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cochrane-simplification-train-3100

cochrane-simplification-train-3100

From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects. Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results. This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.

All included trials randomised participants with acute respiratory infections to receive antibiotics based on procalcitonin levels ('procalcitonin-guided' group) or a control group. The trials were performed in primary care, the emergency department and medical wards, and the intensive care unit. Included participants had acute upper or lower respiratory infections, including pneumonia, bronchitis, exacerbation of chronic obstructive pulmonary disease, and others. All studies were investigator-initiated trials. Half of the trials were funded by national agencies or did not report funding, and half of the trials received funding from the biomarker industry (e.g. Thermo Fisher Scientific). We studied 6708 participants from 26 trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided participants compared to control participants (286 deaths in 3336 procalcitonin-guided participants (8.6%) versus 336 deaths in 3372 controls (10.0%)). There was no significant difference with regard to treatment failures. Results were similar for different clinical settings (primary care, emergency department, intensive care unit) and types of respiratory infection. Regarding antibiotic exposure, participants in the procalcitonin-guided group had a 2.4-day reduction in antibiotic exposure and a reduction in antibiotic-related side effects (16.3% versus 22.1%). The quality of the evidence was high for mortality and antibiotic exposure. Most of the trials did not use blinding, however we did not expect that mortality would be biased by this limitation. The quality of the evidence was moderate for treatment failure and antibiotic-related side effects because the definitions for these endpoints among trials were not identical.

10.1002/14651858.CD007498.pub3

cochrane-simplification-train-3101

cochrane-simplification-train-3101

This update identified one additional study for inclusion, adding data for 2305 participants. This addition more than doubled the overall number of patients eligible for the review. In total, we included four randomised controlled trials (RCTs) with a total of 4187 eligible participants. All studies compared warfarin with aspirin. One RCT additionally compared warfarin with clopidogrel. All included RCTs studied patients with heart failure with reduced ejection fraction. Analysis of all outcomes for warfarin versus aspirin was based on 3663 patients from four RCTs. All-cause mortality was similar for warfarin and aspirin (RR 1.00, 95% CI 0.89 to 1.13; 4 studies; 3663 participants; moderate quality evidence). Oral anticoagulation was associated with a reduction in non-fatal cardiovascular events, which included non-fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism (RR 0.79, 95% CI 0.63 to 1.00; 4 studies; 3663 participants; moderate quality evidence). The rate of major bleeding events was twice as high in the warfarin groups (RR 2.00, 95% CI 1.44 to 2.78; 4 studies; 3663 participants; moderate quality evidence). We generally considered the risk of bias of the included studies to be low. Analysis of warfarin versus clopidogrel was based on a single RCT (N = 1064). All-cause mortality was similar for warfarin and clopidogrel (RR 0.93, 95% CI 0.72 to 1.21; 1 study; 1064 participants; low quality evidence). There were similar rates of non-fatal cardiovascular events (RR 0.85, 95% CI 0.50 to 1.45; 1 study; 1064 participants; low quality evidence). The rate of major bleeding events was 2.5 times higher in the warfarin group (RR 2.47, 95% CI 1.24 to 4.91; 1 study; 1064 participants; low quality evidence). Risk of bias for this study can be summarised as low. There is evidence from RCTs to suggest that neither oral anticoagulation with warfarin or platelet inhibition with aspirin is better for mortality in systolic heart failure with sinus rhythm (high quality of the evidence for all-cause mortality and moderate quality of the evidence for non-fatal cardiovascular events and major bleeding events). Treatment with warfarin was associated with a 20% reduction in non-fatal cardiovascular events but a twofold higher risk of major bleeding complications (high quality of the evidence). We saw a similar pattern of results for the warfarin versus clopidogrel comparison (low quality of the evidence). At present, there are no data on the role of oral anticoagulation versus antiplatelet agents in heart failure with preserved ejection fraction with sinus rhythm. Also, there were no data from RCTs on the utility of non-vitamin K antagonist oral anticoagulants compared to antiplatelet agents in heart failure with sinus rhythm.

This is an update of an earlier review. The evidence is current to September 2015. We only identified one new study with 2305 participants. In total, we analysed four randomised controlled studies with 4187 participants. The comparison of warfarin with aspirin was based on a large number of patients from four high-quality studies. The analysis showed an almost identical risk of death with both drugs. There was not enough evidence to prove benefits of warfarin over aspirin to reduce the possibility of clotting complications, such as a heart attack or stroke. However, patients receiving warfarin experienced serious bleeding twice as often as those taking aspirin. A comparison of warfarin with another antiplatelet drug, clopidogrel, was based on a single medium size study, and it showed similar results: no difference in occurrence of death or clotting complications, but a higher chance of developing of a serious bleed. There is currently no evidence to suggest advantages of warfarin over antiplatelet drugs in heart failure with a normal rhythm. Moreover, treatment with warfarin leads to more bleeding events than aspirin or clopidogrel. It is unlikely that further studies will change these conclusions unless new, more effective and safe drugs become available.

10.1002/14651858.CD003333.pub3

cochrane-simplification-train-3102

cochrane-simplification-train-3102

This update includes forty-eight studies, involving 5721 babies and their mothers, with data available from 40 studies involving 4884 babies and their mothers. Babies were between 24 and 36+6 weeks' gestation at birth and multiple births were included. The data are mostly from high-income countries. Delayed clamping ranged between 30 to 180 seconds, with most studies delaying for 30 to 60 seconds. Early clamping was less than 30 seconds and often immediate. UCM was mostly before cord clamping but some were milked after cord clamping. We undertook subgroup analysis by gestation and type of intervention, and sensitivity analyses by low risk of selection and attrition bias. All studies were high risk for performance bias and many were unclear for other aspects of risk of bias. Certainty of the evidence using GRADE was mostly low, mainly due to imprecision and unclear risk of bias. Delayed cord clamping (DCC) versus early cord clamping (ECC) both with immediate neonatal care after cord clamping (25 studies, 3100 babies and their mothers) DCC probably reduces the number of babies who die before discharge compared with ECC (average risk ratio (aRR) 0.73, 95% confidence interval (CI) 0.54 to 0.98, 20 studies, 2680 babies (moderate certainty)). No studies reported on 'Death or neurodevelopmental impairment' in the early years'. DCC may make little or no difference to the number of babies with severe intraventricular haemorrhage (IVH grades 3 and 4) (aRR 0.94, 95% CI 0.63 to 1.39, 10 studies, 2058 babies, low certainty) but slightly reduces the number of babies with any grade IVH (aRR 0.83, 95% CI 0.70 to 0.99, 15 studies, 2333 babies, high certainty). DCC has little or no effect on chronic lung disease (CLD) (aRR 1.04, 95% CI 0.94 to 1.14, 6 studies, 1644 babies, high certainty). Due to insufficient data, we were unable to form conclusions regarding periventricular leukomalacia (PVL) (aRR 0.58, 95% CI 0.26 to 1.30, 4 studies, 1544 babies, low certainty) or maternal blood loss of 500 mL or greater (aRR 1.14, 95% CI 0.07 to 17.63, 2 studies, 180 women, very low certainty). We identified no important heterogeneity in subgroup or sensitivity analyses. Delayed cord clamping (DCC) with immediate neonatal care with cord intact versus early cord clamping (ECC) (one study, 276 babies and their mothers) There are insufficient data to be confident in our findings, but DCC with immediate neonatal care with cord intact may reduce the number of babies who die before discharge, although the data are also compatible with a slight increase in mortality, compared with ECC (aRR 0.47, 95% CI 0.20 to 1.11, 1 study, 270 babies, low certainty). DCC may also reduce the number of babies who die or have neurodevelopmental impairment in early years (aRR 0.61, 95% CI 0.39 to 0.96, 1 study, 218 babies, low certainty). There may be little or no difference in: severe IVH; all grades IVH; PVL; CLD; maternal blood loss ≥ 500 mL, assessed as low certainty mainly due to serious imprecision. Delayed cord clamping (DCC) with immediate neonatal care after cord clamping versus umbilical cord milking (UCM) (three studies, 322 babies and their mothers) and UCM versus early cord clamping (ECC) (11 studies, 1183 babies and their mothers) There are insufficient data for reliable conclusions about the comparative effects of UCM compared with delayed or early clamping (mostly low or very low certainty). Delayed, rather than early, cord clamping may reduce the risk of death before discharge for babies born preterm. There is insufficient evidence to show what duration of delay is best, one or several minutes, and therefore the optimum time to clamp the umbilical cord remains unclear. Whilst the current evidence supports not clamping the cord before 30 seconds at preterm births, future trials could compare different lengths of delay. Immediate neonatal care with the cord intact requires further study, and there are insufficient data on UCM. The nine new reports awaiting further classification may alter the conclusions of the review once assessed.

We collected and analysed all relevant studies to answer this question (date of search: November 2017). Our updated review included 40 studies which provided data on 4884 babies and their mothers. Studies were undertaken across the world, but mostly in high-income countries. Births were in hospitals which practiced early clamping. For many outcomes there were insufficient data to be really confident of our findings. 1) For delayed cord clamping (with immediate care of the baby after cord clamping) compared with early cord clamping, we found it likely that fewer babies died before discharge (20 studies, 2680 babies). Also, fewer babies may have had any bleeding in the brain (15 studies, 2333 babies), but there was probably no difference in the numbers of babies with very serious brain bleeds (10 studies, 2058 babies). 2) Only one study of 276 babies and their mothers provided data on delayed cord clamping with immediate care of the baby beside the mother with cord intact compared with early cord clamping. This study was small and did not identify any marked differences in health outcomes. 3) For delayed cord clamping (with immediate care of the baby after cord clamping) versus cord milking, there were insufficient data (three studies, 322 babies) to make comparisons between outcomes. 4) For cord milking versus early cord clamping, we found 11 studies providing data with 1183 babies and their mothers. Again, there were insufficient data to make clear comparisons on outcomes. Delayed cord clamping probably reduced the risk of death for babies born preterm. Early cord clamping probably causes harm. No studies showed what length of delay was best, and only a few studies followed babies for health outcomes in early childhood. There is insufficient evidence for reliable conclusions on providing immediate care for the baby beside the mother with the cord intact. Similarly, there is insufficient evidence for reliable conclusions on cord milking. Further studies are in progress.

10.1002/14651858.CD003248.pub4

cochrane-simplification-train-3103

cochrane-simplification-train-3103

We identified three trials in adult dialysis patients (n = 117). There were insufficient data for most outcomes for meta-analysis. In all three trials acidosis improved in the intervention group though there was variation in achieved bicarbonate level. There was no evidence of effect on blood pressure or sodium levels. Some measures of nutritional status/protein metabolism (e.g. SGA, NP NA) were significantly improved by correction in the one trial that looked in these in detail. There was heterogeneity of the effect on serum albumin in two trials. Serum PTH fell significantly in the two trials that estimated this, with no significant effect on calcium or phosphate though both fell after correction. Complex bone markers were assessed in one study, with some evidence for a reduction in bone turnover in those with initial high bone turnover and an increase in low turnover patients. The studies were underpowered to assess clinical outcomes, in the one study that did there was some evidence for a reduction in hospitalisation after correction. The evidence for the benefits and risks of correcting metabolic acidosis is very limited with no RCTs in pre-ESRD patients, none in children, and only three small trials in dialysis patients. These trials suggest there may be some beneficial effects on both protein and bone metabolism but the trials were underpowered to provide robust evidence.

This review found three small trials in adult haemodialysis patients (n = 117). The evidence for the benefits and risks of correcting metabolic acidosis is very limited with no RCTs in pre-ESRD patients and none in children. These trials suggest there may be some beneficial effects on both protein and bone metabolism but the trials were underpowered to provide strong evidence.

10.1002/14651858.CD001890.pub3

cochrane-simplification-train-3104

cochrane-simplification-train-3104

No new studies were found for inclusion in this update from the latest searches. We included eight trials (1644 women). When all chemotherapy regimens were combined, meta-analysis indicated no significant difference in three-, five- and 10-year OS or PFS. For five-year OS, the combined risk ratio (RR) was 1.03 (95% confidence interval (CI) 0.96 to 1.10; 4 studies, 899 participants; moderate-certainly evidence) and for the five-year PFS, the combined RR was 1.06 (95% CI 0.97 to 1.17; 3 studies, 761 participants; moderate-certainly evidence). Results were very similar when trials of different regimens were analysed. Comparing chemotherapy with radiotherapy, only the RR for 10-year PFS in pathological complete remission (PCR) was in favour of whole abdominal radiotherapy 0.51 (95% CI 0.27 to 1.00), while three- and five-year OS rates have no significant difference between the two groups. There is no evidence to suggest that the use of platinum agents, doxorubicin or paclitaxel used as maintenance chemotherapy is more effective than observation alone. Further investigations regarding the effect of paclitaxel used as maintenance chemotherapy are required.

We identified eight trials that used different types of chemotherapy (e.g. platinum agents, doxorubicin, topotecan or paclitaxel) but there was not sufficient evidence to prove any of the drugs were better than observation alone. An important consideration for women with advanced disease is the balance between the benefit of treatment and the harms or adverse effects that these treatments may cause. There were insufficient data to comment on the overall impact of the maintenance chemotherapy on clinical benefit from the women's perspective. We tried to identify all trials and both published and unpublished data in this review; thereby minimising the influence of publication bias. The included trials are graded as moderate quality but this meta-analysis currently provides a reliable assessment of the average treatment effect of platinum and doxorubicin among women with advanced epithelial ovarian cancer. Use of platinum agents, doxorubicin or paclitaxel used as maintenance chemotherapy has not proved effective to prolong the life time of women with epithelial ovarian cancer. Further investigations regarding the effect of paclitaxel used as maintenance chemotherapy are required.

10.1002/14651858.CD007414.pub3

cochrane-simplification-train-3105

cochrane-simplification-train-3105

We identified 51 trials, including 10 cluster-RCTs, that met the inclusion criteria. One trial evaluating mortality included over one million children, and the remaining 50 trials included a total of 84,336 participants. Twenty-four trials were in populations categorized as high burden, including nine trials in children selected because they were helminth-stool positive; 18 with intermediate burden; and nine as low burden. First or single dose of deworming drugs Fourteen trials reported on weight after a single dose of deworming drugs (4970 participants, 14 RCTs). The effects were variable. There was little or no effect in studies conducted in low and intermediate worm burden groups. In the high-burden group, there was little or no effect in most studies, except for a large effect detected from one study area in Kenya reported in two trials carried out over 30 years ago. These trials result in qualitative heterogeneity and uncertainty in the meta-analysis across all studies (I2 statistic = 90%), with GRADE assessment assessed as very low-certainty, which means we do not know if a first dose or single dose of deworming impacts on weight. For height, most studies showed little or no effect after a single dose, with one of the two trials in Kenya from 30 years ago showing a large average difference (2621 participants, 10 trials, low-certainty evidence). Single dose probably had no effect on average haemoglobin (MD 0.10 g/dL, 95% CI 0.03 lower to 0.22 higher; 1252 participants, five trials, moderate-certainty evidence), or on average cognition (1596 participants, five trials, low-certainty evidence). The data are insufficient to know if there is an effect on school attendance and performance (304 participants, one trial, low-certainty evidence), or on physical fitness (280 participants, three trials, very low-certainty evidence). No trials reported on mortality. Multiple doses of deworming drugs The effect of regularly treating children with deworming drugs given every three to six months on weight was reported in 18 trials, with follow-up times of between six months and three years; there was little or no effect on average weight in all but two trials, irrespective of worm prevalence-intensity. The two trials with large average weight gain included one in the high burden area in Kenya carried out over 30 years ago, and one study from India in a low prevalence area where subsequent studies in the same area did not show an effect. This heterogeneity causes uncertainty in any meta-analysis (I2 = 78%). Post-hoc analysis excluding trials published prior to 2000 gave an estimate of average difference in weight gain of 0.02 kg (95%CI from 0.04 kg loss to 0.08 gain, I2 = 0%). Thus we conclude that we do not know if repeated doses of deworming drugs impact on average weight, with a fewer older studies showing large gains, and studies since 2000 showing little or no average gain. Regular treatment probably had little or no effect on the following parameters: average height (MD 0.02 cm higher, 95% CI 0.09 lower to 0.13 cm higher; 13,700 participants, 13 trials, moderate-certainty evidence); average haemoglobin (MD 0.01 g/dL lower; 95% CI 0.05 g/dL lower to 0.07 g/dL higher; 5498 participants, nine trials, moderate-certainty evidence); formal tests of cognition (35,394 participants, 8 trials, moderate-certainty evidence); school performance (34,967 participants, four trials, moderate-certainty evidence). The evidence assessing an effect on school attendance is inconsistent, and at risk of bias (mean attendance 2% higher, 95% CI 5% lower to 8% higher; 20,650 participants, three trials, very low-certainty evidence). No trials reported on physical fitness. No effect was shown on mortality (1,005,135 participants, three trials, low-certainty evidence). Public health programmes to regularly treat all children with deworming drugs do not appear to improve height, haemoglobin, cognition, school performance, or mortality. We do not know if there is an effect on school attendance, since the evidence is inconsistent and at risk of bias, and there is insufficient data on physical fitness. Studies conducted in two settings over 20 years ago showed large effects on weight gain, but this is not a finding in more recent, larger studies. We would caution against selecting only the evidence from these older studies as a rationale for contemporary mass treatment programmes as this ignores the recent studies that have not shown benefit. The conclusions of the 2015 edition have not changed in this update.

In populations of children living in endemic areas, the effect of the first, single dose of deworming drugs on weight is unclear. There was little or no effect in most studies, except for a large effect detected from one study area in Kenya, reported in two trials carried out over 30 years ago in a school where children were heavily infected with worms. This causes uncertainty, which means we do not know if a first dose or single dose of deworming impacts on weight. For height, most studies showed little or no effect, with the exception of the site in Kenya. A single dose of deworming medicine probably has no effect on haemoglobin and cognition. There is insufficient data to know if there is an effect on school attendance, school performance, or physical fitness or mortality. In studies where children were regularly treated with deworming medicine there was little or no effect on weight in all but two trials, irrespective of whether children were heavily infected with worms or not. The two trials with large average weight gains included the Kenya study carried out over 30 years ago, and one study from India carried out over 20 years ago in a low worm burden area where later studies in the same area did not show an effect. In trials from 2000 onwards, which are more relevant given the global reduction in worm burden, there is little or no effect. This causes uncertainty and means we do not know if regularly treating children with deworming medicine improves their weight. Regularly deworming children probably has no effect on height, haemoglobin, cognition, and mortality. We do not know if there is an impact on school attendance, since the evidence is inconsistent and at high risk of bias. There is insufficient data to know if there is an effect on physical fitness. Authors' conclusions For public health programmes to regularly treat all children in endemic areas with deworming drugs, there is quite substantial evidence of no benefit in terms of haemoglobin, cognition, school performance, and mortality. For weight, contemporary studies do not show an effect, but unusually large effects were seen in studies over 20 years ago.

10.1002/14651858.CD000371.pub7

cochrane-simplification-train-3106

cochrane-simplification-train-3106

Two small randomised controlled trials, involving a total of 80 participants with simple elbow dislocations, were included. Both trials were methodologically flawed and potentially biased. One trial, involving 50 participants, compared early mobilisation at three days post reduction versus cast immobilisation. At one year follow-up, the recovery of range of motion appeared better in the early mobilisation group (e.g. participants with incomplete recovery of extension: 1/24 versus 5/26; risk ratio 0.22, 95% confidence interval 0.03 to 1.72). However, the results were not statistically significant. There were no reports of instability or recurrence. One person in each group had residual pain at one year. The other trial, involving 30 participants, compared surgical repair of the torn ligaments versus conservative treatment (cast immobilisation for two weeks). At final follow-up (mean 27.5 months), there were no statistically significant differences between the two groups in the numbers of patients who considered their injured elbow to be inferior to their non-injured elbow (10/14 versus 7/14; RR 1.43, 95% CI 0.77 to 2.66) or in other patient complaints about their elbow such as weakness, pain or weather-related discomfort. There were no reports of instability or recurrence. There were no statistically significant differences between the two groups in range of motion of the elbow (extension, flexion, pronation, and supination) or grip strength at follow-up. No participants had neurological disturbances of the hand but two surgical group participants had recurrent dislocation of the ulnar nerve (no other details provided). One person in each group had radiologically detected myositis ossificans (bone formation within muscles following injury). There is insufficient evidence from randomised controlled trials to determine which method of treatment is the most appropriate for simple dislocations of the elbow in adults. Although weak and inconclusive, the available evidence from a trial comparing surgery versus conservative treatment does not suggest that the surgical repair of elbow ligaments for simple elbow dislocation improves long-term function. Future research should focus on questions relating to non-surgical treatment, such as the duration of immobilisation.

This review includes two trials, involving a total of 80 adults with simple elbow dislocations that had been put back into place (reduced). Both trials were at risk of bias, which means that their results may not be reliable. One trial compared early mobilisation of the elbow with immobilisation for three weeks in a plaster cast. This trial found no firm evidence of differences between the two interventions in the recovery of elbow range of motion or pain at one year. None of the trial participants had an unstable elbow or had suffered another dislocation. The other trial compared surgical repair of the torn ligaments versus conservative treatment (cast immobilisation for two weeks). It found no significant difference between the two groups in the numbers of patients who considered their injured elbow to be inferior to their non-injured elbow or in other patient complaints about their elbow such as weakness, pain or weather-related discomfort. There were also no differences between the groups in the range of motion of the elbow or grip strength at follow-up of around two years. There were two people with surgery-related complications. None of the trial participants had an unstable elbow or had suffered another dislocation. Overall, the review concluded that there was not enough evidence from randomised controlled trials to show which methods of treatment are better for these injuries.

10.1002/14651858.CD007908.pub2

cochrane-simplification-train-3107

cochrane-simplification-train-3107

No new trials were identified in the search for this review update. In total five trials involving 365 participants were included in this review. All trials compared Padma 28 with placebo for at least 16 weeks of follow-up. Pain-free and maximum walking distances both increased significantly in the groups treated with Padma 28, with no significant change in the placebo group. In general, the studies presented results comparing the treatment arms before and after treatment but made no comparisons between the Padma 28 and placebo groups. Pooled data of maximum walking distance after treatment with Padma 28 and placebo from two studies (193 participants) indicated a higher maximum walking distance (mean difference (MD) 95.97 m, 95% confidence interval (CI) 79.07 m to 112.88 m, P < 0.00001, very low quality evidence) in the Padma 28 group compared with placebo. The clinical importance of these observed changes in walking distance is unclear as no quality of life data were reported. There was no effect on ankle brachial index (ABI): change in ABI values between baseline and six months follow up MD -0.01, 95% CI -0.07 to 0.05, 1 study, 56 participants, P = 0.72, very low quality evidence). Mild side effects, especially gastrointestinal discomfort, tiredness and skin eruption, were reported but this outcome was not different between the Padma 28 and placebo groups (odds ratio 1.09, 95% CI 0.42 to 2.83, four studies, 231 participants, P = 0.86, very low quality evidence). Some evidence exists from individual trials to suggest that Padma 28 may be effective in increasing walking distances, at least in the short term (four months), in people with IC. Side effects do not appear to be a problem. However, the longer term effects of treatment are unknown and the clinical significance of the improvements in walking distance are questionable. Moreover, the quality of the evidence is limited by the small sample size of the available trials, limited reporting of statistical analyses that compared treatment groups, and relatively high withdrawal rates that were linked to the outcome. That is, patients were withdrawn if they failed to improve walking distance. There was also evidence of publication bias. We therefore feel there is currently insufficient evidence to draw conclusions regards the effectiveness of Padma 28 in the routine management of IC. Further well-designed research would be required to determine the true effects of this herbal preparation.

This review on the effects of Padma 28 includes five trials with a total of 365 participants (current until September 2015). The review showed that Padma 28 has some beneficial effects in improving maximum and pain-free walking distance. The groups treated with placebo did not show an improved maximum and pain-free walking distance. Unfortunately the studies reported insufficient data to allow the comparison of the change in walking distances in the Padma 28 group with the change in walking distances in the placebo group. Combining the data of maximum walking distance after treatment in two studies showed that there was a longer maximum walking distance in the Padma 28 group compared with the placebo group after 16 weeks of treatment. No change in ankle brachial pressure was observed. Mild side effects such as gastrointestinal discomfort, tiredness and skin eruption were also noted but these were not different between the Padma 28 and placebo groups. Quality of the evidence Overall, the quality of the studies was low, with evidence of publication bias, small number of trials, limited reporting of the analyses that compared treatment groups and bias due to a high percentage of withdrawals in the placebo groups because of lack of improvement or deterioration of the overall condition. We therefore feel there is currently insufficient evidence to draw conclusions about the effectiveness of Padma 28 in the routine management of IC. Further well-designed research would be required to determine the true effects of this herbal preparation.

