0.93), respectively. The summary specificity values for procalcitonin, CRP, and ESR tests at these cutoffs were 0.74 (0.55 to 0.87), 0.39 (0.23 to 0.58), and 0.48 (0.33 to 0.64), respectively. The ESR test does not appear to be sufficiently accurate to be helpful in differentiating children with cystitis from children with pyelonephritis. A low CRP value (< 20 mg/L) appears to be somewhat useful in ruling out pyelonephritis (decreasing the probability of pyelonephritis to < 20%), but unexplained heterogeneity in the data prevents us from making recommendations at this time. The procalcitonin test seems better suited for ruling in pyelonephritis, but the limited number of studies and the marked heterogeneity between studies prevents us from reaching definitive conclusions. Thus, at present, we do not find any compelling evidence to recommend the routine use of any of these tests in clinical practice.

We found 24 relevant studies of which 17 provided data for our primary outcome. Six studies (434 children) provided data for the procalcitonin test; 13 studies (1638 children) provided data for the C-reactive protein test, and six studies (1737 children) provided data for the erythrocyte sedimentation rate test. We found all three tests to be sensitive (summary sensitivity values ranged from 86% to 95%), but not very specific (summary specificity values ranged from 38% to 71%). None of the tests were accurate enough to allow clinicians to confidently differentiate upper from lower urinary tract disease.

10.1002/14651858.CD009185.pub2

cochrane-simplification-train-594

cochrane-simplification-train-594

Twelve double-blind RCTs (n=700) met the inclusion criteria. The meta-analysis was done on seven studies using the total score on the Hamilton Anxiety (HAM-A) scale as a common outcome measure. The result suggests a significant effect towards a reduction of the HAM-A total score in patients receiving kava extract compared with patients receiving placebo (weighted mean difference: 3.9, 95% confidence interval: 0.1 to 7.7; p = 0.05; n = 380). The results of the five studies that were not submitted to meta-analysis largely support these findings. Adverse events as reported in the reviewed trials were mild, transient and infrequent. Compared with placebo, kava extract is an effective symptomatic treatment for anxiety although, at present, the size of the effect seems small. The effect lacks robustness and is based on a relatively small sample. The data available from the reviewed studies suggest that kava is relatively safe for short-term treatment (1 to 24 weeks), although more information is required. Rigorous trials with large sample sizes are needed to clarify the existing uncertainties. Also, long-term safety studies of kava are required.

Twelve trials met the inclusion criteria. The meta-analysis of seven trials suggests a significant treatment effect for the total score on the Hamilton Anxiety Scale in favour of kava extract. Few adverse events were reported in the reviewed trials, which were all mild, transient and infrequent. These data imply that, compared with placebo, kava extract might be an effective symptomatic treatment for anxiety although, at present, the size of the effect seems to be small. Rigorous trials with large sample sizes are needed to clarify the existing uncertainties. Particularly long-term safety studies of kava are needed.

10.1002/14651858.CD003383

cochrane-simplification-train-595

cochrane-simplification-train-595

We included 44 RCTs with a total of 12,284 participants (6042 in SEQ and 6242 in STT). The overall analysis showed that SEQ was significantly more effective than STT (82% vs 75% in the intention-to-treat analysis; RD 0.09, 95% confidence interval (CI) 0.06 to 0.11; P < 0.001, moderate-quality evidence). Results were highly heterogeneous (I² = 75%), and 20 studies did not demonstrate differences between therapies. Reporting by geographic region (RD 0.09, 95% CI 0.06 to 0.12; studies = 44; I² = 75%, based on low-quality evidence) showed that differences between SEQ and STT were greater in Europe (RD 0.16, 95% CI 0.14 to 0.19) when compared to Asia, Africa or South America. European studies also showed a tendency towards better efficacy with SEQ; however, this tendency was reversed in 33% of the Asian studies. Africa reported the closest risk difference (RD 0.14 , 95% 0.07 to 0.22) to Europe among studied regions, but confidence intervals were wider and therefore the quality of the evidence showing SEQ to be superior to STT was reduced for this region. Based on high-quality evidence, subgroup analyses showed that SEQ and STT therapies were equivalent when STT lasted for 14 days. Although, overall, the mean eradication proportion with SEQ was over 80%, we noted a tendency towards a lower average effect with this regimen in the more recent studies (2008 and after); weighted linear regression showed that the efficacies of both regimens evolved differently over the years, having a higher reduction in the efficacy of SEQ (-1.72% yearly) than in STT (-0.9% yearly). In these more recent studies (2008 and after) we were also unable to detect the superiority of SEQ over STT when STT was given for 10 days. Based on very low-quality evidence, subgroup analyses on antibiotic resistance showed that the widest difference in efficacy between SEQ and STT was in the subgroup analysis based on clarithromycin-resistant participants, in which SEQ reached a 75% average efficacy versus 43% with STT. Reporting on adverse events (AEs) (RD 0.00, 95% CI -0.02 to 0.02; participants = 8103; studies = 27; I² = 26%, based on high-quality evidence) showed no significant differences between SEQ and STT (20.4% vs 19.5%, respectively) and results were homogeneous. The quality of the studies was limited due to a lack of systematic reporting of the factors affecting risk of bias. Although randomisation was reported, its methodology (e.g. algorithms, number of blocks) was not specified in several studies. Additionally, the other 'Risk of bias' domains (such as allocation concealment of the sequence randomisation, or blinding during either performance or outcome assessment) were also unreported. However, subgroup analyses as well as sensitivity analyses or funnel plots indicated that treatment outcomes were not influenced by the quality of the included studies. On the other hand, we rated 'length of STT' and AEs for the main outcome as high-quality according to GRADE classification; but we downgraded 'publication date' quality to moderate, and 'geographic region' and 'antibiotic resistance' to low- and very low-quality, respectively. Our meta-analysis indicates that prior to 2008 SEQ was more effective than STT, especially when STT was given for only seven days. Nevertheless, the apparent advantage of sequential treatment has decreased over time, and more recent studies do not show SEQ to have a higher efficacy versus STT when STT is given for 10 days. Based on the results of this meta-analysis, although SEQ offers an advantage when compared with STT, it cannot be presented as a valid alternative, given that neither SEQ nor STT regimens achieved optimal efficacy ( ≥ 90% eradication rate).

We searched electronic databases and conference abstracts to identify any relevant studies. We include 44 studies, which tested and compared the cure rates of SEQ therapy against STTs. Our review covers research up to April 2015. The review indicates that before 2008 the cure rate for SEQ was higher than for STT. However, the cure rate of both treatments is lower than we would wish. The review found that effectiveness depended on several factors, including the geographic region of the study, bacterial resistance, and the date of the study. For example, we found a reduction in the cure rate over time in both STT and SEQ therapies, with a stronger reduction for SEQ. This meant that in the studies published after 2008, SEQ was not more effective than triple therapy when they were both given for 10 days. The evidence collected and combined in this review does not support the use of SEQ therapy, as its effectiveness can be matched and even improved on by better STTs (given for 10 or 14 days, or high acid inhibition). Results for SEQ were only partially successful. We need to find another form of therapy to provide the best treatment for patients. The studies included in this review were of mixed quality, but our analyses do not suggest that study quality was influencing cure rates.

10.1002/14651858.CD009034.pub2

cochrane-simplification-train-596

cochrane-simplification-train-596

We included 12 controlled trials that recruited 982 infants. There was heterogeneity between trials for the outcome IVH, with three trials finding a significant decrease in IVH and one trial finding an increase in IVH in the group receiving phenobarbital. Meta-analysis showed no difference between the phenobarbital-treated group and the control group in either all IVH (typical risk ratio (RR) 0.91; 95% CI 0.77 to 1.08), severe IVH (typical RR 0.77; 95% CI 0.58 to 1.04), posthaemorrhagic ventricular dilation (typical RR 0.89; 95% CI 0.38 to 2.08), severe neurodevelopmental impairment (typical RR 1.44; 95% CI 0.41 to 5.04) or death before hospital discharge (typical RR 0.88; 95% CI 0.64 to 1.21). There was a consistent trend in the trials towards increased use of mechanical ventilation in the phenobarbital-treated group, which was supported by the meta-analysis (typical RR 1.18; 95% CI 1.06 to 1.32; typical risk difference 0.129; 95% CI 0.04 to 0.21), but there was no significant difference in pneumothorax, acidosis or hypercapnia. Postnatal administration of phenobarbital cannot be recommended as prophylaxis to prevent IVH in preterm infants and is associated with an increased need for mechanical ventilation.