10.1002/14651858.CD007371.pub3

cochrane-simplification-train-3108

cochrane-simplification-train-3108

We included 14 trials in this review, with 1152 randomised participants. The studies were published between 1990 and 2009 and were conducted in the United Kingdom, Egypt, Saudi Arabia, and the United States. The age of participants ranged from 2 to 40 years. Three studies were at an overall high risk of bias, seven studies were at an unclear risk of bias, and we judged four studies to be at low risk of bias. The clinical heterogeneity of the included studies precluded pooling of studies in terms of method of administration of LA (e.g., intraligamental injection, infiltration injection, or topical delivery) and variation in the use of supplementary analgesics and follow-up time. Of the seven studies where administration of LA was by infiltration injection, six studies (very low-quality body of evidence, 542 participants analysed, 1 study had overall high risk of bias, 4 studies had overall unclear risk of bias, 1 study had overall low risk of bias) measured postoperative pain. The results were equivocal. There was a decrease in bleeding and increase in soft tissue damage in the LA groups, but we did not judge this to be clinically significant. In the 2 studies where administration of LA was by intraligamental injection, there was no difference in mean pain scores, and they did not report any soft tissue damage (very low-quality body of evidence, 115 participants analysed, 1 study had overall high risk of bias, 1 study had overall unclear risk of bias). One 3-armed study (very low-quality body of evidence, 54 participants analysed, overall high risk of bias) compared the effects of intraligamental and infiltration LA injection with no treatment. There was no evidence of a mean difference in pain, distress, or postoperative anxiety among the three groups. Four studies (very low-quality body of evidence, 343 participants analysed, 2 studies had overall low risk of bias, 2 studies had overall unclear risk of bias) evaluated the effects of topical LA compared with no treatment or placebo. One study (overall unclear risk of bias) with a no-treatment comparator reported lower mean pain in the LA group; all other studies reported no difference in mean pain scores. Two studies reported on bleeding (overall unclear risk of bias): One study reported a clinically insignificant increase in bleeding with no treatment; the other reported no difference. None of the studies reported on participant or child satisfaction. In this review, it was difficult to reach firm conclusions as to the benefit of using local anaesthetic for dental treatment under general anaesthesia. The information reported in the included studies was comprehensive and applicable to the review question, but ultimately it was not sufficient to address the objective of the review. We were unable to pool the included studies in a meta-analysis because of substantial variation in outcome measures, interventions, and treatment types. The use of supplementary analgesia further obscured the effect of local anaesthetics. Based on the literature review and the results of this review, we recommend further randomised controlled trials that minimise bias through adequate allocation concealment and blinding of participants and assessors, and assess the effect of intraoperative local anaesthetic on the volume and type of anaesthetic used and on the cardiovascular system in participants receiving supplementary analgesics as well. Researchers should give consideration to the impact of any changes on the health and well-being of the participant and report baseline measures of pain or distress, or both, and preoperative anxiety.

. The Cochrane Oral Health Group carried out this review and the evidence on which it is based was up-to-date on 2 January 2014. We included 14 studies, which took place from 1990 to 2009 in the UK, Egypt, Saudi Arabia, and the USA. These included 1152 participants aged from 2 to 40 years. Although the 14 studies included addressed our research question, they differed in the way that they delivered the intervention and what they measured. This meant we could not combine their data in our analyses. The results from individual studies for pain, bleeding, and other adverse effects were uncertain. The use of additional different painkillers may have hidden the effect of the LA. Further high-quality trials are needed in order to assess the benefits or harms of LA given to children and young people whilst they are receiving dental treatment under GA. Issues that these trials need to address include local side-effects (e.g., excessive dribbling and accidental lip biting), side-effects on other parts of the body (e.g., the heart), participant and parent satisfaction, dosage, type of anaesthetic, and the effects of extra painkillers (e.g., paracetamol). The quality of the 14 included studies was variable. We assessed three studies as being at overall risk of high bias, seven at unclear risk of bias, and four at low risk of bias.

10.1002/14651858.CD009742.pub2

cochrane-simplification-train-3109

cochrane-simplification-train-3109

The following statistically significant treatment effects in favour of propentofylline are reported. Cognition at 3, 6 and 12 months including MMSE at 12 months. [MD 1.2, 95%CI 0.12 to 2.28, P=0.03] Severity of dementia at 3, 6 and 12 months including CGI at 12 months [MD -0.21, 95%CI -0.39 to -0.03, P=0.03]. Activities of Daily Living (NAB) at 6 and 12 months [MD -1.20, 95%CI -2.22 to -0.18, P=0.02]. Global Assessment (CGI) at 3 months [MD -0.48, 95% CI -0.75 to -0.21, P=0.0006], but not at later times. Tolerability There were minimal data on adverse effects and drop-outs. There were a statistically significant treatment effects in favour of placebo at 12 months, for the number of dropouts [OR=1.43, 95%CI 1.04 to 1.90, P=0.03]. There is limited evidence that propentofylline might benefit cognition, global function and activities of daily living of people with Alzheimer's disease and/or vascular dementia. The meta-analyses reported here are far from satisfactory as a summary of the efficacy of propentofylline, considering the unpublished information on another 1200 patients in randomized trials that exists. Unfortunately Aventis has been unwilling to correspond with the authors, significantly limiting the scope of this review.

Although a number of randomized controlled trials have been undertaken, data were available from only a very limited number of these studies. These limited data suggest that propentofylline may have a beneficial effect on measures of cognitive and global function of people with Alzheimer's or vascular dementia. The unavailability of data, due to failure of Aventis, the manufacturing pharmaceutical company, to release information about unpublished studies prevented a comprehensive systematic review and meta-analysis.

10.1002/14651858.CD002853

cochrane-simplification-train-3110

cochrane-simplification-train-3110

We included 11 trials (6 trials in high-income countries and 5 multicentre trials in high-, middle-, and low-income countries) involving 17,123 children aged 6 months to 6 years. Eight trials recruited participants from a healthcare setting. Ten trials (and all four trials that contributed to the primary outcome) declared funding from vaccine manufacturers. Four trials reported adequate allocation concealment, and 10 trials reported adequate blinding of participants and personnel. Attrition was low for eight trials included in the analysis. The primary outcome showed a small reduction in at least one episode of AOM over at least six months of follow-up (4 trials, 3134 children; RR 0.84, 95% CI 0.69 to 1.02; RD -0.04, 95% CI -0.08 to -0.00; NNTB 25, 95% CI 12.5 to 100; low-quality evidence). The subgroup analyses (i.e. number of courses and types of vaccine administered) showed no differences. There was a reduction in the use of antibiotics in vaccinated children (2 trials, 1223 children; RR 0.70, 95% CI 0.59 to 0.83; RD -0.11, 95% CI -0.16 to -0.06; moderate-quality evidence). We were unable to demonstrate whether there was any difference in the utilisation of health care. The use of influenza vaccine resulted in a significant increase in fever (7 trials, 10,615 children; RR 1.15, 95% CI 1.06 to 1.24; RD 0.02, 95% CI 0.00 to 0.04; low-quality evidence), rhinorrhoea (6 trials, 10,563 children; RR 1.17, 95% CI 1.07 to 1.29; RD 0.09, 95% CI 0.01 to 0.16; low-quality evidence), but no difference in pharyngitis. No major adverse events were reported. Differing from the protocol, the original publication of the review included a subgroup analysis of AOM episodes by season, and the secondary outcome ‘types of influenza vaccine’ was changed to a subgroup analysis. For this update, we removed the subgroup analyses for trial setting, season, and utilisation of health care due to the small number of trials involved. We removed Belshe 2000 from primary and secondary outcomes (courses of vaccine and types of vaccine) because it reported episodes of AOM per person. We did not perform a subgroup analysis by type of adverse event. We have reported each type of adverse event as a separate analysis. Influenza vaccine results in a small reduction in AOM. The observed reduction in the use of antibiotics needs to be considered in light of current recommended practices aimed at avoiding antibiotic overuse. Safety data from these trials were limited. The benefits may not justify the use of influenza vaccine without taking into account the vaccine efficacy in reducing influenza and safety data. We judged the quality of the evidence to be low to moderate. Additional research is needed.

The evidence is current to 15 February 2017. We selected randomised controlled trials comparing influenza vaccine with placebo or no treatment in infants and children aged six months to six years, with or without a history of previous episodes of AOM. We included 11 trials involving 17,123 children. Ten out of 11 trials were funded by vaccine manufacturers. We found a 4% reduction in AOM and about an 11% reduction in the number of antibiotic prescriptions. There was no difference in the number of courses or types of vaccine administered between those who were vaccinated and those who were unvaccinated. Influenza vaccine side effects included an increase in fever, runny nose, and drowsiness. It remains uncertain whether the influenza vaccine reduced visits or admissions to healthcare facilities. Data were insufficient to show that this benefit might be balanced against more serious or rarer side effects from the vaccine. Although we observed a reduction in antibiotic usage, this impact is uncertain because the current practice is to avoid overuse of antibiotics. Coupled with other vaccine safety concerns, the use of influenza vaccine to reduce AOM is not yet justified, and additional research is needed. The overall quality of the evidence was low to moderate.

10.1002/14651858.CD010089.pub3

cochrane-simplification-train-3111

cochrane-simplification-train-3111

We included 48 RCTs in the review. Of these, we assessed one as at low risk of bias, 12 as at high risk of bias and 35 as at unclear risk of bias. The results indicated a greater reduction in gingival recession for subepithelial connective tissue grafts (SCTG) + coronally advanced flap (CAF) compared to guided tissue regeneration with resorbable membranes (GTR rm) + CAF (MD -0.37 mm; 95% CI -0.60 to -0.13, P = 0.002; 3 studies; 98 participants; low-quality evidence). There was insufficient evidence of a difference in gingival recession reduction between acellular dermal matrix grafts (ADMG) + CAF and SCTG + CAF or between enamel matrix protein (EMP) + CAF and SCTG + CAF. Regarding clinical attachment level changes, GTR rm + CAF promoted additional gains compared to SCTG + CAF (MD 0.35; 95% CI 0.06 to 0.63, P = 0.02; 3 studies; 98 participants; low-quality evidence) but there was insufficient evidence of a difference between ADMG + CAF and SCTG + CAF or between EMP + CAF and SCTG + CAF. Greater gains in the keratinized tissue were found for SCTG + CAF when compared to EMP + CAF (MD -1.06 mm; 95% CI -1.36 to -0.76, P < 0.00001; 2 studies; 62 participants; low-quality evidence), and SCTG + CAF when compared to GTR rm + CAF (MD -1.77 mm; 95% CI -2.66 to -0.89, P < 0.0001; 3 studies; 98 participants; very low-quality evidence). There was insufficient evidence of a difference in keratinized tissue gain between ADMG + CAF and SCTG + CAF. Few data exist on aesthetic condition change related to patients' opinion and patients' preference for a specific procedure. Subepithelial connective tissue grafts, coronally advanced flap alone or associated with other biomaterial and guided tissue regeneration may be used as root coverage procedures for treating localised or multiple recession-type defects. The available evidence base indicates that in cases where both root coverage and gain in the width of keratinized tissue are expected, the use of subepithelial connective tissue grafts shows a slight improvement in outcome. There is also some weak evidence suggesting that acellular dermal matrix grafts appear as the soft tissue substitute that may provide the most similar outcomes to those achieved by subepithelial connective tissue grafts. RCTs are necessary to identify possible factors associated with the prognosis of each RCPPS procedure. The potential impact of bias on these outcomes is unclear.

Authors from Cochrane Oral Health carried out this review and the evidence is up to date to 15 January 2018. A total of 48 randomised controlled trials on 1227 adults were included with five studies evaluating multiple recession-type defects and the rest single gingival recessions. Most trials followed participants for 6 months to 12 months. The review looked at different interventions: free gingival grafts (FGG), coronally advanced flap (CAF) alone or associated to acellular dermal matrix grafts (ADMG), enamel matrix protein (EMP), guided tissue regeneration with resorbable membranes (GTR rm), guided tissue regeneration with non-resorbable membranes (GTR nrm), GTR rm associated with bone substitutes, platelet-rich plasma or fibrin (PRP or PRF), growth factors (rhPDGF-BB) associated to bone substitutes (b-TCP), subepithelial connective tissue grafts (SCTG) or xenogeneic collagen matrix (XCM). We did not find any trials evaluating laterally positioned flaps (LPF). The results of this review have shown that most root coverage periodontal plastic surgery procedures led to gains in reduction of gingival recession. However, we are uncertain about which intervention is the most effective as all studies were judged to be at unclear or high risk of bias. Preferably, subepithelial connective tissue grafts, coronally advanced flap alone or associated with another graft or biomaterial and guided tissue regeneration can be used as root coverage procedures for treating recession-type defects. Limited data exist on how these interventions affect the appearance of the teeth. Adverse effects reported in the studies included discomfort and pain, but these were mainly related to the site where the tissue graft was taken, and occurred mainly within the first week after surgery with no influence on root coverage outcomes. Further research is needed on the results to be achieved from each root coverage periodontal plastic procedure. We judged the quality of the evidence to be low or very low mainly due to problems with the design of the studies.

10.1002/14651858.CD007161.pub3

cochrane-simplification-train-3112

cochrane-simplification-train-3112

Nineteen eligible studies involving 4096 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 to 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The risk of CLD in survivors at term equivalent gestational age was significantly reduced with the use of HFOV but this effect was inconsistent across studies, even after the meta-analysis was restricted to studies that applied a high lung volume strategy with HFOV. Subgroup analysis by HFOV strategy showed a similar effect in trials with a more strict lung volume recruitment strategy, targeting a very low fraction of inspired oxygen (FiO2), and trials with a less strict lung volume recruitment strategy and with a somewhat higher or unspecified target FiO2. Subgroup analyses by age at randomisation, routine surfactant use or not, type of high frequency ventilator (oscillator versus flow interrupter), inspiratory to expiratory (I:E) ratio of high frequency ventilator (1:1 versus 1:2) and CV strategy (lung protective or not) could not sufficiently explain the heterogeneity. Pulmonary air leaks, defined as gross air leaks or pulmonary interstitial emphysema, occurred more frequently in the HFOV group, whereas the risk of severe retinopathy of prematurity was significantly reduced. Although in some studies an increased risk of severe grade intracranial haemorrhage and periventricular leukomalacia was found, the overall meta-analysis revealed no significant differences in effect between HFOV and CV. The short-term neurological morbidity with HFOV was only found in the subgroup of two trials not using a high volume strategy with HFOV. Most trials did not find a significant difference in long-term neurodevelopmental outcome, although one recent trial showed a significant reduction in the risk of cerebral palsy and poor mental development. There is evidence that the use of elective HFOV compared with CV results in a small reduction in the risk of CLD, but the evidence is weakened by the inconsistency of this effect across trials. Probably many factors, both related to the intervention itself as well as to the individual patient, interact in complex ways. In addition, the benefit could be counteracted by an increased risk of acute air leak. Adverse effects on short-term neurological outcomes have been observed in some studies but these effects are not significant overall. Most trials reporting long-term outcome have not identified any difference.

Study characteristics. Nineteen eligible studies involving 4096 infants met our inclusion criteria. Results. Insufficient evidence exists to support the routine use of high frequency oscillatory ventilation instead of conventional ventilation for preterm infants with lung disease who are given positive pressure ventilation. High frequency oscillatory ventilation is a way of providing artificial ventilation of the lungs that theoretically may produce less injury to the lungs and therefore reduce the rate of chronic lung disease. This review of the evidence from 19 randomised controlled trials showed that although a small protective effect towards the lungs can be seen, this moderate benefit is highly variable between studies and should be weighed against possible harm.

10.1002/14651858.CD000104.pub4

cochrane-simplification-train-3113

cochrane-simplification-train-3113

The evidence from five trials, involving 952 participants, does not suggest a protective effect of maternal dietary antigen avoidance during pregnancy on the incidence of atopic eczema during the first 18 months of life. Data on allergic rhinitis or conjunctivitis, or both, and urticaria are limited to a single trial each and are insufficient to draw meaningful inferences. Longer-term atopic outcomes have not been reported. The restricted diet during pregnancy was associated with a slightly but statistically significantly lower mean gestational weight gain, a non-significantly higher risk of preterm birth, and a non-significant reduction in mean birthweight. The evidence from two trials, involving 523 participants, did not observe a significant protective effect of maternal antigen avoidance during lactation on the incidence of atopic eczema during the first 18 months or on positive skin-prick tests to cow milk, egg, or peanut antigen at one, two, or seven years. One crossover trial involving 17 lactating mothers of infants with established atopic eczema found that maternal dietary antigen avoidance was associated with a non-significant reduction in eczema severity. Prescription of an antigen avoidance diet to a high-risk woman during pregnancy is unlikely to reduce substantially her child's risk of atopic diseases, and such a diet may adversely affect maternal or fetal nutrition, or both. Prescription of an antigen avoidance diet to a high-risk woman during lactation may reduce her child's risk of developing atopic eczema, but better trials are needed. Dietary antigen avoidance by lactating mothers of infants with atopic eczema may reduce the severity of the eczema, but larger trials are needed.

We included five trials, involving 952 participants. Trials of mothers' avoidance of milk, eggs, and other potentially 'antigenic' foods during pregnancy or breastfeeding, or both, provide inadequate evidence about whether such avoidance helps prevent atopic eczema or asthma in the child. Women who avoided eating these foods gained significantly less weight during pregnancy in the one trial reporting on this outcome, raising the possibility of adverse nutritional effects on the mother or fetus. Finally, one small trial reported an inconclusive response of breastfed infants with atopic eczema when their mothers avoided consumption of cow milk and egg.

10.1002/14651858.CD000133.pub3

cochrane-simplification-train-3114

cochrane-simplification-train-3114

Five trials, which together enrolled 4965 infants, were eligible for inclusion. The investigators of these five trials had prospectively planned to combine their data as part of the NeOProM (Neonatal Oxygen Prospective Meta-analysis) Collaboration. We graded the quality of evidence as high for the key outcomes of death, major disability, the composite of death or major disability, and necrotising enterocolitis; and as moderate for blindness and retinopathy of prematurity requiring treatment. When an aligned definition of major disability was used, there was no significant difference in the composite primary outcome of death or major disability in extremely preterm infants when targeting a lower (SpO₂ 85% to 89%) versus a higher (SpO₂ 91% to 95%) oxygen saturation range (typical RR 1.04, 95% confidence interval (CI) 0.98 to 1.10; typical RD 0.02, 95% CI -0.01 to 0.05; 5 trials, 4754 infants) (high-quality evidence). Compared with a higher target range, a lower target range significantly increased the incidence of death at 18 to 24 months corrected age (typical RR 1.16, 95% CI 1.03 to 1.31; typical RD 0.03, 95% CI 0.01 to 0.05; 5 trials, 4873 infants) (high-quality evidence) and necrotising enterocolitis (typical RR 1.24, 95% 1.05 to 1.47; typical RD 0.02, 95% CI 0.01 to 0.04; 5 trials, 4929 infants; I² = 0%) (high-quality evidence). Targeting the lower range significantly decreased the incidence of retinopathy of prematurity requiring treatment (typical RR 0.72, 95% CI 0.61 to 0.85; typical RD -0.04, 95% CI -0.06 to -0.02; 5 trials, 4089 infants; I² = 69%) (moderate-quality evidence). There were no significant differences between the two treatment groups for major disability including blindness, severe hearing loss, cerebral palsy, or other important neonatal morbidities. A subgroup analysis of major outcomes by type of oximeter calibration software (original versus revised) found a significant difference in the treatment effect between the two software types for death (interaction P = 0.03), with a significantly larger treatment effect seen for those infants using the revised algorithm (typical RR 1.38, 95% CI 1.13 to 1.68; typical RD 0.06, 95% CI 0.01 to 0.10; 3 trials, 1716 infants). There were no other important differences in treatment effect shown by the subgroup analyses using the currently available data. In extremely preterm infants, targeting lower (85% to 89%) SpO₂ compared to higher (91% to 95%) SpO₂ had no significant effect on the composite outcome of death or major disability or on major disability alone, including blindness, but increased the average risk of mortality by 28 per 1000 infants treated. The trade-offs between the benefits and harms of the different oxygen saturation target ranges may need to be assessed within local settings (e.g. alarm limit settings, staffing, baseline outcome risks) when deciding on oxygen saturation targeting policies.

The studies we included were randomised trials that enrolled babies born at less than 28 weeks' gestation, at birth or soon thereafter, and targeted oxygen saturation (SpO₂) ranges of either 85% to 89% or 91% to 95%, for at least the first two weeks of life. We included five trials, which together enrolled 4965 infants, in this review. There were benefits and harms associated with both the target ranges tested. Neither the lower nor the higher target range had a significant effect on the rate of death or major disability (the main outcome), on major disability alone or on blindness. However, infants in whom the lower oxygen range was targeted had, on average, a 2.8% increased risk of death, compared to the infants in whom the higher oxygen range was targeted. They also had a 2.2% increase in the rate of a serious bowel condition known as necrotising enterocolitis. Conversely, the infants in whom the lower oxygen range was targeted had a 4.2% decrease in the rate of a serious eye problem, retinopathy of prematurity, requiring surgery or other treatments. The trade-offs between these benefits and harms may need to be assessed within local settings when deciding on oxygen saturation targeting policies. We rated the quality of the evidence as high for the key outcomes of death, major disability, the composite of death or major disability, and necrotising enterocolitis. We rated the quality of evidence as moderate for the two eye-related outcomes (blindness, retinopathy of prematurity requiring treatment), giving us confidence that the overall results are reliable.

10.1002/14651858.CD011190.pub2

cochrane-simplification-train-3115

cochrane-simplification-train-3115

Five studies, 212 participants, were included. PAN showed improvement of symptoms (RR 1.35; 95% CI 1.01 to 1.79), of the amount and duration of sedative medication and of psychomotor function (WMD -8.71; 95% CI -13.71 to -3.71). At one hour post intervention, no significant differences were found for depression (WMD -2.40; 95% CI -8.70 to 3.89) and anxiety (WMD -3.70; 95% CI -10.53 to 3.12). None of the included studies reported any significant adverse effects of any treatment. Results indicate that PAN may be an effective treatment of the mild to moderate alcoholic withdrawal state. The rapidity of the therapeutic effect of PAN therapy coupled with the minimal sedative requirements, may enable patients to enter the psychological treatment phase more quickly than those on sedative regimens, accelerating the patients recovery. Our review does not provide strong evidence due to the small sample sizes of the included trials. Neither does the review indicate any causes for concern that PAN is more harmful than the benzodiazepines. Clinicians wishing to use PAN may initially wish to do so within trial settings. Further high quality trials should be done to confirm these findings and to investigate whether the PAN therapy has fewer adverse effects than other treatments for the alcohol withdrawal states. Studies to investigate the possible cost-effectiveness of PAN by reducing costly hospital admissions and decreasing post administration supervision also need to be performed.

This review assessed the effects of psychotropic analgesic nitrous oxide (PAN) in treating alcohol withdrawal. All trials were conducted in in-patient settings although PAN is also administered in outpatient settings. The review found that PAN is as effective as sedatives for managing mild to moderate alcohol withdrawal states. Nonetheless, it does not provide strong evidence in favour of the benefits or harms of using PAN over sedatives in managing acute alcohol withdrawal. Further high quality trials should be done before these findings can be confirmed.

10.1002/14651858.CD005190.pub2

cochrane-simplification-train-3116

cochrane-simplification-train-3116

We identified two trials (of high risk of bias) involving 152 patients randomised to gastrojejunostomy (80 patients) and no gastrojejunostomy (72 patients). In both trials, patients were found to be unresectable during exploratory laparotomy. Most of the patients also underwent biliary-enteric drainage. There was no evidence of difference in the overall survival (HR 1.02; 95% CI 0.84 to 1.25), peri-operative mortality or morbidity, quality of life, or hospital stay (MD 0.97 days; 95%CI -0.18 to 2.12) between the two groups. The proportion of patients who developed long-term gastric outlet obstruction was significantly lower in the prophylactic gastrojejunostomy group (2/80; 2.5%) compared with no gastrojejunostomy group (20/72; 27.8%) (RR 0.10; 95%CI 0.03 to 0.37). The operating time was significantly longer in the gastrojejunostomy group compared with no gastrojejunostomy group (MD 45.00 minutes; 95%CI 21.39 to 68.61). Routine prophylactic gastrojejunostomy is indicated in patients with unresectable periampullary cancer undergoing exploratory laparotomy (with or without hepaticojejunostomy).