The review of trials found that there was not enough evidence that postnatal phenobarbital is effective in preventing IVH. Furthermore, phenobarbital suppresses breathing in infants who are breathing spontaneously, causing a need for mechanical ventilation.

10.1002/14651858.CD001691.pub3

cochrane-simplification-train-597

cochrane-simplification-train-597

Eighteen trials (reporting 20 study comparisons) met the review entry criteria. We report findings from 18 group comparisons where data were available (6343 participants, of whom 1692 were children). Ciclesonide versus placebo: The short duration of the included studies means that there is a lack of data with respect to the impact of ciclesonide on asthma exacerbations. At doses of 100 mcg/d or less up to 400 mcg/d in mild to moderate asthma, ciclesonide improved lung function, asthma symptoms and rescue inhaler use, compared with placebo. Dose response outcomes: Comparisons of 100 versus 200 mcg/d, 100 versus 400 mcg/d and 400 versus 800 mcg/d did not yield significant differences in lung function outcomes. Adverse event data were not available in sufficient detail to permit assessment of the safety profile of this drug. Ciclesonide was more effective than placebo, in the short term, in improving lung function in patients with mild to moderate asthma previously treated with inhaled corticosteroids. There remain questions as to dose response, and the lack of data on the longer term impact on exacerbations and safety profile should be addressed in future studies.

The results from this review indicate that CIC at low to moderate doses improves lung function and reduces asthma symptoms compared to placebo, but the short duration of the studies means that there is a lack of information about the impact on asthma exacerbations. Thus the currently recommended doses of CIC of 100-200 mcg daily would seem appropriate. However, the number of studies in the higher dose range are low and further studies are therefore required in adults and children to determine whether higher CIC doses will give significant benefit without increasing adverse events. It will also be important to determine in clinical studies how CIC compares to the other currently available ICS in terms of efficacy and safety in asthmatic adults and children in order to determine the precise role of CIC therapy in asthma. The published data are insufficient to assess the reputed safety advantage of ciclesonide, and better assessment and reporting in studies is required to address this important question.

10.1002/14651858.CD006217.pub2

cochrane-simplification-train-598

cochrane-simplification-train-598

The search identified three studies in which 2,261 participants were randomized to receive either ADT alone, or taxane-based chemotherapy at a dose of 75mg per square meter of body surface area at three-weekly intervals for six or nine cycles in addition to ADT. Primary outcomes Early treatment with taxane-based chemotherapy in addition to ADT probably reduces death from any cause compared to ADT alone (hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.68 to 0.87; moderate-certainty evidence); this would result in 94 fewer deaths per 1,000 men (95% CI 51 to 137 fewer deaths). We downgraded the certainty of evidence due to study limitations related to potential performance bias. Based on the results of one study with 375 participants, the addition of taxane-based chemotherapy to ADT may increase the incidence of Grade III to V adverse events compared to ADT alone (risk ratio (RR) 2.98, 95% CI 2.19 to 4.04; low-certainty evidence); this would result in 405 more Grade III to V adverse events per 1,000 men (95% CI 243 to 621 more events). We downgraded the certainty of evidence due to study limitations and imprecision. Secondary outcomes Early taxane-based chemotherapy in addition to ADT probably reduces the risk of prostate cancer-specific death (RR 0.79, 95% CI 0.70 to 0.89; moderate-certainty evidence). We downgraded the certainty of evidence due to study limitations related to potential performance and detection bias. The addition of taxane-based chemotherapy also probably reduces disease progression compared to ADT alone (HR 0.63, 95% CI 0.56 to 0.71; moderate-certainty evidence). We downgraded the certainty of evidence because of study limitations related to potential performance bias. The addition of taxane-based chemotherapy to ADT may result in a large increase in the risk of treatment discontinuation due to adverse events (RR 79.41, 95% CI 4.92 to 1282.78; low-certainty evidence). We downgraded the certainty of evidence due to study limitations and imprecision. This estimate is derived from a single study with no events in the control arm but a discontinuation rate of 20% in the intervention arm. Taxane-based chemotherapy may increase the incidence of adverse events of any grade (RR 1.11, 95% CI 1.06 to 1.17; low-certainty evidence). We downgraded our assessment of the certainty of evidence due to very serious study limitations. There may be a small improvement, which may not be clinically important, in quality of life at 12 months with combination treatment (mean difference (MD) 2.85 on the Functional Assessment of Cancer Therapy—Prostate scale, 95% CI 0.13 higher to 5.57 higher; low-certainty evidence). We downgraded the certainty of evidence for study limitations related to potential performance, detection and attrition bias. Compared to ADT alone, the early (within 120 days of beginning ADT) addition of taxane-based chemotherapy to ADT for hormone-sensitive prostate cancer probably prolongs both overall and disease-specific survival and delays disease progression. There may be an increase in toxicity with taxane-based chemotherapy in combination with ADT. There may also be a small, clinically unimportant improvement in quality of life at 12 months with taxane-based chemotherapy and ADT treatment.