We identified two trials (of high risk of bias or systematic error) involving 152 patients randomised to gastrojejunostomy (80) and no gastrojejunostomy (72). In both studies, patients were found to be unresectable during operations aimed at surgical removal i.e. the stomach was opened to remove the cancer but the cancer could not be removed. There was no evidence of any difference in the overall survival, surgical complications, quality of life, or hospital stay between the two groups. The proportion of patients who developed long-term stomach outflow obstruction was significantly lower in the prophylactic gastrojejunostomy group (2.5%) compared with no gastrojejunostomy group (27.8%). The operating time was significantly longer in the gastrojejunostomy group compared with no gastrojejunostomy group by about 45 minutes. Routine prophylactic gastrojejunostomy is indicated in patients with unresectable periampullary cancer undergoing open operation of the stomach. There is no information available currently about the necessity for prophylactic gastrojejunostomy in patients with periampullary cancer diagnosed to be unresectable by investigations such as scans. Further trials of low risk of bias are necessary to assess the role of prophylactic gastrojejunostomy in patients with unresectable periampullary cancer.

10.1002/14651858.CD008533.pub3

cochrane-simplification-train-3117

cochrane-simplification-train-3117

Four trials met the inclusion criteria. Three had losses to follow-up > 20% and only one provided an adequate description of allocation concealment. Three included a treatment population (0.5 to 2 g/day of strontium ranelate) and one a prevention population (0.125, 0.5 and 1 g/day). A 37% reduction in vertebral fractures (RR 0.63, 95% CI 0.56, 0.71), and a 14% reduction in non-vertebral fractures with the upper boundary of the confidence interval approaching one (RR 0.86, 95% CI 0.75, 0.98), were demonstrated over three years with 2 g of strontium ranelate daily in a treatment population. An increase in BMD was shown at all sites after two to three years of treatment in both populations. Lower doses of strontium ranelate were superior to placebo and the highest dose demonstrated the greatest reduction in vertebral fractures and increase in BMD. An increased risk of diarrhea with 2 g of strontium ranelate daily was found; however, adverse events did not affect the risk of discontinuing treatment nor did it increase the risk of serious side effects, gastritis or death. Additional data suggests that the risk of vascular and nervous system side-effects is increased with taking 2 g of strontium ranelate daily over three to four years. There is silver level evidence (www.cochranemsk.org) to support the efficacy of strontium ranelate for the reduction of fractures (vertebral and to a lesser extent, non-vertebral) in postmenopausal osteoporotic women and an increase in BMD in postmenopausal women with/without osteoporosis. Diarrhea may occur, however, adverse events leading to study withdrawal were not significantly increased. Potential vascular and neurological side-effects need to be further explored.

Women in the studies took 2 g of strontium ranelate or a placebo (fake tablets or powder). After 2 to 3 years, the number of fractures that occurred and bone mineral density was measured. Bone mineral density is a lab test to measure how dense or strong bones are in the hip, spine or neck. The higher the bone density the better. Benefits of strontium ranelate In women after menopause who have osteoporosis: - strontium ranelate decreases spine fractures: 13 out of 100 women had spine fractures taking strontium ranelate 21 out of 100 women had spine fractures taking a placebo - strontium ranelate may decrease fractures that are not in the spine: 10 out of 100 women had non-spine fractures taking strontium ranelate 12 out of 100 women had non-spine fractures taking a placebo - strontium ranelate increases bone mineral density 1 in 3 women had an increase in spine and hip bone mineral density taking strontium ranelate Harms of strontium ranelate In women after menopause who have osteoporosis: - strontium ranelate did not cause side effects that would make them stop taking it - strontium ranelate did not lead to serious side effects, stomach infections, back pain or death - strontium ranelate increased diarrhea 6 out of 100 women had diarrhea taking strontium ranelate 4 out of 100 women had diarrhea taking a placebo Other research shows that harms could include a chance of blood clots, and seizures, memory loss and consciousness. The cause of these vascular and neurological side effects are not known. This review has several limitations which include difficulty interpreting the change in bone mineral density due to the unique aspects of strontium in bone as well, incomplete follow-up of some patients within the individual trials.

10.1002/14651858.CD005326.pub3

cochrane-simplification-train-3118

cochrane-simplification-train-3118

Seven eligible studies were identified from a total of 2314 references. One new study with 600 patients was added to the original review. Four trials compared IABP to standard treatment and three to other percutaneous left assist devices (LVAD). Data from a total of 790 patients with acute myocardial infarction and cardiogenic shock were included in the updated meta-analysis: 406 patients were treated with IABP and 384 patients served as controls; 339 patients were treated without assisting devices and 45 patients with other LVAD. The HR for all-cause 30-day mortality of 0.95 (95% CI 0.76 to 1.19) provided no evidence for a survival benefit. Different non-fatal cardiovascular events were reported in five trials. During hospitalisation, 11 and 4 out of 364 patients from the intervention groups suffered from reinfarction or stroke, respectively. Altogether 5 out of 363 patients from the control group suffered from reinfarction or stroke. Reocclusion was treated with subsequent re-revascularization in 6 out of 352 patients from the intervention group and 13 out of 353 patients of the control group. The high incidence of complications such as moderate and severe bleeding or infection in the control groups has to be attributed to interventions with other LVAD. Possible reasons for bias were more frequent in small studies with high cross-over rates, early stopping and the inclusion of patients with IABP at randomisation. Available evidence suggests that IABP may have a beneficial effect on some haemodynamic parameters. However, this did not result in survival benefits so there is no convincing randomised data to support the use of IABP in infarct-related cardiogenic shock.

In contrast to the previous version of this review, this update now includes data from one large and six small randomised controlled trials. It allows more definitive conclusions about the potential beneficial or harmful clinical effects of IABP support beyond its immediate haemodynamic effects. Complications such as moderate and severe bleeding were more frequently observed in patients treated with more invasive devices than IABP. Small randomised trials suffered from inadequate power to address deaths and harmful effects of IABP and were biased by frequent cross-over to the more aggressive strategy, early stopping of the trial, or the inclusion of patients with IABP at randomisation. It is most noteworthy that a recently conducted and published large randomised trial showed no evidence for survival benefits of IABP support in patients with infarct-related cardiogenic shock treated by percutaneous coronary intervention (PCI). On the basis of these data, IABP support is no longer strongly recommended by the European Society of Cardiology (ESC) guidelines for treatment of patients with infarct-related cardiogenic shock. Rather, IABP use is based on the personal experience and decision of the physician and the particular circumstances of individual patients.

10.1002/14651858.CD007398.pub3

cochrane-simplification-train-3119

cochrane-simplification-train-3119

We included in this review eight RCTs conducted in an outpatient setting, in Italy, the United Kingdom, the United States of America, China, Russia, and Bangladesh. Five studies compared methotrexate versus placebo, and four studies compared methotrexate versus other DMARDs. The average age of participants varied across studies (26 to 52 years), as did the average duration of psoriatic arthritis (one to nine years). Doses of methotrexate varied from 7.5 mg to 25 mg orally per week, but most studies administered approximately 15 mg or less orally per week. Risk of bias was generally unclear or high across most domains for all studies. We considered only one study to have low risk of selection and detection bias. The main study informing results of the primary comparison (methotrexate vs placebo up to six months) was at low risk of bias for all domains except attrition bias and reporting bias. We restricted reporting of results to the comparison of methotrexate versus placebo for up to six months. Low-quality evidence (downgraded due to bias and imprecision) from a single study (221 participants; methotrexate dose 15 mg orally or less per week) informed results for disease response, function, and disease activity. Disease response, measured by the proportion who responded to treatment according to PsARC (response indicates improvement), was 41/109 in the methotrexate group and 24/112 in the placebo group (risk ratio (RR) 1.76, 95% confidence interval (CI) 1.14 to 2.70). This equates to an absolute difference of 16% more responders with methotrexate (4% more to 28% more), and a number needed to treat for an additional beneficial outcome (NNTB) of 6 (95% CI 5 to 25). Mean function, measured by the HAQ (scale 0 to 3; 0 meaning no functional impairment; minimum clinically important difference 0.22), was 1.0 points with placebo and 0.3 points better (95% 0.51 better to 0.09 better) with methotrexate; absolute improvement was 10% (3% better to 17% better), and relative improvement 30% (9% better to 51% better). Mean disease activity as measured by the DAS28-ESR (scale of 0 to 10; lower score means lower disease activity; minimum clinically important difference unknown) was 3.8 points in the methotrexate group and 4.06 points in the placebo group; mean difference was -0.26 points (95% CI -0.65 to 0.13); absolute improvement was 3% (7% better to 1% worse), and relative improvement 6% (16% better to 3% worse). Low-quality evidence (downgraded due to risk of bias and imprecision) from three studies (n = 293) informed our results for serious adverse events and withdrawals due to adverse events. Due to low event rates, we are uncertain if methotrexate results show increased risk of serious adverse events or withdrawals due to adverse events compared to placebo. Results show 1/141 serious adverse events in the methotrexate group and 4/152 in the placebo group: RR 0.26 (95% CI 0.03 to 2.26); absolute difference was 2% fewer events with methotrexate (5% fewer to 1% more). In all, 9/141 withdrawals in the methotrexate group were due to adverse events and 7/152 in the placebo group: RR 1.32 (95% CI 0.51 to 3.42); absolute difference was 1% more withdrawals (4% fewer to 6% more). One study measured health-related quality of life but did not report these results. No study measured radiographic progression. Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for six months; however we are uncertain if it is more harmful. Effects of methotrexate on health-related quality of life, radiographic progression, enthesitis, dactylitis, and fatigue; its benefits beyond six months; and effects of higher-dose methotrexate have not been measured or reported in a randomised placebo-controlled trial.

We included eight studies published between 1964 and 2014. All studies involved people from rheumatology clinics. Studies were conducted in Italy, United Kingdom, United States of America, China, Russia, and Bangladesh. Five studies compared methotrexate against placebo (345 people), and four studies compared methotrexate against another DMARD (leflunomide (61 people), ciclosporin A (35 people), gold (30 people), and sulfasalazine (24 people)). The average age of people included in these studies varied from 26 to 52 years. The average duration of psoriatic arthritis ranged from one to nine years. The dose of methotrexate consisted of 7.5 mg to 25 mg orally, but for most studies, 15 mg was given orally per week. In most western countries, a dose of 15 mg to 20 mg orally per week is normally used in routine practice. After six months of treatment, comparison with placebo (a fake drug) showed that methotrexate resulted in the following (note that one study measured but did not report quality of life, and no studies measured radiographic progression). Proportion who responded to treatment as measured by the Psoriatic Arthritis Response Criteria 16% more people, or 16 more people out of 100, improved with treatment (4% more to 28% more) 37 out of 100 people taking methotrexate improved 21 out of 100 people taking placebo improved Function (lower scores mean better function) Function was improved by 10% (ranging from 3% better to 17% better), or by 0.30 points (ranging from 0.09 better to 0.51 better) on a 0 to 3 scale (this is expected to be meaningful to patients) People taking methotrexate rated their function as 0.7 point People taking placebo rated their function as 1.0 point Disease activity (lower scores mean less active disease) Disease activity improved by 3% (7% better to 1% worse), or by 0.26 points (0.65 better to 0.13 worse) on a 0 to 10 scale People taking methotrexate had a disease activity score of 3.8 points People taking placebo had a disease activity score of 4.06 points Serious adverse events (more events mean more harm) 2% fewer people, or two fewer people out of 100 (5% fewer to 1% more), reported a serious adverse event with methotrexate One person out of 100 people taking methotrexate had a serious adverse event Three out of 100 people taking placebo had a serious adverse event Withdrawals due to adverse events (more events means more harm) 1% more people, or one more person out of 100 (4% fewer to 6% more), withdrew from treatment with methotrexate Six out of 100 people taking methotrexate withdrew Five out of 100 people taking placebo withdrew Low-quality evidence suggests that methotrexate might lead to slightly greater benefit than placebo for some outcomes (e.g. improving function) but may be no better than placebo for other outcomes (e.g. reducing disease activity). We assessed the quality of the evidence as low due to flawed trial design and imprecision (some results are meaningful to patients and some are not). We are uncertain whether methotrexate causes more harm than placebo due to the small number of reported events.

10.1002/14651858.CD012722.pub2

cochrane-simplification-train-3120

cochrane-simplification-train-3120

One non-randomised study met our inclusion criteria. It analysed retrospective data for 194 women with stage IIIC advanced epithelial ovarian cancer who underwent either ultra-radical (extensive) or standard surgery and reported disease specific overall survival and perioperative mortality. Multivariate analysis, adjusted for prognostic factors, identified better disease specific survival among women receiving ultra-radical surgery, although this was not statistically significant (Hazard ratio (HR) = 0.64, 95% confidence interval (CI): 0.40 to 1.04). In a subset of 144 women with carcinomatosis, those who underwent ultra-radical surgery had significantly better disease specific survival than women who underwent standard surgery (adjusted HR = 0.64, 95% CI 0.41 to 0.98). Progression-free survival and quality of life (QoL) were not reported and adverse events were incompletely documented. The study was at high risk of bias. We found only low quality evidence comparing ultra-radical and standard surgery in women with advanced ovarian cancer and carcinomatosis. The evidence suggested that ultra-radical surgery may result in better survival.  It was unclear whether there were any differences in progression-free survival, QoL and morbidity between the two groups. The cost-effectiveness of this intervention has not been investigated. We are, therefore, unable to reach definite conclusions about the relative benefits and adverse effects of the two types of surgery. In order to determine the role of ultra-radical surgery in the management of advanced stage ovarian cancer, a sufficiently powered randomised controlled trial comparing ultra-radical and standard surgery or well-designed non-randomised studies would be required.

We systematically searched the scientific literature for reports of studies comparing ultra-radical and standard surgery for women with advanced ovarian cancer. We looked for randomised controlled trials, which are regarded as the best type of study, and for non-randomised studies that were analysed using methods that allow for differences between the groups of women receiving different types of surgery. We found only one relevant non-randomised study. It analysed data for 194 women recruited at one centre. Analysis that allowed for the differences in the extent of disease of the women who received the two different types of surgery found better disease specific survival among women receiving ultra-radical surgery. The best estimate was that their risk of death from ovarian cancer was about one third lower than for women who had standard surgery, but it might actually have been anywhere between 60% lower and 4% higher. However, the extent of disease in these women varied a lot so the authors also analysed only the 144 women whose cancer had spread throughout their abdomen. Again, the best estimate was that their risk of death was about one third lower than for women who had standard surgery, but it might have been anywhere between 60% lower and only 2% lower. Although this result seems to suggest that ultra-radical surgery might be better than standard surgery, we need to be cautious as the study was not well designed nor analysed, so it may be over-estimating the real benefits of ultra-radical surgery. The study did not report all deaths, which would have been a more reliable and more important outcome. Neither did it report any differences between the groups in the time before the cancer progressed. It did not report quality of life (QoL) which would be very important to women with this advanced cancer. The cost-effectiveness of this intervention was not investigated. Therefore, we could not reach any definite conclusions about the relative benefits and adverse effects of the two types of surgery. Better designed, large studies are needed in order to compare ultra-radical and standard surgery for women with advanced ovarian cancer.

10.1002/14651858.CD007697.pub2

cochrane-simplification-train-3121

cochrane-simplification-train-3121

Nineteen randomised trials on banding ligation versus non-selective beta-blockers for primary prevention in oesophageal varices were included. Most trials specified that only patients with large or high-risk oesophageal varices were included. Bias control was unclear in most trials. In total, 176 of 731 (24%) of the patients randomised to banding ligation and 177 of 773 (23%) of patients randomised to non-selective beta-blockers died. The difference was not statistically significant in a random-effects meta-analysis (RR 1.09; 95% CI 0.92 to 1.30; I2 = 0%). There was no evidence of bias or small study effects in regression analysis (Egger's test P = 0.997). Trial sequential analysis showed that the heterogeneity-adjusted low-bias trial relative risk estimate required an information size of 3211 patients, that none of the interventions showed superiority, and that the limits of futility have not been reached. When all trials were included, banding ligation reduced upper gastrointestinal bleeding and variceal bleeding compared with non-selective beta-blockers (RR 0.69; 95% CI 0.52 to 0.91; I2 = 19% and RR 0.67; 95% CI 0.46 to 0.98; I2 = 31% respectively). The beneficial effect of banding ligation on bleeding was not confirmed in subgroup analyses of trials with adequate randomisation or full paper articles. Bleeding-related mortality was not different in the two intervention arms (29/567 (5.1%) versus 37/585 (6.3%); RR 0.85; 95% CI 0.53 to 1.39; I2 = 0%). Both interventions were associated with adverse events. This review found a beneficial effect of banding ligation on primary prevention of upper gastrointestinal bleeding in patient with oesophageal varices. The effect on bleeding did not reduce mortality. Additional evidence is needed to determine whether our results reflect that non-selective beta-blockers have other beneficial effects than on bleeding.

This review includes 19 randomised trials on banding ligation versus beta-blockers for patients with high-risk oesophageal varices and no history of bleeding. Bias control was unclear in most trials. There was no difference in mortality among the patients randomised to banding ligation compared with beta-blockers. The trials with adequate bias control based on the assessment of randomisation methods found no difference in bleeding rates. The trials with unclear randomisation methods found that banding ligation reduced bleeding. The effect of banding ligation was associated with the duration of follow-up and publication status of the trials. The results of trials with less than 20 months of follow-up found a better effect of banding ligation compared to trials with longer follow-up. Trials published in abstract form were more positive towards the effect of banding ligation than trials published as full paper articles. The combined evidence suggests that banding ligation and beta-blockers may be used as primary prophylaxis in oesophageal varices in adult patients. Additional evidence from trials with adequate bias control and sufficient follow-up is still needed to determine long-term effects.

10.1002/14651858.CD004544.pub2

cochrane-simplification-train-3122

cochrane-simplification-train-3122

Three trials met the inclusion criteria, with a total of 107 participants in three different health-care settings: A USA veterans administration nursing home; a geriatric centre in Israel; and a community nursing service in Hong Kong. Data were available for three of the pre-stated comparisons. Priefer and colleagues evaluated different time intervals between catheter replacement (n = 17); Firestein and colleagues evaluated the use of antibiotic prophylaxis at the time of replacement (n = 70); and Cheung and colleagues compared two different types of cleaning solutions (n = 20). All the included trials were small and under-powered. The reporting of the trials was inadequate and as a result, risk of bias assessment was judged to be unclear for the majority of the domains in two out of the three trials. There was insufficient evidence to indicate that (i) there was a lower incidence of symptomatic UTI in people whose catheter was changed both monthly and when clinically indicated (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.13 to 0.95; very low quality evidence) compared to only when clinically indicated, (ii) there was not enough evidence to assess the effect of antibiotic prophylaxis on reducing: positive urine cultures at 7 days (RR 0.91, 95% CI 0.79 to 1.04); infection (RR 1.41, 95% CI 0.55 to 3.65); or death (RR 2.12, 95% CI 0.20 to 22.30; very low quality evidence), (iii) there was no statistically significant difference in the incidence of asymptomatic bacteruria at 7 days (RR 0.80, 95% CI 0.42 to 1.52) between people receiving water or chlorhexidine solution for periurethral cleansing at the time of catheter replacement. However, none of the 16 participants developed a symptomatic catheter-associated urinary tract infection (CAUTI) at day 14. The following outcomes were considered critical for decision-making and were also selected for the 'Summary of findings' table: (i) participant satisfaction, (ii) condition-specific quality of life, (iii) urinary tract trauma, and (iv) formal economic analysis. However, none of the trials reported these outcomes. None of the trials compared the following comparisons: (i) replacing catheter versus other policy e.g. washouts, (ii) replacing in the home environment versus clinical environment, (iii) clean versus aseptic technique for replacing catheter, (iv) lubricant A versus lubricant B or no lubricant, and (v) catheter user versus carer versus health professional performing the catheter replacement procedure. There is currently insufficient evidence to assess the value of different policies for replacing long-term urinary catheters on patient outcomes. In particular, there are a number of policies for which there are currently no trial data; and a number of important outcomes which have not been assessed, including patient satisfaction, quality of life, urinary tract trauma, and economic outcomes. There is an immediate need for rigorous, adequately powered randomised controlled trials which assess important clinical outcomes and abide by the principles and recommendations of the CONSORT statement.

This review identified that there is currently insufficient high-quality evidence which evaluates the effectiveness of different policies for replacing long-term urinary catheters. Only three randomised clinical trials, which included a total of 107 participants, were eligible and included in this review. These trials evaluated: (i) different time intervals for catheter replacement, (ii) the use of antibiotics to prevent infection and (iii) the use of different cleaning solutions. There was insufficient evidence to suggest that replacing the catheter monthly and when there was a clinical reason to do so reduced bacteria in the urine compared to replacing the catheter only when there was a clinical reason to do so. However, there was not enough evidence to say whether using antibiotics at the time of replacing the catheter for prevention of infection was effective or whether using water to cleanse during catheter replacement was as effective as an anti-bacterial washing solution. None of the trials reported any adverse effects relating to the policies investigated. All three trials which were included in this review were very small with methodological flaws. Therefore new trials are needed in order to definitely answer this research question. The evidence in this review is current up to 19 May 2016.

10.1002/14651858.CD011115.pub2

cochrane-simplification-train-3123

cochrane-simplification-train-3123

Four trials involving 132 people were included. Two studies compared nasal mask with the Oracle oral mask and showed no significant difference in compliance at one month (mean difference (MD) 0.17 hours per night, 95%CI 0.54 to 0.87). There were also no significant differences in any of the physiological parameters (e.g. AHI, arousal index, minimum oxygen saturation), Epworth Sleepiness Scale (ESS), or symptoms of OSA. A single study comparing nasal mask with nasal pillows showed a significant difference in compliance when expressed as the percentage of days used in favour of nasal pillows (nasal pillows mean 94.1± SD 8.3%; nasal mask 85.7 ± 23.5%, P = 0.02), however there were no significant differences in the mean daily use for all days or when use was greater than 0 minutes per day. Nasal pillows were also associated with fewer overall adverse effects (P < 0.001) and greater interface satisfaction (P = 0.001). One study comparing nasal mask with face mask showed that compliance was significantly greater with use of a nasal mask (MD 1.0 hour per night,95% CI 0.3 to 1.8). Nasal mask was also associated with significantly lower ESS scores and was the preferred interface in almost all patients. Due to the limited number of studies available comparing various interface types, the optimum form of CPAP delivery interface remains unclear. The results of our review suggest that nasal pillows or the Oracle oral mask may be useful alternatives when a patient is unable to tolerate conventional nasal masks. The face mask can not be recommended as a first line interface, but may be considered if nasal obstruction or dryness limits the use of a nasal mask. Further randomised studies comparing the different forms of CPAP delivery interface now available for the treatment of OSA, in larger groups of patients and for longer durations, are required.

This review compares the different interface options for CPAP in patients with OSA. Four trials involving 132 people were included. Two studies compared nasal masks with an oral mask called the Oracle, and there did not appear to any significant differences between the two in terms of compliance, sleep study recordings, sleepiness or other symptoms of OSA. One study assessing nasal masks versus nasal pillows (consisting of prongs that rest within the nostrils) showed that patients using the nasal pillows had fewer overall side effects and reported greater satisfaction. The nose mask performed better than the face mask (which covers both the nose and mouth) with one study showing greater compliance and less sleepiness, and was the preferred mask in almost all patients. The choice of interface for a particular person will need to be tailored to the individual. Further trials comparing the many interfaces for CPAP in the treatment of OSA are needed.

10.1002/14651858.CD005308.pub2

cochrane-simplification-train-3124

cochrane-simplification-train-3124

Forty nine studies (12,067 patients) were identified. Thirty eight compared ACEi with placebo, four compared AIIRA with placebo and seven compared ACEi and AIIRA directly. There was no significant difference in the risk of all-cause mortality for ACEi versus placebo (RR 0.91, 95% CI 0.71 to 1.17) and AIIRA versus placebo (RR 0.99, 95% CI 0.85 to 1.17). A subgroup analysis of studies using full-dose ACEi versus studies using half or less than half the maximum tolerable dose of ACEi showed a significant reduction in the risk of all-cause mortality with the use of full-dose ACEi (RR 0.78, 95% CI 0.61 to 0.98). Baseline mortality rates were similar in the ACEi and AIIRA studies. The effects of ACEi and AIIRA on renal outcomes (ESKD, doubling of creatinine, prevention of progression of micro- to macroalbuminuria, remission of micro- to normoalbuminuria) were similarly beneficial. Reliable estimates of effect of ACEi versus AIIRA could not be obtained from the three studies in which they were compared directly because of their small sample size. Although the survival benefits of ACEi are known for patients with DKD, the relative effects on survival of ACEi with AIIRA are unknown due to the lack of adequate direct comparison studies. In placebo controlled studies, only ACEi (at the maximum tolerable dose, but not lower so-called renal doses) were found to significantly reduce the risk of all-cause mortality. Renal and toxicity profiles of these two classes of agents were not significantly different.

However studies have focused on kidney protection rather than over mortality. The aim of this review was to assess the benefits and harms or ACEI and AIIRA therapy in patients with DKD. Fifty studies (13,215 patients) were identified comparing ACEi to placebo, AIIRA to placebo and ACEi to AIIRA. The risk of death from any cause was not significantly reduced with the use of ACEi versus placebo, AIIRA versus placebo or ACEi versus AIIRA. However when we looked at the studies which used the maximum dose tolerated of ACEi rather than the lower, so-called renal doses, there was a significant reduction in the risk of death due to any cause. We were unable to determine which drug provides better protection due to the lack of head-to-head trials.

10.1002/14651858.CD006257

cochrane-simplification-train-3125

cochrane-simplification-train-3125

Three crossover studies (Korner 1978; Tuck 1982; Jirapaet 1993) were identified that compared a form of kinesthetic stimulation to control for the treatment of apnea of prematurity. No study reported a clinically important reduction (> 50%) in apnea. Using a lower threshold (> 25%), Korner 1978 reported less apnea and bradycardia in infants while on an oscillating water bed. Tuck 1982 demonstrated a reduction in frequency of apneas (> 12 seconds) associated with bradycardia (< 100 bpm), apneas associated with hypoxia (TcP02 < 50 mmHg), and apneas requiring stimulation in infants on a rocking bed. Individual patient data were not available from the author to determine if there was an important reduction in clinical apnea. No outcome could be extracted from the study using a 'vertical pulsating stimulus' by Jirapaet 1993 that was consistent with the definition of clinically important apnea. Jirapaet 1993 reported no infants required resuscitation or ventilation. Adverse events such as death, intraventricular hemorrhage and neurodevelopmental disability were not reported. There is insufficient evidence to recommend kinesthetic stimulation as treatment for clinically significant apnea of prematurity. Previous reviews have suggested that kinesthetic stimulation is not effective at preventing apnea of prematurity (Henderson-Smart 2005) and is not as effective as theophylline at treating clinically significant apnea of prematurity (Osborn 2005).

Three controlled studies have used different gentle rocking motions (irregularly oscillating water beds, regularly rocking bed trays or a vertical pulsating stimulus) to reduce the occurrence of apnea in a total of 49 babies. However, there was no clinically useful reduction of periods of apnea, although only a small number of infants were studied. Shorter breathing pauses were reported to be reduced by one study but it is not thought to be clinically important. No harm has reported to be done to the preterm infants with these interventions.

10.1002/14651858.CD000499

cochrane-simplification-train-3126

cochrane-simplification-train-3126

Only one trial with only eight participants met all the inclusion criteria and provided the primary outcome measure for this review. In this trial, four participants treated with neurotrophin-3 had more improvement after six months on the Neuropathy Impairment Score, mean difference -9.50 (95% CI -13.77 to -5.23), than those four treated with placebo. Small trials of exercise training, creatine monohydrate, orthoses and purified bovine brain ganglioside injections (Cronassial) showed no significant benefit in people with genetically undefined CMT1 or CMT2. Small trials of exercise, creatine, purified brain gangliosides, and orthoses have been performed. None showed significant benefit. A very small trial of neurotrophin-3 showed possible minor benefit which needs to be replicated in a larger trial. None of the two trials were large enough to detect moderate benefit or harm. Larger RCTs are needed for any form of pharmacological intervention as well as as for any form of physical intervention. Outcome measures should include a validated composite scale such as the Charcot-Marie-Tooth neuropathy scale.

There have been few trials of treatment for Charcot-Marie Tooth disease. One very small trial of the nerve growth promoting factor, neurotrophin-3, showed possible benefit but needs to be replicated. Trials of exercise, orthosis, creatine and ganglioside injections have been done but did not show significant benefit. These were all too small to identify moderate benefit or harm. Trials of vitamin C for the commonest type of Charcot-Marie Tooth disease are in progress.

10.1002/14651858.CD006052.pub2

cochrane-simplification-train-3127

cochrane-simplification-train-3127

In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age. Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference. Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD. MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence. Maintenance therapy Nine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates. In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.

In this review update, 74 studies involving 5175 patients with lupus nephritis could be studied. Treatments included intravenous (given through a vein) cyclophosphamide, oral (tablets by mouth) mycophenolate mofetil (MMF), azathioprine, and tacrolimus (used alone or together with MMF). We also found studies of treatments called “biologic” therapies, that have been designed to change very specific parts of the body’s immune system that cause it to attack itself. We looked particularly at key outcomes such as whether treatment prevented patients from needing dialysis and controlled the lupus damage to the kidney tissue (called remission). We also looked at serious side-effects including death, infection, infertility, and hair loss. After combining the available studies, compared with cyclophosphamide, MMF may be better at getting the lupus damage to the kidneys under control. However, the range where the actual effect may suggest that MMF may make little or no difference to disease remission compared to treatment with cyclophosphamide. MMF treatment given with tacrolimus may lead to more disease remission. MMF may result in less hair loss and worse diarrhoea, but we were not certain whether MMF reduces infertility or other serious side effects. MMF was better than azathioprine for preventing kidney disease in the longer term. None of the studies told us whether treatment had any effect on death or need for dialysis, and there was very low certainty of evidence for the use of biologics in patients with lupus nephritis. Patients with lupus nephritis may have similar or slightly better outcomes when treated with MMF or MMF with tacrolimus compared to those patients who receive intravenous cyclophosphamide. We are still not certain which is the best treatment for lupus nephritis to protect against needing dialysis in the longer term.

10.1002/14651858.CD002922.pub4

cochrane-simplification-train-3128

cochrane-simplification-train-3128

Sixteen studies (enrolling 809 children) were identified. Risk of bias assessment indicated that study quality was poor or poorly reported with only four and five studies respectively reporting adequate allocation concealment or blinding of study participants and investigators. Treatment with rhGH (28 IU/m²/wk) compared with placebo or no specific therapy resulted in a significant increase in height standard deviation score (HSDS) at one year (8 studies, 391 children: MD 0.82, 95% CI 0.56 to 1.07), and a significant increase in height velocity at six months (2 studies, 27 children: MD 2.85 cm/6 mo, 95% CI 2.22 to 3.48) and one year (7 studies, 287 children: MD 3.88 cm/y, 95% CI 3.32 to 4.44). Height velocity, though reduced, remained significantly greater than untreated children during the second year of therapy (1 study, 82 children: MD 2.30 cm/y, 95% CI 1.39 to 3.21). Compared to the 14 IU/m²/wk group, there was a 1.18 cm/y increase in height velocity in the 28 IU/m²/wk group (3 studies, 150 children: 1.18 cm/y, 95% CI 0.52 to 1.84) . The frequency of reported side effects of rhGH was generally similar to that of the control group. One year of 28 IU/m²/wk rhGH in children with CKD resulted in a 3.88 cm increase in height velocity above that of untreated patients. Studies were too short to determine if continuing treatment resulted in an increase in final adult height.

This review of 16 studies enrolling 809 children found that rhGH increased height in children with CKD by about 4 cm after 1 year and by a further 2 cm after 2 years of treatment compared with no treatment. The frequency of reported side effects of rhGH was generally similar to that of the control group.

10.1002/14651858.CD003264.pub3

cochrane-simplification-train-3129

cochrane-simplification-train-3129

Out of 14,717 citations, only one study met the inclusion criteria. The included RCT recruited women and girl children who received post-exposure prophylaxis (PEP) after rape from sexual assault services in South Africa between August 2007 and May 2008. Participants (n (number) =274) were randomised into a telephone support (n=136) and control (n=138) group. Control group participants received usual care (an interactive information session) from the sexual assault service during the 28 days in which they had to take PEP, with no further contact from the study staff. Telephone support group participants received standard care and phone calls from a counsellor throughout the 28 days when they had to take PEP. Overall, adherence to PEP was not significantly (P=0.13) different between the intervention (38.2%) and control (31.9 %) groups. Also, the proportion of participants who read a pamphlet, did not return to collect medication or with a depression were not significantly different between the intervention and control groups (P=0.006, P=0.42, P=0.72 respectively). The proportion of participants who used a diary was significantly (P=0.001) higher in the intervention group (78.8%) versus the control group (69.9%). The study authors reported that there were no recorded adverse events. The RCT did not provide information about participants’ and providers’ evaluation outcomes, or economic outcomes. The study had a moderate risk of bias. We found only one RCT, with a moderate risk of bias, which showed that providing PEP support by phone calls did not result in higher adherence to PEP. However, the RCT was conducted in an upper-middle-income country with high HIV prevalence, on a high-risk population and the applicability of its results on other settings and contexts is unclear. There is a need for robust evidence from various settings on the effectiveness of using phone calls for providing PEP support and for other HIV prevention interventions.

The aim of this review was to assess the effectiveness HIV prevention interventions delivered by phone calls compared to the standard way of delivering care. After a comprehensive search of various scientific databases and other resources, we found only one relevant study. This study was done in sexual assault services in South Africa. Study participants were women and girls who were given medication to prevent HIV infection (so called 'post-exposure prophylaxis' or 'PEP') after they had been raped. The participants were divided into two groups: one group of participants only received standard care and participants in the other group were given standard care and support via telephone calls to help them take their HIV prevention medication. Overall, only about one third of the participants took their HIV prevention medication for 28 days. The participants who received the phone calls were not more likely to take their medication than participants who only received standard care. Also, the phone calls did not decrease the number of participants with depression and did not increase the number of participants who read an information pamphlet or returned to collect HIV prevention medication. Only a higher percentage of participants who received the calls used a medication diary compared to the participants who did not receive the calls. No harmful effects of this intervention were reported. We could not find any information about other relevant outcomes, such as participants’ and healthcare providers’ satisfaction with the telephone intervention or costs. We urgently need more studies conducted in various settings comparing the effectiveness of the phone calls to other ways of delivering HIV prevention interventions to prevent new HIV infections.

10.1002/14651858.CD009190.pub2

cochrane-simplification-train-3130

cochrane-simplification-train-3130

We included 27 studies (3003 participants) that were followed up for a median of six months. Study interventions included alternative anticoagulant locking solutions (19 studies, 2216 patients), systemic agents (6 studies, 664 patients) and low or no dose heparin (2 studies, 123 patients). The most common comparison treatment was a locking solution of heparin 5000 IU/mL, used in 17 studies. No significant effect on catheter malfunction was observed for alternative anticoagulant locking solutions (RR 0.96, 95% CI 0.74 to 1.26), systemic agents (RR 0.59, 95% CI 0.28 to 1.23), or low or no dose heparin (RR 0.90, 95% CI 0.10 to 8.31). A significant reduction on incidence of catheter-related bacteraemia was observed for alternative anticoagulant locking solutions (RR 0.46, 95% CI 0.32 to 0.66) but not systemic agents (RR 2.41, 95% CI 0.89 to 6.55), and could not be assessed in reports of low or no dose heparin studies. No significant effect on all-cause mortality was observed for alternative anticoagulant locking solutions (RR 0.88, 95% CI 0.54 to 1.43) or systemic agents (RR 0.78, 95% CI 0.37 to 1.65), and was not reported in studies of low or no dose heparin. Bleeding events were only reported in eight studies, including only 2/5 studies of systemic warfarin, with no clear effect demonstrated (RR 1.43, 95% CI 0.86 to 2.39). For individual agents, recombinant tissue plasminogen (rt-PA) was the only locking solution shown to reduce catheter malfunction (RR 0.58, 95% CI 0.37 to 0.91) based on the results of a single study. No significant on catheter malfunction was observed for other individual classes of alternative anticoagulant locking solutions (citrate: RR 1.14, 95% CI 0.76 to 1.69; antibiotic: RR 1.48, 95% CI 0.79 to 2.77; ethanol: RR 0.88, 95% CI 0.21 to 3.67). On the other hand, all individual classes of alternative anticoagulant locking solutions, except ethanol, reduced catheter-related bacteraemia (citrate: RR 0.49, 95% CI 0.36 to 0.68; antibiotic: RR 0.27, 95% CI 0.11 to 0.70; rt-PA: RR 0.35, 95% CI 0.13 to 0.93; ethanol: RR 0.33, 95% CI 0.03 to 4.05). No significant effect on all-cause mortality was observed for any individual agent within the class of alternative locking solutions. Studies were mainly of low quality and underpowered with an average participant number of 75 and study duration of six months. The interpretation of the study evidence was further limited by the variation in tested interventions and outcome reporting. The relative net benefit of anticoagulant therapies for prevention of catheter malfunction remains uncertain. Multiple agents appear to reduce catheter-related bacteraemia although the lack of clear assessment of harms and the limitations of study quality mean these results should be interpreted with caution. Methodological approaches can be used to avoid methods of reporting unduly affecting on the results of meta-analyses incorporating studies employed mixed reporting methods. Further high quality randomised studies, including safety outcomes, are needed.

This review focused on randomised controlled trials (RCTs) of anticoagulants compared with conventional care for the prevention of catheter malfunction patients receiving haemodialysis. We found 27 studies, involving 3003 patients followed for an average six months, which assessed alternative anticoagulant locking solutions, systemic agents and low or no dose heparin. Catheter malfunction were not affected by any of these classes of agents. Subgroup analysis showed that the only agent reducing catheter malfunction was recombinant tissue plasminogen locking solution based on the results of a single study. A significant reduction was observed on the incidence of catheter-related bacteraemia for alternative anticoagulant locking solutions. There was no evidence to suggest that alternative anticoagulants to heparin locking solutions had an effect on death rates or bleeding events, although only a small proportion of studies reported bleeding events. Further high quality information is needed on both potential benefits and safety of alternative approaches to maintaining dialysis access catheter function.

10.1002/14651858.CD009631.pub2

cochrane-simplification-train-3131

cochrane-simplification-train-3131

We identified 20 studies that had analyzed a total of 1947 eyes of 1866 participants (individual studies ranged from 8 to 346 participants who were randomized). The studies were conducted in eight different countries: one in Brazil, three in China, three in Cuba, one in Egypt, two in Iran, two in Thailand, seven in Turkey, and one in Venezuela. Overall risk of bias was unclear, as many studies did not provide information on randomization methods or masking to prevent performance and detection bias. The risk ratio for recurrence of pterygium using conjunctival autograft versus amniotic membrane transplant was 0.87 (95% confidence interval (CI) 0.43 to 1.77) and 0.53 (95% CI 0.33 to 0.85) at 3 months and 6 months, respectively. These estimates include participants with primary and recurrent pterygia. We performed a subgroup analysis to compare participants with primary pterygia with participants with recurrent pterygia. For participants with primary pterygia, the risk ratio was 0.92 (95% CI 0.37 to 2.30) and 0.58 (95% CI 0.27 to 1.27) at 3 months and 6 months, respectively. We were only able to estimate the recurrence of pterygia at 6 months for participants with recurrent pterygia, and the risk ratio comparing conjunctival autograft with amniotic membrane transplant was 0.45 (95% CI 0.21 to 0.99). One included study was a doctoral thesis and did not use allocation concealment. When this study was excluded in a sensitivity analysis, the risk ratio for pterygium recurrence at 6 months' follow-up was 0.43 (95% CI 0.30 to 0.62) for participants with primary and recurrent pterygium. One of the secondary outcomes, the proportion of participants with clinical improvement, was analyzed in only one study. This study reported clinical outcome as the risk of non-recurrence, which was seen in 93.8% of participants in the conjunctival limbal autograft group and 93.3% in the amniotic membrane transplant group at 3 months after surgery. We did not analyze data on the need for repeat surgery, vision-related quality of life, and direct and indirect costs of surgery due to an insufficient number of studies reporting these outcomes. Thirteen studies reported adverse events associated with conjunctival autograft surgery and amniotic membrane transplant surgery. Adverse events that occurred in more than one study were granuloma and pyogenic granuloma and increased intraocular pressure. None of the included studies reported that participants had developed induced astigmatism. In association with pterygium excision, conjunctival autograft is associated with a lower risk of recurrence at six months' after surgery than amniotic membrane transplant. Participants with recurrent pterygia in particular have a lower risk of recurrence when they receive conjunctival autograft surgery compared with amniotic membrane transplant. There are few studies comparing the two techniques with respect to visual acuity outcomes, and we identified no studies that reported on vision-related quality of life or direct or indirect costs. Comparison of these two procedures in such outcome measures bears further investigation. There were an insufficient number of studies that used adjunctive mitomycin C to estimate the effects on pterygium recurrence following conjunctival autograft or amniotic membrane transplant.

We considered the type of pterygium surgery to be better if it the pterygium returned in a smaller proportion of people at three and six months after the surgery. We searched online databases of published medical articles to find studies that had assigned participants to one of the two surgeries. We included in our review only the studies in which the participants were assigned randomly to their surgery, so that they had an equal chance of being assigned to either one. Study participants could have this growth for the first time (primary pterygium) or could need another surgery because their growth had returned previous surgery. The evidence is current to November 2015. We found 20 studies that compared the two surgeries in a total of 1947 eyes. We combined information from the studies to determine which surgery was better. Six months after surgery, the pterygium returned only one third to over half as often in people who had CAG surgery than in people who had AMT surgery. This difference could not be explained by chance alone. The studies we found did not answer all of our questions. We still want to know the effects of the surgeries on clarity of vision, quality of vision, quality of life and costs. More research studies are needed that answer these questions. The overall quality of the evidence in favor of CAG is low to moderate because of issues in the conduct of the studies and results were sometimes not similar across studies. Future published research may have an impact on the conclusions provided in this review.

10.1002/14651858.CD011349.pub2

cochrane-simplification-train-3132

cochrane-simplification-train-3132

Two randomised controlled studies were eligible for inclusion in the review. Both studies were of moderate quality and used active control comparisons (another type of meditation, relaxation, biofeedback). Anti-anxiety drugs were used as standard treatment. The duration of trials ranged from 3 months (12 weeks) to 18 weeks. In one study transcendental meditation showed a reduction in anxiety symptoms and electromyography score comparable with electromyography-biofeedback and relaxation therapy. Another study compared Kundalini Yoga (KY), with Relaxation/Mindfulness Meditation. The Yale-Brown Obsessive Compulsive Scale showed no statistically significant difference between groups. The overall dropout rate in both studies was high (33-44%). Neither study reported on adverse effects of meditation. The small number of studies included in this review do not permit any conclusions to be drawn on the effectiveness of meditation therapy for anxiety disorders. Transcendental meditation is comparable with other kinds of relaxation therapies in reducing anxiety, and Kundalini Yoga did not show significant effectiveness in treating obsessive-compulsive disorders compared with Relaxation/Meditation. Drop out rates appear to be high, and adverse effects of meditation have not been reported. More trials are needed.

Although meditation therapy is widely used in many anxiety-related conditions there is still a lack of studies in anxiety disorder patients. The small number of studies included in this review do not permit any conclusions to be drawn on the effectiveness of meditation therapy for anxiety disorders. Transcendental meditation is comparable with other kinds of relaxation therapies in reducing anxiety, and Kundalini Yoga did not show significant effectiveness in treating obsessive-compulsive disorders compared with Relaxation/Meditation. Drop out rates appear to be high, and adverse effects of meditation have not been reported. More trials are needed.

10.1002/14651858.CD004998.pub2

cochrane-simplification-train-3133

cochrane-simplification-train-3133

We included two small trials (involving a total of 99 pregnant women) that compared guided imagery with quiet rest. The trials were conducted in Canada and the USA. We assessed both trials as at high risk of performance bias, and low risk of attrition bias; one trial was at low risk for selection, detection, and reporting bias, while the other was at unclear risk for the same domains. We could not perform a meta-analysis because the two included studies reported different outcomes, and the frequency of the intervention was slightly different between the two studies. One study performed guided imagery for 15 minutes at least twice daily for four weeks, or until the baby was born (whichever came first). In the other study, the intervention included guided imagery, self-monitoring of blood pressure, and thermal biofeedback-assisted relaxation training for four total hours; the participants were instructed to practice the procedures twice daily and complete at least three relief relaxation breaks each day. The control groups were similar - one was quiet rest, and the other was quiet rest as bed rest. None of our primary outcomes were reported in the included trials: severe hypertension (either systolic blood pressure of 160 mmHg or higher, or diastolic blood pressure of 110 mmHg or higher); severe pre-eclampsia, or perinatal death (stillbirths plus deaths in the first week of life). Only one of the secondary outcomes was measured. Low-certainty evidence from one trial (69 women) suggests that guided imagery may make little or no difference in the use of antihypertensive drugs (risk ratio 1.27, 95% confidence interval 0.72 to 2.22). There is insufficient evidence to inform practice about the use of guided imagery for hypertension in pregnancy. The available evidence for this review topic is sparse, and the effect of guided imagery for treating hypertension during pregnancy (compared with quiet rest) remains unclear. There was low-certainty evidence that guided imagery made little or no difference to the use of antihypertensive drugs, downgraded because of imprecision. The two included trials did not report on any of the primary outcomes of this review. We did not identify any trials comparing guided imagery with no intervention, or with another non-pharmacological method for hypertension. Large and well-designed RCTs are needed to identify the effects of guided imagery on hypertension during pregnancy and on other relevant outcomes associated with short-term and long-term maternal and neonatal health. Trials could also consider utilisation and costs of health service.

We searched for evidence (October 2018) and found two trials (involving 99 women) conducted in Canada and the USA. Both trials compared guided imagery with quiet rest. There were no trials comparing guided imagery with no intervention, or other with another non-pharmacological method for hypertension. The two included studies reported different outcomes and the Intervention frequency was slightly different between the two studies. One study performed guided imagery for 15 minutes at least twice daily for four weeks or until the baby was born (whichever came first). The other study involved guided imagery, self-monitoring of blood pressure, and thermal biofeedback-assisted relaxation training for a total of four hours; the women were instructed to practice the procedures twice daily and complete at least three relaxation breaks each day. The control groups between the two studies were similar - one used quiet rest and the other used quiet rest as bed rest. Neither trial reported data for our main outcomes of interest: severe hypertension, severe pre-eclampsia, or death of the baby during birth or within the first week of life. The trials provided data for only one of our secondary outcomes of interest. Low-certainty evidence from the one trial (69 women) suggests that, compared with quiet rest, guided imagery may make little or no difference in the use of antihypertensive drugs. We included two small trials comparing guided imagery with quiet rest. We did not identify any trials comparing guided imagery with no intervention, or another non-pharmacological treatment for hypertension. The available evidence for this review is sparse and the effect of guided imagery for treating hypertension during pregnancy (compared with quiet rest) remains unclear. The included trials did not report on any of the main outcomes in this review and only provided low-certainty evidence on the uncertain effect on the use of antihypertensive drugs. There is insufficient evidence to inform practice about using guided imagery for hypertension in pregnancy. Large and well-designed studies are needed to identify the effects of guided imagery on hypertension during pregnancy and on other relevant outcomes associated with the short-term and long-term health of mothers and their babies. The trials should also consider the use and costs of health services.

10.1002/14651858.CD011337.pub2

cochrane-simplification-train-3134

cochrane-simplification-train-3134

We found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo. We found one trial (18 participants) that fulfilled the selection criteria, comparing different doses of alglucosidase alfa. The trial provided low-quality evidence (this was a small trial, there were no numerical results available by dose group, random sequence generation and allocation concealment were unclear, and there was a lack of blinding). The duration of alglucosidase alfa treatment ranged from 52 weeks (the length of the original study) to up to three years (including the extended phase of the trial), with a median duration of treatment being 2.3 years. The trial only reported that clinical responses including cardiac function and motor development, as well as the proportion of children that were free of invasive ventilation, were similar in the 20 mg/kg every two weeks and the 40 mg/kg every two weeks groups (low-quality evidence). Long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy (low-quality evidence). In relation to the number of children experiencing one or more infusion-related events, there was no significant difference between dose groups, risk ratio 0.83 (95% confidence interval 0.40 to 1.76) (low-quality of evidence). However, of note, at 52 weeks, five children in the 20 mg/kg every two weeks dose group experienced a total of 41 mild or moderate (none severe) infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 123 infusion-related events. By the end of the extended phase of the trial, five children in the 20 mg/kg every two weeks dose group experienced a total of 47 infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 177 infusion-related events. The trial was supported by the Genzyme Corporation. The search found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo. One small randomized controlled trial provided no robust evidence for which dosing schedule of alglucosidase alfa was more effective to treat infantile-onset Pompe disease. It is not deemed ethical to proceed with new placebo-controlled trials, therefore a randomized controlled trial with a large sample size comparing different dosing schedules of enzyme replacement therapy is needed. The main clinical outcomes (i.e. cardiac function, invasive ventilation, survival, motor development, adverse events (e.g. the development of antibodies)) should be standardized when evaluated and reported.