The evidence is current to August 2018. We found three studies (specifically, randomized controlled trials) with a total of 2,261 people. The studies compared docetaxel (an anti-cancer drug) and hormone therapy to hormone therapy alone. Taxane-based chemotherapy in addition to hormone therapy likely improves overall and cancer-specific survival and reduces disease progression. There may also be a small but unimportant improvement in quality of life at 12 months. There may also be an increase in side effects when people are treated with taxane-based chemotherapy. We judged the certainty of the evidence to be moderate for time-to-death from any cause, risk of prostate cancer-specific death and the time to disease progression. This means that our estimates are likely to be close to the truth, but there were limitations in the studies that reduce our confidence in the results. The certainty of the evidence was low for Grade III to V adverse events (side effects), adverse events of all grades, people stopping treatment due to adverse events, and quality of life. This means that the true effect of the treatment may be substantially different from what this review shows, because of limitations in the studies and imprecision (variability in estimates).

10.1002/14651858.CD012816.pub2

cochrane-simplification-train-599

cochrane-simplification-train-599

This review includes eight RCTs (767 participants analysed in morning and evening arms). The trials used different lipid-lowering regimens with statins (lovastatin: two trials; simvastatin: three trials; fluvastatin: two trials; pravastatin: one trial). All trials compared the effects between morning and evening statin administration. Trial length ranged from four to 14 weeks. We found a high risk of bias in the domain of selective reporting in three trials and in the domain of incomplete outcome data in one trial of the eight trials included. None of the studies included were judged to be at low risk of bias. None of the included RCTs reported data on cardiovascular mortality, cardiovascular morbidity, incidence of cardiovascular events, or deaths from any cause. Pooled results showed no evidence of a difference in total cholesterol (MD 4.33, 95% CI -1.36 to 10.01), 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence), low-density lipoprotein cholesterol (LDL-C) levels (MD 4.85 mg/dL, 95% CI -0.87 to 10.57, 473 participants, five trials, mean follow-up 9 weeks, low-quality evidence), high-density lipoprotein cholesterol (HDL-C) (MD 0.54, 95% CI -1.08 to 2.17, 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence) or triglycerides (MD -8.91, 95% CI -22 to 4.17, 510 participants, five trials, mean follow-up 9 weeks, low-quality evidence) between morning and evening statin administration. With regard to safety outcomes, five trials (556 participants) reported adverse events. Pooled analysis found no differences in statins adverse events between morning and evening intake (OR 0.71, 95% CI 0.44 to 1.15, 556 participants, five trials, mean follow-up 9 weeks, low-quality evidence). Limited and low-quality evidence suggested that there were no differences between chronomodulated treatment with statins in people with hyperlipidaemia as compared to conventional treatment with statins, in terms of clinically relevant outcomes. Studies were short term and therefore did not report on our primary outcomes, cardiovascular clinical events or death. The review did not find differences in adverse events associated with statins between both regimens. Taking statins in the evening does not have an effect on the improvement of lipid levels with respect to morning administration. Further high-quality trials with longer-term follow-up are needed to confirm the results of this review.

We found eight randomised controlled trials that compared the effects between morning and evening statin administration in 767 people. Each trial evaluated different types and doses of statins. These trials were published between 1990 and 2013 and were conducted in the USA, Canada, Germany, Finland, Japan, South Korea and Thailand. This review includes evidence identified up to November 2015. No trials assessed CVD clinical events or deaths. Evaluation of the available evidence indicated that there were no differences between evening or morning administration of statins in terms of lipid levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides). Additionally, there was no difference in the rate of adverse events associated with statins between both regimens. The evidence in this review is of low quality because of study limitations and imprecision. Larger studies are required to confirm these results.

10.1002/14651858.CD009462.pub2