We searched medical databases for clinical trials of enzyme replacement therapy in children with Pompe disease. We found no randomised trials (where people taking part in the trial have equal chances of being in the treatment or the control group) comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo (a 'dummy' drug). We found one trial (18 children) that compared two doses of recombinant human alglucosidase alfa (an enzyme replacement therapy): 20 mg/kg every two weeks (low dose) and 40 mg/kg every two weeks (high dose). The duration of treatment ranged from 52 weeks (the length of the original study) to up to three years (including the extension phase of the study), with a median (the middle number) duration of treatment being 2.3 years. There were very limited numerical results available by dose group, the trial showed no evidence in favour of a high dose as opposed to a low dose. It described that the clinical responses including cardiac function, motor development (development of a child's muscles and their ability to move around and manipulate their environment), as well as the proportion of children that were free of invasive ventilation,were similar in the two groups (low-quality evidence). Long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival (time without requiring a machine to help with breathing) and improved cardiomyopathy (heart disease) (low-quality evidence). In relation to the number of children experiencing one or more infusion-related events, there was no significant difference between the different dose groups (low-quality evidence), although, of note, at 52 weeks, five children in the low-dose group experienced a total of 41 mild or moderate (none were severe) infusion-related events and the six children in the high dose-group experienced a total of 123 infusion-related events. By the end of the extension phase, five children in the low-dose group experienced a total of 47 infusion-related events and the six children in the high-dose group experienced a total of 177 infusion-related events. New trials should be undertaken with adequate number of participants to detect effectiveness and safety at different doses of alglucosidase alfa. The main clinical outcomes (i.e. cardiac function, time to ventilation, survival, motor development and side effects) should be standardized when evaluated and reported. The evidence that this small trial provided to the review was of low quality. The trial was supported by the Genzyme Corporation.

10.1002/14651858.CD011539.pub2

cochrane-simplification-train-3135

cochrane-simplification-train-3135

We identified 16 trials, of which six were eligible for inclusion. The six included studies randomized 546 women with singleton gestations and threatened preterm labor (PTL) at 23 0/7 to 34 6/7 weeks. A total of 277 women were randomized to knowledge and 269 to no knowledge of FFN. No trials were identified on asymptomatic women or multiple gestations. The risk of bias of included studies was mixed. For selected important outcomes, preterm birth before 37, 34, and 32 weeks, and maternal hospitalization, we graded the quality of the evidence and created a 'Summary of findings' table. For these outcomes, the evidence was graded as mainly low quality due to the imprecision of effect estimates. Management based on knowledge of FFN results may reduce preterm birth before 37 weeks (20.7%) versus controls without such knowledge (29.2%) (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.52 to 1.01; 5 trials; 434 women; low-quality evidence). However, management based on knowledge of FFN results may make little or no difference to preterm birth before 34 (RR 1.09, 95% CI 0.54 to 2.18; 4 trials; 357 women; low-quality evidence) or maternal hospitalization (RR 1.06, 95% CI 0.79 to 1.43; 5 trials; 441 women; low-quality evidence). The evidence for preterm birth before 32 weeks is uncertain because the quality was found to be very low (average RR 0.79, 95% CI 0.16 to 3.96; 4 trials; 357 women; very low-quality evidence). For all other outcomes, for which there were available data (preterm birth less than 28 weeks; gestational age at delivery (weeks); birthweight less than 2500 g; perinatal death; tocolysis; steroids for fetal lung maturity; time to evaluate; respiratory distress syndrome; neonatal intensive care unit (NICU) admission; and NICU days), knowledge of FFN results may make little or no difference to the outcomes. The evidence from this review suggests that management based on knowledge of FFN results may reduce preterm birth before 37 weeks. However, our confidence in this result is limited as the evidence was found to be of low quality. Effects on other substantive outcomes are uncertain due to serious concerns in study design, inconsistency, and imprecision of effect estimates. No trials were identified on asymptomatic women, or multiple gestations. Future studies are needed that include specific populations (e.g. singleton gestations with symptoms of preterm labor), a study group managed with a protocol based on the FFN results, and that report not only maternal but also important perinatal outcomes. Cost-effectiveness analyses are also needed.

We found six randomised controlled studies involving 546 women who were pregnant with one baby and were showing signs of preterm labor at between 23 to 34 weeks' gestation. We graded the following evidence as mainly low quality because of the low number of women in the studies and a wide variation in findings. We found that the number of births before 37 weeks may be slightly reduced when women and their doctors know the results of the FFN test (20.7% versus 29.2%; 5 trials; 434 women). However, knowledge of FFN results may make little or no difference for the other outcomes with available data, including: maternal hospitalization (5 trials; 441 women); use of uterine relaxants (tocolysis) to try to prevent labor; earlier preterm births; women’s gestational age at delivery; babies with a birthweight less than 2500 g; newborn deaths; the number of babies with respiratory distress syndrome; giving steroids to mature the unborn babies’ lungs; and number of days in a neonatal intensive care unit (NICU). This review of six studies did not find enough evidence to say whether or not the FFN test should be used in the management of women showing signs of preterm labor. A screening test such as FFN can only be considered effective if interventions based on the screening results, such as giving drugs to relax the uterus, reduce the number of preterm births. Further research should be encouraged.

10.1002/14651858.CD006843.pub3

cochrane-simplification-train-3136

cochrane-simplification-train-3136

Three trials met the inclusion criteria and these randomised 579 women, of whom all were assessed at the end of the trials. Two trials assessing 373 participants with stage III to IV persistent or recurrent disease, found that women who received combination therapy had a significantly lower risk of death and disease progression than women who received single agent ifosfamide, after adjustment for performance status (HR = 0.75, 95% confidence interval (CI): 0.60 to 0.94 and HR = 0.72, 95% CI: 0.58 to 0.90 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of nausea and vomiting, where significantly more women experienced these ailments in the combination therapy group than the Ifosamide group (RR = 3.53, 95% CI: 1.33 to 9.37). In one trial there was no statistically significant difference in the risk of death and disease progression in women who received whole body irradiation and chemotherapy, after adjustment for age and FIGO stage (HR = 0.71, 95% CI: 0.48 to 1.05 and HR = 0.79, 95% CI: 0.53 to 1.18 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of haematological and neuropathy morbidities, where significantly less women experienced these morbidities in the whole body irradiation group than the chemotherapy group (RR= 0.02, 95% CI: 0.00 to 0.16) for haematological morbidity and all nine women in the trial experiencing neuropathy morbidity were in the chemotherapy group). In advanced stage metastatic uterine carcinosarcoma as well as recurrent disease adjuvant combination, chemotherapy with ifosfamide should be considered. Combination chemotherapy with ifosfamide and paclitaxel is associated with lower risk of death compared with ifosfamide alone. In addition, radiotherapy to the abdomen is not associated with improved survival.

In addition, radiotherapy to the abdomen was not associated with improved survival, as we found in one trial that there was no difference in the risk of death and disease progression in women who received whole abdominal irradiation and chemotherapy, after adjustment for age and stage of disease. Previous studies have shown that doxorubicin, despite being established in the treatment of uterine carcinoma, does not seem to be highly active. Adverse events were comprehensively reported for the comparisons of combination therapy and ifosfamide and whole body irradiation and chemotherapy. More women experienced side effects when they received combination therapy than ifosamide alone and chemotherapy than whole body irradiation. The effect of therapy on quality of life was not reported in any of the trials.

10.1002/14651858.CD006812.pub3

cochrane-simplification-train-3137

cochrane-simplification-train-3137

We included 13 RCTs (839 people). Studies were at risk of selection, performance, and detection bias (owing to lack of blinding for self-reported outcomes) and had low risk of attrition and reporting bias. We prioritized the findings when aerobic exercise was compared with no exercise control and present them fully here. Eight trials (with 456 participants) provided low-quality evidence for pain intensity, fatigue, stiffness, and physical function; and moderate-quality evidence for withdrawals and HRQL at completion of the intervention (6 to 24 weeks). With the exception of withdrawals and adverse events, major outcome measures were self-reported and were expressed on a 0 to 100 scale (lower values are best, negative mean differences (MDs)/standardized mean differences (SMDs) indicate improvement). Effects for aerobic exercise versus control were as follows: HRQL: mean 56.08; five studies; N = 372; MD -7.89, 95% CI -13.23 to -2.55; absolute improvement of 8% (3% to 13%) and relative improvement of 15% (5% to 24%); pain intensity: mean 65.31; six studies; N = 351; MD -11.06, 95% CI -18.34 to -3.77; absolute improvement of 11% (95% CI 4% to 18%) and relative improvement of 18% (7% to 30%); stiffness: mean 69; one study; N = 143; MD -7.96, 95% CI -14.95 to -0.97; absolute difference in improvement of 8% (1% to 15%) and relative change in improvement of 11.4% (21.4% to 1.4%); physical function: mean 38.32; three studies; N = 246; MD -10.16, 95% CI -15.39 to -4.94; absolute change in improvement of 10% (15% to 5%) and relative change in improvement of 21.9% (33% to 11%); and fatigue: mean 68; three studies; N = 286; MD -6.48, 95% CI -14.33 to 1.38; absolute change in improvement of 6% (12% improvement to 0.3% worse) and relative change in improvement of 8% (16% improvement to 0.4% worse). Pooled analysis resulted in a risk ratio (RR) of moderate quality for withdrawals (17 per 100 and 20 per 100 in control and intervention groups, respectively; eight studies; N = 456; RR 1.25, 95%CI 0.89 to 1.77; absolute change of 5% more withdrawals with exercise (3% fewer to 12% more). Three trials provided low-quality evidence on long-term effects (24 to 208 weeks post intervention) and reported that benefits for pain and function persisted but did not for HRQL or fatigue. Withdrawals were similar, and investigators did not assess stiffness and adverse events. We are uncertain about the effects of one aerobic intervention versus another, as the evidence was of low to very low quality and was derived from single trials only, precluding meta-analyses. Similarly, we are uncertain of the effects of aerobic exercise over active controls (ie, education, three studies; stress management training, one study; medication, one study) owing to evidence of low to very low quality provided by single trials. Most studies did not measure adverse events; thus we are uncertain about the risk of adverse events associated with aerobic exercise. When compared with control, moderate-quality evidence indicates that aerobic exercise probably improves HRQL and all-cause withdrawal, and low-quality evidence suggests that aerobic exercise may slightly decrease pain intensity, may slightly improve physical function, and may lead to little difference in fatigue and stiffness. Three of the reported outcomes reached clinical significance (HRQL, physical function, and pain). Long-term effects of aerobic exercise may include little or no difference in pain, physical function, and all-cause withdrawal, and we are uncertain about long-term effects on remaining outcomes. We downgraded the evidence owing to the small number of included trials and participants across trials, and because of issues related to unclear and high risks of bias (performance, selection, and detection biases). Aerobic exercise appears to be well tolerated (similar withdrawal rates across groups), although evidence on adverse events is scarce, so we are uncertain about its safety.

We searched for studies until June 2016, and found 13 studies (839 individuals). Most studies (61.5%) included only female participants. Average age of participants was 41 years (minimum 32 to maximum 56 years). According to the inclusion/exclusion criteria, most participants were not doing exercises before starting the study. Aerobic interventions were compared with controls (wait list, treatment as usual, daily activities as usual) over six to 24 weeks. On average, exercise sessions were provided two to three times per week for 35 minutes each session. Exercises involved walking, cycling, running, and doing low-impact aerobics and aquacise. Participants exercised at different intensities, starting light and increasing as the study progressed. All programs were supervised. Key results at the end of treatment The findings of aerobic exercise compared with no exercise control were prioritised and are presented fully here. Moderate-quality evidence revealed that aerobic exercise improved HRQL, and low-quality evidence showed improvement in physical function and decreased pain, fatigue, and stiffness compared with control. Similar numbers of people dropped out of the aerobic interventions group and the comparison group. Minor adverse events were reported, but reporting was inconsistent in these studies. Four studies explored long-term effects at 24 to 208 weeks after the intervention ended. They reported benefits for pain and physical function among exercisers and noted no other effects. Best estimates of what happened in people with fibromyalgia when they did aerobic exercise compared with when they received control interventions Each outcome below was measured on a scale from 0 to 100, on which lower scores were better. HRQL after 12 to 24 weeks: People who exercised were 7% better (or 7 points, ranging from 3 to 13 points) and rated their HRQL as 48 points versus 56 points in the control group. Pain after 6 to 24 weeks: People who exercised were 11% better (or 11 points, ranging from 4 to 18 points) and rated their pain as 56 points versus 65 points in the control group. Fatigue after 14 to 24 weeks: Those who exercised were 6% better (or 6 points, ranging from 12 better to 0.3 worse) and rated their fatigue as 63 points versus 68 points in the control group. Stiffness after 16 weeks: Those who exercised were 8% better (or 8 points, ranging from 1 to 15) and rated their stiffness as 61 points versus 69 points in the control group. Physical function after 8 to 24 weeks: The aerobic exercise group was 10% better (or 10 points, ranging from 15 to 5) and participants rated their physical function as 37 points versus 46 points in the control group. Other results: Withdrawal from treatment A total of 20 out of 100 people dropped out of the aerobic group compared with 17 out of 100 from the control group (3% more, ranging from 3% fewer to 12% more) for any reason. Adverse events We do not have precise information about adverse events associated with aerobic exercise. Some reports describe increased pain or fatigue, and one of the 496 participants doing aerobic exercise experienced a foot bone (metatarsal) stress fracture. This may have happened by chance. Quality of the evidence Evidence shows that aerobic exercise may improve HRQL, pain, stiffness, and physical function, and probably leads to similar numbers of people dropping out from each group. Aerobic exercise does not seem to improve fatigue. The quality of the evidence was considered to be low or moderate because of the small numbers of people included in the studies, some issues involving study design, and low certainty of results.

10.1002/14651858.CD012700

cochrane-simplification-train-3138

cochrane-simplification-train-3138

We included a single study in this review comparing lumbar sympathectomy with prostanoids for the treatment of CLI in people with non-reconstructable PAD. The single study included 200 participants with Buerger's disease, a form of PAD, 100 in each treatment group, but only 162 were actually included in the analyses. The study compared an open surgical technique for lumbar sympathectomy with the prostanoid, iloprost, and followed participants for 24 weeks. Risk of bias was low for most evaluated domains. Due to the nature of the treatment, blinding of the participants and those providing the treatment would be impossible as a surgical procedure was compared with intravenous injections. It was not mentioned if blinded assessors evaluated the study outcomes, therefore, we judged subjective outcomes (i.e. pain reduction) to be at unclear risk of detection bias and objective outcomes (i.e. ulcer healing, amputation and mortality) at low risk of detection bias. We also rated the risk of attrition bias as unclear; 38 out of 200 (19%) participants were not included in the analysis without clear explanation (16 of 100 in the iloprost arm and 22 of 100 in the sympathectomy arm). The quality of evidence was low due to serious imprecision because the study numbers were low and there was only one study included. The single included study reported on the outcome of complete healing without pain or major amputation, which fell under three separate outcomes for our review: relief of rest pain, complete ulcer healing and avoidance of major amputation. We chose to keep the outcome as a singularly reported outcome in order to not introduce bias into the outcomes, which may have been the case if reported separately. The limited evidence suggests participants who received prostaglandins had improved complete ulcer healing without rest pain or major amputation when compared with those who received lumbar sympathectomy (RR 1.63, 95% CI 1.30 to 2.05), but as it was the only included study, we rated the data as low-quality and could not draw any overall conclusions. The study authors stated that more participants who received prostaglandins reported adverse effects, such as headache, flushing, nausea and abdominal discomfort, but only one participant experienced severe enough adverse effects to drop out. Five participants who underwent lumbar sympathectomy reported minor wound infection (low-quality evidence). There was no reported mortality in either of the treatment groups (low-quality evidence). The included study did not report on claudication distances, quality of life or functional status, ankle brachial pressure index (ABPI), tissue oxygenation or toe pressures, or progression to minor amputation, complications or provide any cost-effectiveness data. Low-quality evidence from a single study in a select group of participants (people with Buerger's disease) suggests that prostaglandins are superior to open surgical lumbar sympathectomy for complete ulcer healing without rest pain or major amputation, but possibly incur more adverse effects. Further studies are needed to better understand if prostaglandins truly are more efficacious than open surgical lumbar sympathectomy and if there are any concerns with adverse effects. It would be of great importance for future studies to include other forms of PAD (as Buerger's disease is a select type of PAD), other methods of sympathectomy as well as data on quality of life, complications and cost-effectiveness.

For this review we only identified one study that met the inclusion criteria (current until 29 March 2017). This study randomised 200 participants (162 included in analysis) and compared surgical lumbar sympathectomy with the prostaglandin, iloprost, in people with Buerger's disease, a form of PAD, and followed participants for 24 weeks. This study found evidence of increased complete ulcer healing without rest pain or major amputation in the participants who received intravenous prostaglandin compared with those that received surgical lumbar sympathectomy. However, those who received prostaglandins were more likely to report adverse events such as headache, flushing, nausea and abdominal discomfort. There were no reported deaths in either treatment group. The single included study did not report on other planned outcomes for this review such as walking distances and quality of life or functional status. The single study was limited to the specific form of PAD known as Buerger's disease, and to surgical lumbar sympathectomy, making it difficult to generalise the findings to all types of PAD and all methods of lumbar sympathectomy. Overall, the study had little risk of bias due to design. Blinding of the participants and those that administered the treatment would be impossible, but there was no mention of blinding of the people who evaluated the outcomes, which would have been a possibility. Due to this, we rated the outcomes that had subjective measures (measures that can be influenced by or based on personal beliefs or feelings), such as relief of rest pain as unclear risk of bias, but the outcomes that had objective measures (measures that are not influenced by or based on personal beliefs or feelings) such as ulcer healing, amputation and mortality as low risk of bias. Also, there was a large number of participants not included in the analysis (38 of the 200, 19%), in both groups, with inadequate reasons as to why, so we rated bias due to incomplete outcome data as unclear. The quality of the evidence, therefore, was low for the outcomes evaluated as the number of participants included was low and only a single study reported evidence.

10.1002/14651858.CD009366.pub2

cochrane-simplification-train-3139

cochrane-simplification-train-3139

Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin-sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 μmol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference -51.90 μmol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group. There is evidence of short-term benefit from using sapropterin in some people with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term. There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria.

The review identified two trials of sapropterin dihydrochloride; one in children and adults with no restricted diet and one in just children whose diet was restricted. The trials used different doses of sapropterin dihydrochloride (10 mg/kg/day and 20 mg/kg/day). We could not combine any data due to different formats of presentation. We found evidence to show that some people with mild or moderate phenylketonuria can benefit from the use of sapropterin dihydrochloride in the short term; the concentration of blood phenylalanine was lowered after treatment in both trials. The trial with the higher dose also measured the outcome change in protein tolerance. It reported an increase in protein tolerance in response to sapropterin. There were no adverse effects associated with the use of sapropterin dihydrochloride in the short term. We found no evidence on the effects of long-term treatment. We could not draw any conclusions on its benefits in severe phenylketonuria.

10.1002/14651858.CD008005.pub4

cochrane-simplification-train-3140

cochrane-simplification-train-3140

Seven trials were included, but only six trials (919 participants) contributed data. There was no evidence that pneumococcal vaccination during pregnancy reduces the risk of neonatal infection (risk ratio (RR) 0.66; 95% confidence interval (CI) 0.30 to 1.46; two trials, 241 pregnancies, low quality evidence). Although the data suggest an effect in reducing pneumococcal colonization in infants by 16 months of age (average RR 0.33; 95% CI 0.11 to 0.98; one trial, 56 pregnancies), there was no evidence of this effect in infants at two to three months of age (average RR 1.13; 95% CI 0.46 to 2.78; two trials, 146 pregnancies, low quality evidence) or by six to seven months of age (average RR 0.67, 95% CI 0.22 to 2.08; two trials, 148 pregnancies, low quality evidence). None of the trials included in this review reported neonatal death as a result of pneumococcal infection. Neonatal antibody levels were reported as geometric mean and 95% CI. There were inconsistent results between studies. Two studies showed significantly higher immunoglobulin G (IgG) levels in cord blood in the pneumococcal vaccine group when compared with the control group for all serotypes. In contrast, another trial showed no difference in neonatal antibody levels between the pneumococcal vaccine group and the control group. Maternal antibody levels were also reported as geometric mean and 95% CI. One study showed significantly higher IgG levels in maternal serum in women immunized with pneumococcal vaccine when compared with control vaccine regardless of any serotypes. Another study showed significantly higher maternal antibody levels only for serotype 14, but no evidence of an effect for other serotypes. The percentage of women with seroprotection was measured in one trial at delivery and at 12 months post-delivery. At delivery, results favored the intervention group for serotype 6 (RR 1.49, 95% CI 1.31 to 1.69), serotype 14 (RR 1.40, 95% CI 1.25 to 1.56) and serotype 19 (RR 2.29, 95% CI 1.89 to 2.76). There were no group differences seen at 12 months post-delivery for serotypes 6 or 14 (RR 1.06, 95% CI 1.00 to 1.12 and RR 1.06, 95% CI 0.98 to 1.15, respectively), but results favored the intervention group for serotype 19 (RR 1.59, 95% CI 1.37 to 1.85). No significant difference for tenderness at the injection site between women who received pneumococcal vaccine and those who received control vaccine (average RR 3.20; 95% CI 0.32 to 31.54; two trials, 130 women). The overall quality of evidence is low for primary outcomes. Most outcomes had wide confidence intervals crossing the line of no effect, and most of the included trials had small numbers of participants and few events which led to downgrading evidence for imprecision of findings. There is insufficient evidence to assess whether pneumococcal vaccination during pregnancy could reduce infant infections.

Although the incidence of invasive pneumococcal disease is variable across the world, the rate of serious illness or death is high in children who get this infection. The Streptococcus pneumoniae (pneumococcus) organism colonizes the upper respiratory tract and can cause bacteremia, meningitis, pneumonia and other lower respiratory tract, and upper respiratory tract infections, including otitis media and sinusitis. Newborn vaccination schedules of three primary doses with a booster dose could reduce the impact of pneumococcal disease in immunized children, but these vaccinations have no protective effect in infants less than three months of age. Maternal pneumococcal immunization during pregnancy may be a way of preventing pneumococcal disease during the infant's first months of life. We included seven randomized controlled trials. A total of 919 pregnant women participated in the six randomized controlled trials that contributed data to this review. The trials compared 23-valent pneumococcal polysaccharide vaccine with control vaccine. All women received a single injection of pneumococcal or control vaccine (where used). The women’s mean gestational age at the time of immunization was between 27 and 38 weeks, where stated. Only two trials with 241 pregnancies reported on neonatal infections. This was not enough information to say whether pneumococcal vaccination during pregnancy led to fewer infant infections. Two trials with 146 pregnancies reported on infant nasal carriage of pneumococci (pneumococcal colonization), which was not enough evidence to show an effect in reducing colonization at two to three months of age or six to seven months of age. The included trials were of reasonable quality. There was no difference between pneumococcal vaccine and control vaccine for tenderness at the injection site. No serious adverse events were reported in the trials.

10.1002/14651858.CD004903.pub4

cochrane-simplification-train-3141

cochrane-simplification-train-3141

Four trials (1429 participants) comparing PDT with verteporfin to PDT with 5% dextrose in water were included in this review. Participants received on average five treatments over two years. The risk ratio of losing 3 or more lines of visual acuity at 24 months comparing the intervention with the control group was 0.80 (95% confidence interval (CI) 0.73 to 0.88). The risk ratio of losing 6 or more lines of visual acuity at 24 months comparing the intervention with the control group was 0.66 (95% CI 0.56 to 0.83). The results at 12 months were similar to those at 24 months. The most serious adverse outcome, severe visual acuity decrease within one week of treatment, occurred in 11 per 1000 patients (95% CI 3 to 48). Infusion related back pain was experienced by 20 per 1000 (95% CI 6 to 70). Two further trials compared different treatment regimens: standard versus delayed light application; retreatment every two months versus every three months. Neither trial demonstrated differences in effectiveness. The overall quality of the evidence included in this review was considered to be high. Five out of the six trials were funded by the manufacturers of verteporfin. Photodynamic therapy in people with choroidal neovascularisation due to AMD is effective in preventing clinically significant visual loss with a relative risk reduction of approximately 20%. Modified treatment regimens have not convincingly shown increased effectiveness. There was no evidence on quality of life and little on cost.

This review includes four randomised trials involving 1429 participants. All four trials compared verteporfin therapy to 5% dextrose water (placebo treatment). Photodynamic therapy reduces the risk of vision loss caused by "wet" age-related macular degeneration. More people treated with verteporfin also experienced improvements in vision compared to the placebo group, however, the absolute numbers experiencing vision improvement after this treatment was low (80 per 1000). A small number of people may experience acute vision loss within one week after treatment (in approximately 1 in 100 people) and infusion related back pain can occur (in approximately 1 in 50 people).

10.1002/14651858.CD002030.pub3

cochrane-simplification-train-3142

cochrane-simplification-train-3142

Seventy-four studies enrolling 7049 infants were included. Results from only a few studies could be combined in meta-analyses and for most analyses the GRADE assessments indicated low- or moderate-quality evidence. There was high-quality evidence for the beneficial effect of sucrose (24%) with non-nutritive sucking (pacifier dipped in sucrose) or 0.5 mL of sucrose orally in preterm and term infants: Premature Infant Pain Profile (PIPP) 30 s after heel lance WMD -1.70 (95% CI -2.13 to -1.26; I2 = 0% (no heterogeneity); 3 studies, n = 278); PIPP 60 s after heel lance WMD -2.14 (95% CI -3.34 to -0.94; I2 = 0% (no heterogeneity; 2 studies, n = 164). There was high-quality evidence for the use of 2 mL 24% sucrose prior to venipuncture: PIPP during venipuncture WMD -2.79 (95% CI -3.76 to -1.83; I2 = 0% (no heterogeneity; 2 groups in 1 study, n = 213); and intramuscular injections: PIPP during intramuscular injection WMD -1.05 (95% CI -1.98 to -0.12; I2 = 0% (2 groups in 1 study, n = 232). Evidence from studies that could not be included in RevMan-analyses supported these findings. Reported adverse effects were minor and similar in the sucrose and control groups. Sucrose is not effective in reducing pain from circumcision. The effectiveness of sucrose for reducing pain/stress from other interventions such as arterial puncture, subcutaneous injection, insertion of nasogastric or orogastric tubes, bladder catherization, eye examinations and echocardiography examinations are inconclusive. Most trials indicated some benefit of sucrose use but that the evidence for other painful procedures is of lower quality as it is based on few studies of small sample sizes. The effects of sucrose on long-term neurodevelopmental outcomes are unknown. Sucrose is effective for reducing procedural pain from single events such as heel lance, venipuncture and intramuscular injection in both preterm and term infants. No serious side effects or harms have been documented with this intervention. We could not identify an optimal dose due to inconsistency in effective sucrose dosage among studies. Further investigation of repeated administration of sucrose in neonates is needed. There is some moderate-quality evidence that sucrose in combination with other non-pharmacological interventions such as non-nutritive sucking is more effective than sucrose alone, but more research of this and sucrose in combination with pharmacological interventions is needed. Sucrose use in extremely preterm, unstable, ventilated (or a combination of these) neonates needs to be addressed. Additional research is needed to determine the minimally effective dose of sucrose during a single painful procedure and the effect of repeated sucrose administration on immediate (pain intensity) and long-term (neurodevelopmental) outcomes.

We searched the medical literature widely up to February 2016 for studies that investigated the pain-relieving effect of sucrose for minor medical procedures in newborn full-term and premature babies. We included randomised controlled trials only, as these provide the most reliable medical evidence. We identified 74 studies that reported on a total of more than 7000 infants in this Cochrane Review. Thirty-eight studies included full-term babies only, 31 included premature babies only, and five included both full-term and premature babies. Heel lance was the painful procedure in 38 studies, and venipuncture in nine; the remaining studies investigated a wide variety of other minor painful procedures. The studies used a variety of delivery methods for the sucrose solution (oral syringe, dropper or sucrose-dipped pacifier), as well as a range of concentrations and volumes of dose. Sucrose treatment was compared with giving the babies a similar volume of water, a pacifier, routine care, breastfeeding, 'facilitated tucking' (holding the infant in a flexed position with arms close to the body and hands placed to promote sucking), laser acupuncture, swaddling, warmth, anaesthetic cream for the skin (EMLA), or a combination of these. The studies used a range of pain assessment scales to measure their results. We did not identify any studies that received funding from the industry. There was high-quality evidence that sucrose reduces different measures of newborn pain during heel lance, venipuncture and intramuscular injection. However, sucrose does not provide effective pain relief during circumcision. There is conflicting evidence for whether sucrose reduces pain for other minor painful procedures and further research is needed to investigate these more thoroughly. Twenty-nine studies reported on adverse events (harms of the sucrose and other treatments) and found that the number of minor adverse events (e.g. choking or gagging) was very low, and was similar in the different groups (so not attributable to the sucrose treatment). No major adverse events were reported. Although sucrose has been widely studied as a pain reliever for newborn babies, most studies have included few babies and have used many different measures of pain to assess its effectiveness. We identified high-quality evidence that sucrose reduces pain for heel lance, venipuncture and intramuscular injection. The quality of evidence was low or moderate in favour for the use of sucrose for other painful procedures.

10.1002/14651858.CD001069.pub5

cochrane-simplification-train-3143

cochrane-simplification-train-3143

Thirty-three trials were included. They recruited 2293 participants with insomnia, aged 15 to 98 years, some with medical conditions contributing to insomnia (stroke, end-stage renal disease, perimenopause, pregnancy, psychiatric diseases). They evaluated needle acupuncture, electroacupuncture, acupressure or magnetic acupressure. Compared with no treatment (two studies, 280 participants) or sham/placebo (two studies, 112 participants), acupressure resulted in more people with improvement in sleep quality (compared to no treatment: OR 13.08, 95% confidence interval (CI) 1.79 to 95.59; compared to sham/placebo: OR 6.62, 95% CI 1.78 to 24.55). However, when assuming that dropouts had a worse outcome in sensitivity analysis the beneficial effect of acupuncture was inconclusive. Compared with other treatment alone, acupuncture as an adjunct to other treatment might marginally increase the proportion of people with improved sleep quality (13 studies, 883 participants, OR 3.08, 95% CI 1.93 to 4.90). On subgroup analysis, only needle acupuncture but not electroacupuncture showed benefits. All trials had high risk of bias and were heterogeneous in the definition of insomnia, participant characteristics, acupoints and treatment regimen. The effect sizes were generally small with wide confidence intervals. Publication bias was likely present. Adverse effects were rarely reported and they were minor. Due to poor methodological quality, high levels of heterogeneity and publication bias, the current evidence is not sufficiently rigorous to support or refute acupuncture for treating insomnia. Larger high-quality clinical trials are required.

This review was conducted to examine the efficacy and safety of acupuncture in treating insomnia. Thirty-three randomised controlled trials were eligible for inclusion in the review, involving 2293 participants. We considered all studies to have a high risk of bias. They were diverse in the types of participants, acupuncture treatments and sleep outcome measures used, which limited our ability to draw reliable conclusions. Currently there is a lack of high-quality clinical evidence to inform us about the efficacy and safety of acupuncture.

10.1002/14651858.CD005472.pub3

cochrane-simplification-train-3144

cochrane-simplification-train-3144

Nine trials met the inclusion criteria. Live birth rate per woman was significantly lower after IVF/ICSI with PGS compared to IVF/ICSI without PGS in women of advanced maternal age and in women with repeated IVF failure (OR 0.59; 95% CI 0.44 to 0.81 and OR 0.41, 95% CI 0.20 to 0.88 respectively). In good prognosis patients a similar trend was seen, albeit not significant (OR 0.50, 95% CI 0.20 to 1.26, random effects model). PGS as currently performed significantly decreases live birth rates in women of advanced maternal age and those with repeated IVF failure. Trials in which PGS was offered to women with a good prognosis suggested similar outcomes. PGS technique development is still ongoing in an effort to increase its efficacy. This involves biopsy at other stages of development (polar body or trophectoderm biopsy) and other methods of analysis (comparative genome hybridisation (CGH) or array-based technologies) than used by the trials included in this review. These new developments should be properly evaluated before their routine clinical application. Until such trials have been performed, PGS should not be offered as routine patient care in any form.

This review shows that PGS in fact decreases live birth rates in women of advanced maternal age and in women with repeated IVF failure. PGS should not be applied in routine patient care. New forms of PGS that perform the procedure at other stages of development and/or use a different method of analysis should first be evaluated in clinical trials before being introduced into clinical practice.

10.1002/14651858.CD005291.pub2

cochrane-simplification-train-3145

cochrane-simplification-train-3145

We identified 11 studies for potential inclusion. Of those, we included three studies involving 97 women. Two additional studies are ongoing. Two trials examined in-utero fetal tracheal occlusion with standard (postnatal) care in fetuses with severe diaphragmatic hernia. Whilst the trials utilised fetal interventions that were similar, there were important differences in how access was gained to the fetus and in the timing and mode of delivery. Therefore, we did not combine these trials in meta-analysis and the results are examined in separate comparisons. One trial examined the effect of antenatal corticosteroids versus placebo. Overall, the methodological quality of the trials was variable and no data were available for a number of this review's secondary outcomes. In-utero fetal occlusion by maternal laparotomy versus standard postnatal management (one trial, 24 women) For the primary infant outcome (perinatal mortality), there were no data suitable for inclusion in the analysis. There was no difference between groups in terms of long-term infant survival (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.66 to 1.69). In-utero fetal occlusion by minimally invasive fetoscopy versus standard postnatal management (one trial, 41 women) The primary infant outcome (perinatal mortality) was not reported. Minimally invasive fetoscopy was associated with a small reduction in the mean gestational age at birth (mean difference (MD) -1.80 weeks, 95% CI -3.13 to -0.47), but there was no clear difference in the risk of preterm birth before 37 weeks (RR 1.75, 95% CI 0.78 to 3.92). Long-term infant survival (three to six months) (RR 10.50, 95% CI 1.48 to 74.71) was increased with the intervention when compared with standard management, and there was a corresponding reduction in pulmonary hypertension (RR 0.58, 95% CI 0.36 to 0.93) associated with the intervention. There was no difference between groups in terms of preterm ruptured membranes (< 37 weeks) (RR 1.47, 95% CI 0.56 to 3.88) or maternal infectious morbidity (RR 3.14, 95% CI 0.14 to 72.92), and there were no maternal blood transfusions. Antenatal corticosteroids versus placebo (one trial, 32 women) We also included one trial (involving 32 women) examining the effect of antenatal corticosteroids versus placebo. There was no clear difference in the incidence of perinatal mortality (our primary infant outcome) between the group of women who received antenatal corticosteroids and the placebo control (RR 1.24, 95% CI 0.50 to 3.08). Data (mean only) were reported for two of our secondary outcomes (mechanical ventilation and days of hospital admission) but standard deviations (SDs) were not provided. For the purposes of this review and to permit further analysis we have estimated the SDs based on the reported P values reported in the trial report, although our estimation does assume that the SD is the same in both the intervention and control groups. There were no differences between the antenatal corticosteroid group and the placebo control in terms of days of mechanical ventilation (MD 18.00 days, 95% CI -14.77 to 50.77) or days of hospital admission (MD 17.00 days, 95% CI -13.93 to 47.93) . There is currently insufficient evidence to recommend in-utero intervention for fetuses with CDH as a part of routine clinical practice. We identified three small studies, with only one study adequately reporting on the primary outcome of this review - perinatal mortality, and there were few data pertaining to many of this review's secondary outcomes. WIth regard to the administration of antenatal corticosteroids, there remains a gap in current research, and a large multicentre trial with adequate statistical power should be undertaken to answer this unresolved question. More studies are needed to further examine the effect of in-utero fetal tracheal occlusion on important neonatal outcomes and long-term infant survival and health. Long-term follow-up is of particular importance, and should include morbidity and mortality measures. Further studies should examine the benefits of an in-utero intervention on subgroups with moderate and severe congenital diaphragmatic hernia. Indeed, there are three ongoing studies, being conducted by European, North and South American fetal medicine centres, which will contribute to this gap. Ongoing research and any implementation into clinical practice should include standardisation of the procedure, inclusion criteria and long-term childhood follow-up.

We included three randomised controlled studies (involving 97 women). The quality of the studies was variable and a number of this review's important outcomes were not reported in the trials. Two studies compared in-utero fetal tracheal occlusion with standard postnatal repair, but differences between the two studies meant that we were unable to combine the data in our analyses. Neither study reported on perinatal deaths. In single studies, in-utero fetal occlusion was associated with a slightly lower gestational age at birth but no clear difference in the risk of preterm birth before 37 weeks; the occurrence of pulmonary hypertension was reduced. there was no difference between groups in terms of preterm rupture of membranes < 37 weeks or maternal infectious morbidity and there were no maternal blood transfusions. Long-term infant survival was improved with in-utero tracheal occlusion in one study, but not in the other. In the third study, antenatal corticosteroids were compared with placebo and there was no difference in the number of perinatal deaths. Nor was there any difference in terms of the number of days that babies were given mechanical ventilation or the number of days babies spent in hospital. We conclude that the current evidence is too limited by small numbers of pregnancies and the variable methodological quality of the trials to recommend intervention (treatment) in pregnancy for women and their unborn babies with CDH. Further high-quality trials are needed in this area. WIth regard to the administration of antenatal corticosteroids, there remains a gap in current research, and a large, high-quality trial should be undertaken to answer this unresolved question. More studies are needed to further examine the effect of in-utero fetal tracheal occlusion on important neonatal outcomes and long-term infant survival and health. Long-term follow-up is of particular importance, and should include morbidity and mortality measures. Further studies should examine the benefits of an in-utero intervention in relation to the severity of the congenital diaphragmatic hernia (i.e. moderate and severe). Indeed, there are three ongoing studies, being conducted by European, North and South American fetal medicine centres, which will contribute to this gap. Ongoing research and any implementation into clinical practice should include standardisation of the procedure, inclusion criteria and long-term childhood follow-up.

10.1002/14651858.CD008925.pub2

cochrane-simplification-train-3146

cochrane-simplification-train-3146

We included two trials, but data were available for only 339 men in one trial, of whom 188 underwent invasive urodynamic studies. We found evidence of risk of bias, such as lack of outcome information for 24 men in one arm of the trial. Statistically significant evidence suggests that the tests did change clinical decision making. Men in the invasive urodynamics arm were more likely to have their management changed than men in the control arm (proportion with change in management 24/188 (13%) vs 0/151 (0%), risk ratio (RR) 39.41, 95% confidence interval (CI) 2.42 to 642.74). However, the quality of the evidence was low. Low-quality evidence indicates that men in the invasive urodynamics group were less likely to undergo surgery as treatment for voiding LUTS (164/188 (87%) vs 151/151 (100%), RR 0.87, 95% CI 0.83 to 0.92). Investigators observed no difference in urine flow rates before and after surgery for LUTS (mean percentage increase in urine flow rate, 140% in invasive urodynamic group vs 149% in immediate surgery group, P value = 0.13). Similarly, they found no differences between groups with regards to International Prostate Symptom Score (IPSS) (mean percentage decrease in IPSS score, 58% in invasive urodynamics group vs 59% in immediate surgery group, P value = 0.22). No evidence was available to demonstrate whether differences in management equated to improved health outcomes, such as relief of symptoms of voiding dysfunction or improved quality of life. No evidence from randomised trials revealed the adverse effects associated with invasive urodynamic studies. Although invasive urodynamic testing did change clinical decision making, we found no evidence to demonstrate whether this led to reduced symptoms of voiding dysfunction after treatment. Larger definitive trials of better quality are needed, in which men are randomly allocated to management based on invasive urodynamic findings or to management based on findings obtained by other diagnostic means. This research will show whether performance of invasive urodynamics results in reduced symptoms of voiding dysfunction after treatment.

We found two trials, which included around 350 men, although information was available for only 339 men in one trial. Evidence was not sufficient to show whether invasive urodynamic tests led to better patient outcomes. Some evidence suggests that these tests did alter management decisions, resulting in fewer men undergoing surgery. No evidence indicates whether this change in management led to fewer symptoms in men after treatment, and it is not known whether patients reported a better quality of life. No information obtained from the included trials reveals how common side effects were in those undergoing invasive urodynamic testing. Not enough information from trials is available regarding the benefits of invasive urodynamic testing for men with voiding dysfunction. More research is needed in which people are randomly assigned to treatment decisions based on their symptoms, physical examination findings and results of non-invasive tests alone, or based on the extra information provided by invasive urodynamic tests. Future studies will help healthcare providers determine whether patients benefit from these extra tests, and whether the tests provide good value for healthcare systems.

10.1002/14651858.CD011179.pub2

cochrane-simplification-train-3147

cochrane-simplification-train-3147

Two studies are included, which involved a total of 114 people with penetrating abdominal injuries. Both studies are at moderate risk of bias because the randomisation methods are not fully described, and the original study protocols are no longer available. The studies were undertaken in Finland between 1992 and 2002, by the same two researchers. In one study, 51 people were randomised to surgery or an observation protocol. None of the participants in the study died. Seven people had complications: 5 (18.5%) in the surgical group and 2 (8.3%) in the observation group; the difference was not statistically significant (P = 0.42; Fischer's exact). Among the 27 people who had surgery, 6 (22.2%) surgeries were negative laparotomies, and 15 (55.6%) were non-therapeutic. In the other study, 63 people were randomised to diagnostic laparoscopy (surgery) or an observation protocol. There were no deaths and no unnecessary surgeries in either group. Four people did not receive the intervention they were assigned. There was no difference in therapeutic operations between the two groups: 3 of 28 in the diagnostic laparoscopy group versus 1 of 31 in the observation protocol group (P = 0.337). Based on the findings of 2 studies involving a total of 114 people, there is no evidence to support the use of surgery over an observation protocol for people with penetrating abdominal trauma who have no signs of peritonitis and are stable.

The authors of this review sought to identify every study where people with an abdominal injury were randomised to surgery or observation. The authors searched a variety of medical databases but only identified 2 studies, involving 51 and 63 people respectively, both of which took place in Finland and were conducted by the same researchers. Both studies included people with penetrating abdominal injuries, from having been stabbed. The review authors considered both studies to be at moderate risk of bias, since only part of the randomisation process was described and the study protocols were not available to enable full assessment of overall quality. In one study (1992-1994) people received either an observation protocol or mandatory surgery. None of the people in the study died, and there was no difference in the number of people with medical complications between the study groups. One of the harms mentioned by the study authors was that surgery was performed on some people who did not actually need it. Unnecessary surgery can subject people to potential complications. In the other study (1997-2002) people received an observation protocol or diagnostic laparoscopy (minimal surgery). No one died in either group, and there were no differences between the groups in the number of surgeries needed. There were no unnecessary surgeries in either group. Based on the findings of these two small studies, there is no evidence to support the use of surgical management over an observation protocol for people with abdominal trauma showing no signs of bleeding or infection. The authors recommend that future randomised controlled studies clearly report the type of injury, number of damaged organs, extent of damage of internal organs, and complications in the people included.

10.1002/14651858.CD007383.pub3

cochrane-simplification-train-3148

cochrane-simplification-train-3148

We found 11 RCTs (1884 women) suitable for inclusion in the review. Most studies were at unclear or high risk of bias. The main limitations in the overall quality of the evidence were high risk of bias, unexplained heterogeneity and serious imprecision and indirectness. There were no data on our primary outcome — live birth per woman randomised — in any review comparisons. NSAIDs vs. placebo/no treatment We are uncertain of an effect on ongoing pregnancy when NSAIDs were compared to placebo/no treatment (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.71 to 1.59; 4 studies, 1159 participants; I² = 53%; very low quality evidence). Results suggest that if the chance of ongoing pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of NSAIDs is estimated to be between 12% and 24%. Subgroup analysis according to the type of NSAID yielded similar results. We are also uncertain of an effect on miscarriage rates when NSAIDs were compared to placebo/no treatment (RR 0.62, 95% CI 0.33 to 1.16; 4 studies, 525 participants; I² = 43%; very low quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 21%, the chance following the use of NSAIDs is estimated to be between 7% and 27%. The results were similar when two studies were excluded due to high risk of bias. Concerning the secondary outcomes, we are uncertain of an effect on clinical pregnancy rates (RR 1.23, 95% CI 1.00 to 1.52; 6 studies, 1570 participants; I² = 49%; low-quality evidence); on ectopic pregnancy (RR 0.56, 95% CI 0.05 to 5.89; 1 study, 72 participants); on multiple pregnancy (RR 2.00, 95% CI 0.18 to 21.67; 1 study, 180 participants); and on side effects (RR 1.39, 95% CI 0.02 to 119.35; 3 studies, 418 participants; I² = 79%). The evidence suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 30%, the chance following the use of NSAIDs is estimated to be between 31% and 45%. If the chance of ectopic pregnancy following placebo or no treatment is assumed to be 5%, the chance following the use of NSAIDs is estimated to be between 0.3% and 31%. If the chance of multiple pregnancy following placebo or no treatment is assumed to be 1%, the chance following the use of NSAIDs is estimated to be between 0.2 % and 24%. There were no cases of congenital anomalies during antenatal ultrasound screening of the women in one study. NSAID vs. another NSAID Only one study compared piroxicam with indomethacin: we are uncertain of an effect on ongoing pregnancy (RR 1.12, 95% CI 0.63 to 2.00; 1 study, 170 participants; very low quality evidence); and on miscarriage (RR 1.00, 95% CI 0.44 to 2.28; 1 study, 170 participants; very low quality evidence). The evidence suggests that if the chance of ongoing pregnancy following indomethacin is assumed to be 20%, the chance following the use of piroxicam is estimated to be between 13% and 40%; while for miscarriage, the evidence suggests that if the chance following indomethacin is assumed to be 12%, the chance following the use of piroxicam is estimated to be between 5% and 27%. Similar results were reported for clinical pregnancy (RR 1.07, 95% CI 0.71 to 1.63; 1 study, 170 participants; very low quality evidence). There were no data for the other outcomes specified in this review. NSAID vs. aspirin No study reported this comparison. Currently we are uncertain of an effect of the routine use of NSAIDs as co-treatments in infertile women undergoing assisted reproduction in order to improve ongoing pregnancy and miscarriage rates. This is based on available data from RCTs, where very low quality evidence showed that there is no single outcome measure demonstrating a benefit with their use. Further large, well-designed randomised placebo-controlled trials reporting on live births are required to clarify the exact role of NSAIDs.

We performed a comprehensive literature search of the standard medical databases (from database inception to February 2019) in consultation with the Cochrane Gynaecology and Fertility Group Information Specialist, for all randomised controlled trials (studies in which participants are assigned to a treatment group using a random method) investigating the efficiency of NSAIDs compared to the use of placebo or no treatment or compared to each other in infertile women undergoing IVF. We searched for and included studies irrespective of language and country of origin. Two review authors independently selected and evaluated studies, extracted data, and attempted to contact the authors of studies for which data were missing. We found 11 studies (2384 women); data were not available in one study, so we analysed data on 1884 patients; two studies were published as abstracts in international conference reports; and we found one ongoing trial that met our inclusion requirements. We are uncertain of an effect on ongoing pregnancy and miscarriage when NSAIDs were compared to placebo/no treatment. Results suggest that if the chance of ongoing pregnancy and miscarriage following placebo or no treatment is assumed to be 15% and 21%, respectively, the chance following the use of NSAIDs is estimated to be between 12% and 24%, and 7% and 27%, respectively. Only one study compared piroxicam with indomethacin: we are uncertain of an effect on ongoing pregnancy and on miscarriage. The evidence suggests that if the chance of ongoing pregnancy following indomethacin is assumed to be 20%, the chance following the use of piroxicam is estimated to be between 13% and 40%; while for miscarriage, the evidence suggests that if the chance following indomethacin is assumed to be 12%, the chance following the use of piroxicam is estimated to be between 5% and 27%. Concerning the secondary outcomes, we are equally uncertain of any effect. Currently we are uncertain of an effect of the routine use of NSAIDs as co-treatments in infertile women undergoing assisted reproduction in order to improve pregnancy rates. This is based on available data from randomised controlled trials, where no single outcome reported in the studies demonstrated a benefit with their use. The quality of the evidence was very low for all outcomes. This is because of several limitations including poorly reported study methods, imprecision, small study numbers and low numbers of events reported.

10.1002/14651858.CD007618.pub2

cochrane-simplification-train-3149

cochrane-simplification-train-3149

We identified two trials of GCS that included 2615 patients and two small studies of IPC that included 177 patients. Overall, physical methods were not associated with a significant reduction in DVTs during the treatment period (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.70 to 1.04) or deaths (OR 1.12, 95% CI 0.87 to 1.45). Use of GCS was not associated with any significant reduction in risk of DVT (OR 0.88, 95% CI 0.72 to 1.08) or death (OR 1.13, 95% CI 0.87 to 1.47) at the end of follow up. IPC was associated with a non-significant trend towards a lower risk of DVTs (OR 0.45, 95% CI 0.19 to 1.10) with no evidence of an effect on deaths (OR 1.04, 95% CI 0.37 to 2.89). Evidence from randomised trials does not support the routine use of GCS to reduce the risk of DVT after acute stroke. There is insufficient evidence to support the routine use of IPC to reduce the risk of DVT in acute stroke and further larger randomised studies of IPC are needed to reliably assess the balance of risks and benefits of this intervention.

We found two randomised trials of graduated compression stockings, involving 2615 participants, and two small trials of intermittent pneumatic compression involving 177 participants. Graduated compression stockings were no better than 'best medical treatment' in reducing the risk of DVT after stroke. Stockings caused more skin problems (for example ulcers and blisters) on the legs. Intermittent pneumatic compression appeared promising but was not proven to be definitely beneficial. The evidence does not support routine use of graduated compression stockings or intermittent pneumatic compression in patients with a recent stroke. The trials that are ongoing at present should provide reliable evidence on the benefits and harms of intermittent pneumatic compression.

10.1002/14651858.CD001922.pub3

cochrane-simplification-train-3150

cochrane-simplification-train-3150

Eleven randomized controlled trials met our criteria for inclusion, representing 7695 patients in the United States, China, India and Sweden. Advance provision did not decrease pregnancy rates (odds ratio (OR) 0.98, 95% confidence interval (CI) 0.76 to 1.25 in studies for which we included twelve-month follow-up data; OR 0.48, 95% CI 0.18 to 1.29 in a study with seven-month follow-up data; OR 0.92, 95% CI 0.70 to 1.20 in studies for which we included six-month follow-up data; OR 0.49, 95% CI 0.09 to 2.74 in a study with three-month follow-up data), despite reported increased use (single use: OR 2.47, 95% CI 1.80 to 3.40; multiple use: OR 4.13, 95% CI 1.77 to 9.63) and faster use (weighted mean difference (WMD) -12.98 hours, 95% CI -16.66 to -9.31 hours). Advance provision did not lead to increased rates of sexually transmitted infections (OR 1.01, 95% CI 0.75 to 1.37), increased frequency of unprotected intercourse, or changes in contraceptive methods. Women who received emergency contraception in advance were equally likely to use condoms as other women. Advance provision of emergency contraception did not reduce pregnancy rates when compared to conventional provision. Results from primary analyses suggest that advance provision does not negatively impact sexual and reproductive health behaviors and outcomes. Women should have easy access to emergency contraception, because it can decrease the chance of pregnancy. However, the interventions tested thus far have not reduced overall pregnancy rates in the populations studied.

We searched for studies comparing women who got emergency contraception in advance to women who got it in standard ways. We examined whether these groups had different rates of pregnancy or sexually transmitted infections. We also studied how often and how quickly both groups used emergency contraception. Finally, we looked at whether advance provision of emergency contraception changed sexual behavior. Studies showed that the chance of pregnancy was similar regardless of whether or not women have emergency contraception on hand before unprotected sex. Women who had emergency contraception in advance were more likely to report use of the medication, and to use it sooner after sex. Having emergency contraception on hand did not change use of other kinds of contraception or change sexual behavior.

10.1002/14651858.CD005497.pub2

cochrane-simplification-train-3151

cochrane-simplification-train-3151

No new studies were identified for this update. A single RCT with a total of 30 PAAs met the inclusion criteria. There was a low risk of selection bias and detection bias. However, the risks of performance bias, attrition bias and reporting bias were unclear from the study. Despite being an RCT, the certainty of the evidence was downgraded to moderate due to the small sample size, resulting in wide confidence intervals (CIs); only 30 PAAs were randomised over a period of five years (15 PAAs each in the groups receiving endovascular stent graft and undergoing conventional open surgery). The primary patency rate at one year was 93.3% in the endovascular group and 100% in the surgery group (RR 0.94, 95% CI 0.78 to 1.12; moderate-certainty evidence). The assisted patency rate at one year was similar in both groups (RR 1.00, 95% CI 0.88 to 1.13; moderate-certainty evidence). There was no clear evidence of a difference between the two groups in the primary or assisted patency rates at four years (13 grafts were patent from 15 PAA treatments in each group; RR 1.00, 95% CI 0.76 to 1.32; moderate-certainty evidence); the effects were imprecise and compatible with the benefit of either endovascular stent graft or surgery or no difference. Mean hospital stay was shorter in the endovascular group (4.3 days for the endovascular group versus 7.7 days for the surgical group; mean difference (MD) -3.40 days, 95% CI -4.42 to -2.38; P < 0.001; moderate-certainty evidence). Mean operating time was also reduced in the endovascular group (75.4 minutes in the endovascular group versus 195.3 minutes in the surgical group; MD -119.90 minutes, 95% CI -137.71 to -102.09; P < 0.001; moderate-certainty evidence). Limb salvage was 100% in both groups. Data on local wound complications were not published in the trial report. Evidence to determine the effectiveness of endovascular stent graft versus conventional open surgery for the treatment of asymptomatic PAAs is limited to data from one small study. At one year there is moderate-certainty evidence that primary patency may be improved in the surgery group but assisted primary patency rates were similar between groups. At four years there was no clear benefit from either endovascular stent graft or surgery to primary or assisted primary patency (moderate-certainty evidence). As both operating time and hospital stay were reduced in the endovascular group (moderate-certainty evidence), it may represent a viable alternative to open repair of PAA. A large multicenter RCT may provide more information in the future. However, difficulties in recruiting enough patients are likely, unless it is an international collaboration including a number of high volume vascular centres.

An extensive search of the medical literature databases was performed (current up to 29 January 2019). Only one completed RCT was found. In the published RCT, 30 PAAs were treated (15 by the endovascular technique and 15 by the surgical technique). Each case was followed up for a minimum of four years. In the group of participants treated using the endovascular technique there were two blockages. One case was re-stented and the other case required a surgical bypass. In the surgical group too, there were two blockages, which did not require any treatment. There were no limb losses. The time taken to complete the procedure and the length of hospital stay were shorter in the endovascular group. No information on wound complications was given in the trial report. The major limitation of this study was that there were only 15 PAAs in each group so our certainty in the evidence is downgraded from high to moderate. Due to the limitations of the current evidence, we are unable to determine the effects of an endovascular stent graft versus conventional open surgery for the treatment of asymptomatic PAAs. A larger multicenter clinical trial is required so we can be more confident in the findings. We cannot say if there was a clear overall benefit on patency to either group (moderate-certainty evidence). As both operating time and hospital stay were reduced in the endovascular group (moderate certainty evidence), it may represent a viable alternative to open repair of PAA.

10.1002/14651858.CD010149.pub3

cochrane-simplification-train-3152

cochrane-simplification-train-3152

Six trials, all from the USA, involving 2343 participants, were included. A meta-analysis of four trials comparing CBT with a no-intervention control (1771 participants) reported that the relative risk of violence was 0.86 (favouring the intervention group) with a 95% confidence interval (CI) of 0.54 to 1.38. This is a small effect size, and the width of the CI suggests no clear evidence for an effect. One study (Wisconsin Study) compared CBT with process-psychodynamic group treatment and reported a relative risk of new violence of 1.07 (95% CI 0.68 to 1.68). Even though the process-psychodynamic treatment did marginally better than CBT, this result is equivocal. Finally, one small study (N = 64) compared a combined CBT treatment for substance abuse and domestic violence (SADV) with a Twelve-Step Facilitation (TSF) group. An analysis involving 58 participants investigated the effect on reduction in frequency of physical violence episodes. The effect size was 0.30 (favouring TSF) with 95% CI from -0.22 to 0.81. There are still too few randomised controlled trials to draw conclusions about the effectiveness of cognitive behaviour therapy for male perpetrators of domestic violence.

We included trials that involved both types of participants. The review found all randomised controlled evaluations of the effects of CBT on men's physical violence to their female partners worldwide, but there were only six small trials with a total of 2343 participants that met the inclusion criteria. The results of four of these trials, which compared men who received CBT with men getting no treatment, were combined. This was not able to show us whether or not CBT was better than no treatment. Similarly, the individual results of the other two trials, which compared CBT with another treatment, were inconclusive. Overall, the evidence from the included studies is insufficient to draw any conclusions.

10.1002/14651858.CD006048.pub2

cochrane-simplification-train-3153

cochrane-simplification-train-3153

We identified 1432 references; after screening, we included 60 studies in the final qualitative analyses. Among these, 54 (including 3021 patients) were also included in the quantitative analyses. With respect to the analyses for the first of our primary outcomes, (short-term remission), the most studied of the included psychological therapies was CBT (32 studies), followed by BT (12 studies), PT (10 studies), CT (three studies), SP (three studies) and PD (two studies). The quality of the evidence for the entire network was found to be low for all outcomes. The quality of the evidence for CBT vs NT, CBT vs SP and CBT vs PD was low to very low, depending on the outcome. The majority of the included studies were at unclear risk of bias with regard to the randomisation process. We found almost half of the included studies to be at high risk of attrition bias and detection bias. We also found selective outcome reporting bias to be present and we strongly suspected publication bias. Finally, we found almost half of the included studies to be at high risk of researcher allegiance bias. Overall the networks appeared to be well connected, but were generally underpowered to detect any important disagreement between direct and indirect evidence. The results showed the superiority of psychological therapies over the WL condition, although this finding was amplified by evident small study effects (SSE). The NMAs for ST-remission, ST-response and ST-improvement on a continuous scale showed well-replicated evidence in favour of CBT, as well as some sparse but relevant evidence in favour of PD and SP, over other therapies. In terms of ST-dropouts, PD and 3W showed better tolerability over other psychological therapies in the short term. In the long term, CBT and PD showed the highest level of remission/response, suggesting that the effects of these two treatments may be more stable with respect to other psychological therapies. However, all the mentioned differences among active treatments must be interpreted while taking into account that in most cases the effect sizes were small and/or results were imprecise. There is no high-quality, unequivocal evidence to support one psychological therapy over the others for the treatment of panic disorder with or without agoraphobia in adults. However, the results show that CBT - the most extensively studied among the included psychological therapies - was often superior to other therapies, although the effect size was small and the level of precision was often insufficient or clinically irrelevant. In the only two studies available that explored PD, this treatment showed promising results, although further research is needed in order to better explore the relative efficacy of PD with respect to CBT. Furthermore, PD appeared to be the best tolerated (in terms of ST-dropouts) among psychological treatments. Unexpectedly, we found some evidence in support of the possible viability of non-specific supportive psychotherapy for the treatment of panic disorder; however, the results concerning SP should be interpreted cautiously because of the sparsity of evidence regarding this treatment and, as in the case of PD, further research is needed to explore this issue. Behaviour therapy did not appear to be a valid alternative to CBT as a first-line treatment for patients with panic disorder with or without agoraphobia.

The results of the review show that in general talking therapies are more effective than no treatment. There was no strong evidence to support one talking therapy over the others for the treatment of panic disorder with or without agoraphobia in adults. However, there was some low-quality evidence in favour of cognitive behaviour therapy (CBT), psychodynamic therapy and supportive psychotherapy over other talking therapies for short-term remission and short-term reduction in symptoms. The results concerning supportive psychotherapy should, however, be treated with caution because of the small amount of evidence available about this treatment. On the other hand, beyond the evidence regarding its efficacy, psychodynamic therapy also showed promising results in terms of tolerability: as a way of assessing how well people tolerated the talking therapies, we assessed short-term dropout rates. We found that there were fewer dropouts in psychodynamic therapy and third-wave CBT, suggesting that people tolerate these therapies better than other therapies. More high-quality research is needed to be able to fully compare the effectiveness of different talking therapies. In particular, more new studies are needed that compare the specific talking therapies CBT, psychodynamic therapy and supportive psychotherapy for the treatment of panic disorder with or without agoraphobia.

10.1002/14651858.CD011004.pub2

cochrane-simplification-train-3154

cochrane-simplification-train-3154

We identified two RCTs (160 participants) that fulfilled our inclusion criteria. As these two trials evaluated different diet supplements (enriched skim milk powder (SMP) and vitamin C) with different outcomes (gout flare prevention for enriched SMP and sUA reduction for vitamin C), we reported the results separately. One trial including 120 participants, at moderate risk of bias, compared SMP enriched with glycomacropeptides (GMP) with unenriched SMP and with lactose over three months. Participants were predominantly men aged in their 50's who had severe gout. The frequency of acute gout attacks, measured as the number of flares per month, decreased in all three groups over the study period. The effects of enriched SMP (SMP/GMP/G600) compared with the combined control groups (SMP and lactose powder) at three months in terms of mean number of gout flares per month were uncertain (mean ± standard deviation (SD) flares per month: 0.49 ± 1.52 in SMP/GMP/G60 group versus 0.70 ± 1.28 in control groups; mean difference (MD) -0.21, 95% confidence interval (CI) -0.76 to 0.34; low-quality evidence). The number of withdrawals due to adverse effects was similar in both groups although again the results were imprecise (7/40 in SMP/GMP/G600 group versus 11/80 in control groups; risk ratio (RR) 1.27, 95% CI 0.53 to 3.03; low-quality evidence). The findings for adverse events were also uncertain (2/40 in SMP/GMP/G600 group versus 3/80 in control groups; RR 1.33, 95% CI 0.23 to 7.66; low-quality evidence). Gastrointestinal events were the most commonly reported adverse effects. Pain from self reported gout flares (measured on a 10-point Likert scale) improved slightly more in the SMP/GMP/G600 group compared with controls (mean ± SD reduction -1.97 ± 2.28 points in SMP/GMP/G600 group versus -0.94 ± 2.25 in control groups; MD -1.03, 95% CI -1.96 to -0.10; low-quality evidence). This was an absolute reduction of 10% (95% CI 20% to 1% reduction), which may not be of clinical relevance. Results were imprecise for the outcome improvement in physical function (mean ± SD Health Assessment Questionnaire (HAQ)-II (scale 0 to 3, 0 = no disability): 0.08 ± 0.23 in SMP/GMP/G60 group versus 0.11 ± 0.31 in control groups; MD -0.03, 95% CI -0.14 to 0.08; low-quality evidence). Similarly, results for sUA reduction were imprecise (mean ± SD reduction: -0.025 ± 0.067 mmol/L in SMP/GMP/G60 group versus -0.010 ± 0.069 in control groups; MD -0.01, 95% CI -0.04 to 0.01; low-quality evidence). The study did not report tophus regression and health-related quality of life impact. One trial including 40 participants, at moderate to high risk of bias, compared vitamin C alone with allopurinol and with allopurinol plus vitamin C in a three-arm trial. We only compared vitamin C with allopurinol in this review. Participants were predominantly middle-aged men, and their severity of gout was representative of gout in general. The effect of vitamin C on the rate of gout attacks was not assessed. Vitamin C did not lower sUA as much as allopurinol (-0.014 mmol/L in vitamin C group versus -0.118 mmol/L in allopurinol group; MD 0.10, 95% CI 0.06 to 0.15; low-quality evidence). The study did not assess tophus regression, pain reduction or disability or health-related quality of life impact. The study reported no adverse events and no participant withdrawal due to adverse events. While dietary supplements may be widely used for gout, this review has shown a paucity of high-quality evidence assessing dietary supplementation.

After searching the medical literature up to 6 June 2013 we found two studies The first study (120 participants) compared enriched skim milk powder (with peptides with probable anti-inflammatory effect) to standard skim milk and to lactose powder, and the second study (40 participants) compared vitamin C with allopurinol - a drug commonly used in gout. In the first study, the enriched milk aimed to reduce the frequency of gout attacks, while in the second study the vitamin C aimed to reduce the uric acid levels in blood. People with gout enrolled in both studies were predominantly middle-aged men; in the skim milk study, participants with gout appeared severe as they had very frequent attacks and 20% to 43% presented with tophi, while in the vitamin C study, participants appeared similar to ordinary participants with gout. Gout attacks People who consumed enriched skim milk powder had 0.21 fewer gout attacks per month at three months (from 0.76 fewer to 0.34 more), or 2.5 fewer gout attacks per year: - People who consumed enriched skim milk powder had 0.49 gout attacks per month (or six gout attacks per year). - People who consumed standard skim milk powder or lactose had 0.70 gout attacks per month (or eight gout attacks per year). Withdrawals due to adverse events 4 more people out of 100 who consumed enriched skim milk powder discontinued the supplement at three months (4% more withdrawals). - 18 out of 100 stopped consuming enriched skim milk powder. - 14 out of 100 stopped consuming standard skim milk powder or lactose. Pain reduction, serum uric acid (sUA) levels and physical function were uncertain. Effect on tophus regression was not measured. Serum uric acid levels - People who consumed vitamin C showed an sUA level reduction of 0.014 mmol/L after eight weeks (or 2.8% sUA reduction) - People who were administered allopurinol showed an sUA level reduction of 0.118 mmol/L after eight weeks (or 23.6% sUA reduction). There were no reports of side effects or withdrawals due to side effects in the vitamin C or allopurinol treatment groups. Effects of vitamin C on gout attacks, pain reduction, physical function and tophus regression were not measured. Low-quality evidence from one study indicated enriched skim milk, compared with standard skim milk or lactose powder, may not reduce the frequency of gout attacks or improve physical function or uric acid levels, but may reduce pain. Further research is likely to change these estimates. We do not have precise information about side effects and complications, but possible side effects may include nausea or diarrhoea. Compared with the commonly used medicine allopurinol, low-quality evidence from one study indicated the effect of vitamin C in reducing sUA levels is smaller and probably clinically unimportant. Other possible benefits of vitamin C are uncertain, as they were not evaluated in the study. No side effects were reported. Further research is likely to change these estimates.

10.1002/14651858.CD010156.pub2

cochrane-simplification-train-3155

cochrane-simplification-train-3155

Two trials met the inclusion criteria. Both trials commenced prior to the widespread availability of prostate-specific antigen (PSA) screening; hence the results may not be applicable to men with PSA-detected disease. One trial (N = 142), conducted in the US, was judged to be of poor quality. All cause (overall) mortality was not significantly different between RP and WW groups after fifteen years of follow up (Hazard Ratio (HR) 0.9 (95% Confidence Interval (CI) 0.56 to 1.43). The second trial (N = 695), conducted in Scandinavia, was judged to be of good quality. After 12 years of follow up, the trial results were compatible with a beneficial effect of RP on the risks of overall mortality, prostate cancer mortality and distant metastases compared with WW but the precise magnitude of the effect is uncertain as indicated by the width of the confidence intervals for all estimates (risk difference (RD) -7.1% (95% CI -14.7 to 0.5); RD -5.4% (95% CI -11.1 to 0.2); RD -6.7% (95% CI -13.2 to -0.2), respectively). Compared to WW, RP increased the absolute risks of erectile dysfunction (RD 35% (95% CI 25 to 45)) and urinary leakage (RD 27% (95% CI 17 to 37)). These estimates must be interpreted cautiously as they are derived from data obtained from a self-administered questionnaire survey of a sample of the trial participants (N = 326), no baseline quality of life data were obtained and nerve-sparing surgery was not routinely performed on trial participants undergoing RP. The existing trials provide insufficient evidence to allow confident statements to be made about the relative beneficial and harmful effects of RP and WW for patients with localised prostate cancer. The results of ongoing trials should help to inform treatment decisions for men with screen-detected localised prostate cancer.

Two completed randomised controlled trials were identified. One trial was considered to be of good quality whilst the second trial was of poor quality. The two trials commenced prior to the widespread use of the prostate-specific antigen (PSA) blood test as a screening test for prostate cancer, and hence did not involve many men with PSA-detected cancers. Ongoing trials (PIVOT; ProtecT; START) will provide evidence of the comparative effects of RP and observation protocols for men with PSA-detected cancers. The one good quality trial included in this review involved men with cancers detected by methods other than screening who were randomly allocated to either RP or WW and followed up for 12 years. This single trial does not provide sufficient evidence to allow confident statements to be made about the magnitude of any beneficial and harmful effects of RP compared with WW for men with clinically detected prostate cancers. The trial results indicate that RP is likely to reduce the risks of overall mortality, prostate-cancer mortality and distant metastases (cancer spread) compared to WW, but the magnitude of the effect is unclear. Furthermore, the risk reductions appear to have been limited to men less than 65 years of age. This trial also provides evidence that RP increases the risks of erectile dysfunction and urinary leakage. However, because of the manner in which the data on adverse effects were collected in the trial, confident statements cannot be made about how frequently these adverse effects occur. In addition, nerve-sparing surgery, which has the potential to reduce these complications, was not routinely performed on participants in the trial. A shared approach to decision-making is required whereby patients and their healthcare providers openly discuss the patient's personal values, preferences, and the limitations of the available evidence on potential benefits and potential harms of these treatment options.

10.1002/14651858.CD006590.pub2

cochrane-simplification-train-3156

cochrane-simplification-train-3156

Twenty-four new trials were identified since the 2009 update, bringing the total number of included trials to 90. There were 65 trials of bupropion and ten trials of nortriptyline, with the majority at low or unclear risk of bias. There was high quality evidence that, when used as the sole pharmacotherapy, bupropion significantly increased long-term cessation (44 trials, N = 13,728, risk ratio [RR] 1.62, 95% confidence interval [CI] 1.49 to 1.76). There was moderate quality evidence, limited by a relatively small number of trials and participants, that nortriptyline also significantly increased long-term cessation when used as the sole pharmacotherapy (six trials, N = 975, RR 2.03, 95% CI 1.48 to 2.78). There is insufficient evidence that adding bupropion (12 trials, N = 3487, RR 1.19, 95% CI 0.94 to 1.51) or nortriptyline (4 trials, N = 1644, RR 1.21, 95% CI 0.94 to 1.55) to nicotine replacement therapy (NRT) provides an additional long-term benefit. Based on a limited amount of data from direct comparisons, bupropion and nortriptyline appear to be equally effective and of similar efficacy to NRT (bupropion versus nortriptyline 3 trials, N = 417, RR 1.30, 95% CI 0.93 to 1.82; bupropion versus NRT 8 trials, N = 4096, RR 0.96, 95% CI 0.85 to 1.09; no direct comparisons between nortriptyline and NRT). Pooled results from four trials comparing bupropion to varenicline showed significantly lower quitting with bupropion than with varenicline (N = 1810, RR 0.68, 95% CI 0.56 to 0.83). Meta-analyses did not detect a significant increase in the rate of serious adverse events amongst participants taking bupropion, though the confidence interval only narrowly missed statistical significance (33 trials, N = 9631, RR 1.30, 95% CI 1.00 to 1.69). There is a risk of about 1 in 1000 of seizures associated with bupropion use. Bupropion has been associated with suicide risk, but whether this is causal is unclear. Nortriptyline has the potential for serious side-effects, but none have been seen in the few small trials for smoking cessation. There was no evidence of a significant effect for selective serotonin reuptake inhibitors on their own (RR 0.93, 95% CI 0.71 to 1.22, N = 1594; 2 trials fluoxetine, 1 paroxetine, 1 sertraline) or as an adjunct to NRT (3 trials of fluoxetine, N = 466, RR 0.70, 95% CI 0.64 to 1.82). Significant effects were also not detected for monoamine oxidase inhibitors (RR 1.29, 95% CI 0.93 to 1.79, N = 827; 1 trial moclobemide, 5 selegiline), the atypical antidepressant venlafaxine (1 trial, N = 147, RR 1.22, 95% CI 0.64 to 2.32), the herbal therapy St John's wort (hypericum) (2 trials, N = 261, RR 0.81, 95% CI 0.26 to 2.53), or the dietary supplement SAMe (1 trial, N = 120, RR 0.70, 95% CI 0.24 to 2.07). The antidepressants bupropion and nortriptyline aid long-term smoking cessation. Adverse events with either medication appear to rarely be serious or lead to stopping medication. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressant effect and that they are of similar efficacy to nicotine replacement. Evidence also suggests that bupropion is less effective than varenicline, but further research is needed to confirm this finding. Evidence suggests that neither selective serotonin reuptake inhibitors (e.g. fluoxetine) nor monoamine oxidase inhibitors aid cessation.

The evidence is current to July 2013. This update includes 24 new studies, and this review includes 90 studies overall. The studies included people who smoked and people who had recently quit smoking. There were 65 trials of bupropion, which is licensed for use as a smoking cessation medication under the trade name 'Zyban'. There were ten trials of nortriptyline which is a tricyclic antidepressant which is not licensed specifically for smoking cessation. We only included studies which measured long term quitting (whether or not people had quit smoking at six months or longer from the start of the study). Trials of bupropion (Zyban) for smoking cessation show high quality evidence that it increases the likelihood of a quit attempt being successful after at least six months (44 trials, over 13,000 participants). The side effects of bupropion include insomnia, dry mouth and nausea and rarely (1:1000) seizures and perhaps psychiatric problems, but the last is unclear. There is also moderate quality evidence, limited by a relatively small number of included studies and participants, that the antidepressant nortriptyline increases quit rates (six trials, 975 participants). The side effects of this medication include dry mouth, constipation, nausea, and sedation, and it can be dangerous in overdose. Selective serotonin reuptake inhibitor antidepressants (for example, fluoxetine), monoamine oxidase inhibitor antidepressants (for example, selegiline), and the antidepressant venlaxafine have not been shown to help smoking cessation, nor has the herbal therapy St John's wort, or S-Adenosyl-L-Methionine (SAMe), a dietary supplement that is thought to have antidepressant properties. The way in which bupropion and nortriptyline might work is not fully understood. Both appear to help people quit smoking whether or not they have a history of depression, or have depressive symptoms when they stop smoking. The likelihood of quitting using bupropion or nortriptyline appears to be similar to that for nicotine replacement therapy, but the likelihood of quitting using bupropion appears to be lower than the likelihood of quitting using varenicline.

10.1002/14651858.CD000031.pub4

cochrane-simplification-train-3157

cochrane-simplification-train-3157

Five randomised trials met our inclusion criteria (n = 302). Three studies objectively measured infant breastfeeding using standardised assessment tools. Pooled analysis of two studies (n = 155) showed no change on a 10-point feeding scale following frenotomy (mean difference (MD) -0.1, 95% confidence interval (CI) -0.6 to 0.5 units on a 10-point feeding scale). A third study (n = 58) showed objective improvement on a 12-point feeding scale (MD 3.5, 95% CI 3.1 to 4.0 units of a 12-point feeding scale). Four studies objectively assessed maternal pain. Pooled analysis of three studies (n = 212) based on a 10-point pain scale showed a reduction in maternal pain scores following frenotomy (MD -0.7, 95% CI -1.4 to -0.1 units on a 10-point pain scale). A fourth study (n = 58) also showed a reduction in pain scores on a 50-point pain scale (MD -8.6, 95% CI -9.4 to -7.8 units on a 50-point pain scale). All studies reported no adverse effects following frenotomy. These studies had serious methodological shortcomings. They included small sample sizes, and only two studies blinded both mothers and assessors; one did not attempt blinding for mothers nor for assessors. All studies offered frenotomy to controls, and most controls underwent the procedure, suggesting lack of equipoise. No study was able to report whether frenotomy led to long-term successful breastfeeding. Frenotomy reduced breastfeeding mothers’ nipple pain in the short term. Investigators did not find a consistent positive effect on infant breastfeeding. Researchers reported no serious complications, but the total number of infants studied was small. The small number of trials along with methodological shortcomings limits the certainty of these findings. Further randomised controlled trials of high methodological quality are necessary to determine the effects of frenotomy.

Five randomised controlled trials enrolling 302 infants met the inclusion criteria. In an infant with tongue-tie and feeding difficulties, surgical release of the tongue-tie does not consistently improve infant feeding but is likely to improve maternal nipple pain. Further research is needed to clarify and confirm this effect. The quality of the evidence is very low to moderate because overall only a small number of studies have looked at this condition, the total number of babies included in these studies was low and some studies could have been better designed.

10.1002/14651858.CD011065.pub2

cochrane-simplification-train-3158

cochrane-simplification-train-3158

The risk of bias in the included studies was low. The overall quality of the evidence based on the GRADE approach was moderate. No statistically significant differences were found between interleukin 10 and placebo for complete remission (CDAI < 150 with a 100 point decrease in CDAI from baseline; RR=1.43; 95% CI 0.62 to 3.29; I2=40%) or clinical remission (CDAI < 150; RR=1.29; 95% CI 0.79 to 2.11; I2= 0%). Patients treated with interleukin 10 were significantly more likely to withdraw from the studies due to adverse events (RR=13.50; 95% CI 3.89 to 46.79; I2=0%). Interleukin 10 does not appear to provide any benefit for the treatment of active Crohn's disease. This systematic review shows that interleukin 10 does not increase the number of remissions (complete or clinical), but increases the rate of withdrawal due to adverse events relative to placebo. The quality of the evidence regarding the efficacy of IL-10 is moderate and although further research may have an impact on point estimates of efficacy further randomized trials are unlikely to be undertaken.

This systematic review showed that this drug does not increase the number of remissions but increases the number of patients that withdrew from the included studies due to side effects. The methodological quality of the included studies was high. Further studies of this agent for the treatment of active Crohn's disease are unlikely to be undertaken.

10.1002/14651858.CD005109.pub3

cochrane-simplification-train-3159

cochrane-simplification-train-3159

We included 21 trials and identified eight ongoing trials. The included trials evaluated metformin (11 trials), sibutramine (six trials), orlistat (four trials), and one trial arm investigated the combination of metformin and fluoxetine. The ongoing trials evaluated metformin (four trials), topiramate (two trials) and exenatide (two trials). A total of 2484 people participated in the included trials, 1478 participants were randomised to drug intervention and 904 to comparator groups (91 participants took part in two cross-over trials; 11 participants not specified). Eighteen trials used a placebo in the comparator group. Two trials had a cross-over design while the remaining 19 trials were parallel RCTs. The length of the intervention period ranged from 12 weeks to 48 weeks, and the length of follow-up from baseline ranged from six months to 100 weeks. Trials generally had a low risk of bias for random sequence generation, allocation concealment and blinding (participants, personnel and assessors) for subjective and objective outcomes. We judged approximately half of the trials as having a high risk of bias in one or more domain such as selective reporting. The primary outcomes of this review were change in body mass index (BMI), change in weight and adverse events. All 21 trials measured these outcomes. The secondary outcomes were health-related quality of life (only one trial reported results showing no marked differences; very low certainty evidence), body fat distribution (measured in 18 trials), behaviour change (measured in six trials), participants' views of the intervention (not reported), morbidity associated with the intervention (measured in one orlistat trial only reporting more new gallstones following the intervention; very low certainty evidence), all-cause mortality (one suicide in the orlistat intervention group; low certainty evidence) and socioeconomic effects (not reported). Intervention versus comparator for mean difference (MD) in BMI change was -1.3 kg/m2 (95% confidence interval (CI) -1.9 to -0.8; P < 0.00001; 16 trials; 1884 participants; low certainty evidence). When split by drug type, sibutramine, metformin and orlistat all showed reductions in BMI in favour of the intervention. Intervention versus comparator for change in weight showed a MD of -3.9 kg (95% CI -5.9 to -1.9; P < 0.00001; 11 trials; 1180 participants; low certainty evidence). As with BMI, when the trials were split by drug type, sibutramine, metformin and orlistat all showed reductions in weight in favour of the intervention. Five trials reported serious adverse events: 24/878 (2.7%) participants in the intervention groups versus 8/469 (1.7%) participants in the comparator groups (risk ratio (RR) 1.43, 95% CI 0.63 to 3.25; 1347 participants; low certainty evidence). A total 52/1043 (5.0%) participants in the intervention groups versus 17/621 (2.7%) in the comparator groups discontinued the trial because of adverse events (RR 1.45, 95% CI 0.83 to 2.52; 10 trials; 1664 participants; low certainty evidence). The most common adverse events in orlistat and metformin trials were gastrointestinal (such as diarrhoea, mild abdominal pain or discomfort, fatty stools). The most frequent adverse events in sibutramine trials included tachycardia, constipation and hypertension. The single fluoxetine trial reported dry mouth and loose stools. No trial investigated drug treatment for overweight children. This systematic review is part of a series of associated Cochrane reviews on interventions for obese children and adolescents and has shown that pharmacological interventions (metformin, sibutramine, orlistat and fluoxetine) may have small effects in reduction in BMI and bodyweight in obese children and adolescents. However, many of these drugs are not licensed for the treatment of obesity in children and adolescents, or have been withdrawn. Trials were generally of low quality with many having a short or no post-intervention follow-up period and high dropout rates (overall dropout of 25%). Future research should focus on conducting trials with sufficient power and long-term follow-up, to ensure the long-term effects of any pharmacological intervention are comprehensively assessed. Adverse events should be reported in a more standardised manner specifying amongst other things the number of participants experiencing at least one adverse event. The requirement of regulatory authorities (US Food and Drug Administration and European Medicines Agency) for trials of all new medications to be used in children and adolescents should drive an increase in the number of high quality trials.

We found 21 randomised controlled studies (clinical studies where people are randomly put into one of two or more treatment groups) comparing various drugs plus a behaviour changing intervention such as diet, exercise or both (= intervention groups) usually with placebo (a pretend drug) plus a behaviour changing intervention (= control groups). We also identified eight ongoing studies (studies which are currently running but not completed yet). A total of 2484 children and adolescents took part in the included studies. The length of the intervention period ranged from 12 weeks to 48 weeks, and the length of follow-up ranged from six months to 100 weeks. The included studies investigated metformin (10 studies), sibutramine (six studies), orlistat (four studies) and one study group evaluated the combination of metformin and fluoxetine. The ongoing studies are investigating metformin (four studies), topiramate (two studies) and exenatide (two studies). Most studies reported on body mass index (BMI) and bodyweight: BMI is a measure of body fat and is calculated from weight and height measurements (kg/m2). In children, BMI is often measured in a way that takes into account sex, weight and height as children grow older (BMI z score). The average change in BMI across control groups was between a 1.8 kg/m2 reduction to a 0.9 kg/m2 increase, while across all intervention groups the average reduction was more pronounced (1.3 kg/m2 reduction). The same effect was observed for weight change: on average, children and adolescents in the intervention groups lost 3.9 kg more weight than the children and adolescents in the control groups. Study authors reported an average of serious side effects in 24 per 1000 participants in the intervention groups compared with an average of 17 per 1000 participants in the control groups. The numbers of participants dropping out of the study because of side effects were 40 per 1000 in the intervention groups and 27 per 1000 in the control groups. The most common side effects in the orlistat and metformin studies were gut (such as diarrhoea and mild tummy pain). Common side effects in the sibutramine trials included increased heart rate (tachycardia), constipation and high blood pressure. The fluoxetine study reported dry mouth and loose stools. One study reported health-related quality of life (a measure of physical, mental, emotional and social functioning) and found no marked differences between intervention and control. No study reported the participants' views of the intervention or socioeconomic effects. Only one study reported on morbidity (how often a disease occurs in a specific area) associated with the intervention, where there were more gallstones after the orlistat treatment. Study authors reported one suicide in the orlistat intervention group. However, studies were not long enough to reliably investigate death from any cause. No study investigated drug treatment for children who were only overweight (obese children have a much higher weight, BMI or BMI z score than children being overweight). This evidence is up to date to March 2016. The overall certainty of the evidence was low or very low, mainly because there were only a few studies per outcome measurement, the number of included children or adolescents was small, and due to variation in the results of the studies. In addition, many children or adolescents left the studies before the study had finished.

10.1002/14651858.CD012436

cochrane-simplification-train-3160

cochrane-simplification-train-3160

We included 15 trials (39,908 participants) that evaluated antihypertensive pharmacotherapy for a mean duration of follow-up of 4.2 years. This review provides moderate-quality evidence to show that antihypertensive drugs do not reduce sudden death (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.81 to 1.15) but do reduce both non-fatal myocardial infarction (RR 0.85, 95% CI 0.74, 0.98; absolute risk reduction (ARR) 0.3% over 4.2 years) and fatal myocardial infarction (RR 0.75, 95% CI 0.62 to 0.90; ARR 0.3% over 4.2 years). Withdrawals due to adverse effects were increased in the drug treatment group to 12.8%, as compared with 6.2% in the no treatment group. Although antihypertensive drugs reduce the incidence of fatal and non-fatal myocardial infarction, they do not appear to reduce the incidence of sudden death. This suggests that sudden cardiac death may not be caused primarily by acute myocardial infarction. Continued research is needed to determine the causes of sudden cardiac death.

We found 15 trials including 39,908 people that investigated whether blood pressure-lowering drugs reduce sudden death. This review presents moderate-quality evidence to show that blood pressure-lowering drugs reduce heart attacks but do not appear to reduce sudden cardiac death. This suggests that sudden cardiac death may not be caused primarily by heart attack. Continued research is needed to determine the causes of sudden cardiac death.

10.1002/14651858.CD011745.pub2

cochrane-simplification-train-3161

cochrane-simplification-train-3161

A total of 13 studies involving 906 participants are included in the review. The trials were different from one another in terms of type of breathing exercise performed, number of participants enrolled, number and duration of sessions completed, outcomes reported and statistical presentation of data. Asthma severity in participants from the included studies ranged from mild to moderate, and the samples consisted solely of outpatients. The following outcomes were measured: quality of life, asthma symptoms, number of acute exacerbations and lung function. Eleven studies compared breathing exercise with inactive control, and two with asthma education control groups. All eight studies that assessed quality of life reported an improvement in this outcome. An improvement in the number of acute exacerbations was observed by the only study that assessed this outcome. Six of seven included studies showed significant differences favouring breathing exercises for asthma symptoms. Effects on lung function were more variable, with no difference reported in five of the eleven studies that assessed this outcome, while the other six showed a significant difference for this outcome, which favoured breathing exercises. As a result of substantial heterogeneity among the studies, meta-analysis was possible only for asthma symptoms and changes in the Asthma Quality of Life Questionnaire (AQLQ). Each meta-analysis included only two studies and showed a significant difference favouring breathing exercises (MD -3.22, 95% CI -6.31 to -0.13 for asthma symptoms; MD 0.79, 95% CI 0.50 to 1.08 for change in AQLQ). Assessment of risk of bias was impaired by incomplete reporting of methodological aspects of most of the included trials. Even though individual trials reported positive effects of breathing exercises, no reliable conclusions could be drawn concerning the use of breathing exercises for asthma in clinical practice. This was a result of methodological differences among the included studies and poor reporting of methodological aspects in most of the included studies. However, trends for improvement are encouraging, and further studies including full descriptions of treatment methods and outcome measurements are required.

The trials were different in terms of type of breathing exercises performed, number of participants enrolled, number and duration of sessions completed, outcomes reported and statistical presentation of data. As a result, we were not able to compare the results from these trials using a meta-analysis for all outcomes. Meta-analysis was possible for only two outcomes (asthma symptoms and change in Asthma Quality of Life Questionnaire—AQLQ), each of which was reported in only two studies. Both meta-analyses showed a significant difference favouring breathing exercises. The methods used to conduct these studies were not as well reported as we would have liked, and so the quality of the trials was unclear. Overall the quality of the evidence included in the review was very low. Even though individual trials reported positive effects of breathing exercises, no conclusive evidence in this review supports or refutes the efficacy of such intervention in the treatment of adult patients with asthma.

10.1002/14651858.CD001277.pub3

cochrane-simplification-train-3162

cochrane-simplification-train-3162

In this Cochrane Review update we did not include any new RCT compared with the first review version. Accordingly, four RCTs (388 participants) met the inclusion criteria. These trials evaluated the human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate. Included trials reported data on mortality and bleeding. The studies were conducted in Japan, Italy and the Netherlands. We classified the included trials as: 1) including patients with or without leukemia which did not report data for the leukemia subgroup (366 participants); and 2) only including patients with leukemia (22 participants). Overall, the risk of bias of the included trials was high, since the trial authors did not provide a detailed description about trial design and execution. According to the GRADE recommendations, we judged the overall quality of the body of evidence for all prefixed outcomes as 'very low', due to methodological limitations and very small sample size. One trial, including 10 participants with leukemia and comparing dermatan sulphate with heparin, reported no deaths during trial treatment. In terms of bleeding data, we were unable to pool results from two studies that were only conducted with leukemia patients due to the inconsistency in the measurement and reporting of this outcome. One trial, including 12 participants with leukemia, found very low quality evidence that tranexamic acid can reduce the cumulative hemorrhagic score in participants compared with those assigned to placebo (P = 0.0015, very low quality evidence). On the contrary, there is no evidence that dermatan sulphate compared with placebo reduces new events of hemorrhagic diathesis (1/5 (20%) versus 2/5 (40%); RR 0.50; 95% CI 0.06 to 3.91; P = 0.51, very low quality evidence). No thromboembolic complications were reported in either trial that included patients with leukemia only (very low quality evidence). The safety profile was inconclusive. The included trials did not assess overall mortality, resolution of respiratory failure, renal failure or shock. Due to a lack of new RCTs, our conclusions in this Cochrane Review update are the same as the previous review version. We included four RCTs which reported mortality and bleeding data. It is not possible to determine whether human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate are effective or harmful for patients presenting with DIC related to acute or chronic leukemia. The quality of the evidence was low to very low. Therefore, prescription of these interventions for treating DIC in patients with acute and chronic leukemia can neither be supported nor rejected, unless new evidence from a large high-quality trial alters this conclusion.

We included four trials that had a limited number of patients (388) and assessed four different interventions: human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate with heparin or placebo. Two trials included patients either with or without leukemia. The other two trials only included patients with leukemia. The studies were published between 1989 and 2007, and were conducted in Japan, Italy and the Netherlands. All trials have a high risk of bias. There were no deaths reported in a trial comparing dermatan sulphate with heparin. Two small trials which included patients with leukemia only (22 participants) reported bleeding data. These results were not compiled due to inconsistency in the measurement and reporting of that outcome. One trial found very low quality evidence that tranexamic acid compared with placebo reduces bleeding in leukemia patients. On the contrary, there is no evidence that dermatan sulphate compared with placebo reduces new events of hemorrhagic diathesis in patients with leukemia. Saftey profile is inconclusive. No thromboembolic complications were reported in both the trials. These trials did not report overall mortality, resolution of respiratory failure, renal failure and shock. Accordingly, the clinical benefits and harms of the human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate are unknown in this population. The confidence in the results of this review is very low. The studies have limitations in the way they were designed and executed. Moreover, the limited number of patients included in the studies led to imprecise results. Well conducted larger studies will provide more information about the effect of human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate for treating DIC in patients with acute or chronic leukemia. This plain language summary is current as of 7 May 2015. Search date: 7 May 2015

10.1002/14651858.CD008562.pub3

cochrane-simplification-train-3163

cochrane-simplification-train-3163

We included five RCTs involving 825 participants. The studies were carried out in the USA and Europe, and were published between 1987 and 2017. Risk of bias across the studies varied. Most had low risk for selection, reporting and attrition bias, and a high risk for performance and detection bias because blinding was inadequate or absent. All participants had mild to moderate hearing loss. The average age across all five studies was between 69 and 83 years. The duration of the studies ranged between six weeks and six months. There was a large beneficial effect of hearing aids on hearing-specific health-related quality of life associated with participation in daily life as measured using the Hearing Handicap Inventory for the Elderly (HHIE, scale range 1 to 100) compared to the unaided/placebo condition (mean difference (MD) -26.47, 95% confidence interval (CI) -42.16 to -10.77; 722 participants; three studies) (moderate-quality evidence). There was a small beneficial effect of hearing aids on general health-related quality of life (standardised mean difference (SMD) -0.38, 95% CI -0.55 to -0.21; 568 participants; two studies) (moderate-quality evidence). There was a large beneficial effect of hearing aids on listening ability (SMD -1.88, 95% CI -3.24 to -0.52; 534 participants; two studies) (moderate-quality evidence). Adverse effects were measured in only one study (48 participants) and none were reported (very low-quality evidence). The available evidence concurs that hearing aids are effective at improving hearing-specific health-related quality of life, general health-related quality of life and listening ability in adults with mild to moderate hearing loss. The evidence is compatible with the widespread provision of hearing aids as the first-line clinical management in those who seek help for hearing difficulties. Greater consistency is needed in the choice of outcome measures used to assess benefits from hearing aids. Further placebo-controlled studies would increase our confidence in the estimates of these effects and ascertain whether they vary according to age, gender, degree of hearing loss and type of hearing aid.

The evidence is up to date to 23 March 2017. We found five clinical studies involving 825 adults with mild to moderate hearing loss who were randomly given either hearing aids, no hearing aids or placebo hearing aids. Studies involved older adults with the average age within studies between 69 and 83 years. The duration of the studies was between six weeks and six months. We found evidence in three studies that hearing aids have a large beneficial effect in improving the ability of adults with mild to moderate hearing loss to take part in everyday situations. Hearing aids have a small beneficial effect in improving general health-related quality of life, such as physical, social, emotional and mental well-being, and have a large effect in improving the ability to listen to other people. Only one study attempted to measure harms due to hearing aids. None were reported. We judged the evidence that hearing aids improve the ability to take part in everyday situations, improve general health-related quality of life and improve listening ability to be of moderate quality. This means that while we are reasonably confident that the reported benefits of hearing aids are real, there is a possibility that if further studies are conducted the size of the benefit might differ. We judged the quality of evidence for harms to be very low, because this was only measured in one small study. We found that hearing aids improve the ability of adults with mild to moderate hearing loss to take part in everyday life, their general quality of life and their ability to listen to other people. If an adult with mild to moderate hearing loss seeks help for their hearing difficulties, hearing aids are an effective clinical option. It is important that future studies measure benefits consistently and report benefits separately for different age groups, genders, levels of hearing loss and types of hearing aids.

10.1002/14651858.CD012023.pub2

cochrane-simplification-train-3164

cochrane-simplification-train-3164

We included one randomised controlled trial involving 2782 participants. The study investigated the effects of mobile phone messaging in alleviating anxiety in women waiting for prenatal biochemical screening results for Down syndrome, by providing fast reporting of results before a follow-up appointment. The study measured health outcomes using the Spielberger State-Trait Anxiety Inventory (STAI), which includes a scale (20 to 80 points, higher score indicates higher anxiety) to describe how the respondent feels at a particular moment in time (state anxiety). The study, which was at high risk of bias, found that women who had received their test result early by text message had a mean anxiety score 2.48 points lower than women who had not yet received their result (95% CI - 8.79 to 3.84). Women with a serum-negative test result receiving their result early had a mean anxiety score 5.3 points lower (95% CI - 5.99 to -4.61) than women in the control group. Women with a serum-positive test result receiving their result early by text message had a mean anxiety score 1.2 points higher (95% CI - 3.48 to 5.88) than women in the control group.The evidence was of low quality due to high risk of bias in the included study, and the fact that the evidence comes from one study only. The study did not report on other outcomes of interest, such as patient satisfaction, adverse events or cost. We found very limited evidence of low quality that communicating results of medical investigations by mobile phone messaging may make little or no difference to women's anxiety overall or in women with positive test results, but may reduce anxiety in women with negative test results. However, with only one study included in this review, this evidence is insufficient to inform recommendations at this time. More research is needed on the effectiveness and user evaluation of these interventions. In particular, more research should be conducted into the potential risks and limitations of these interventions.

This review studied whether mobile phone applications such as Short Message Service (SMS) and Multimedia Message Service (MMS) can be useful to send information to patients about their test results. We also looked at possible risks of communicating in this way. Our review found only one study evaluating the use of mobile phone messaging for communicating results of medical investigations. This study was at high risk of bias. The study suggested that the early communication of an antenatal screen test result by text messaging would not result in a difference in the anxiety scores of all pregnant women (irrespective of the test result) or when their test result is positive, however may reduce anxiety in pregnant women when their test result is negative. The usefulness of mobile phone messaging in other situations, or potential negative consequences, are not yet known.

10.1002/14651858.CD007456.pub2

cochrane-simplification-train-3165

cochrane-simplification-train-3165

We included three studies, enrolling 1158 participants. Each study reported an increased rate of recovery with intraoperative mild hypothermia, but the effect sizes were not sufficient for certainty. A total of 1086 of the 1158 participants (93.8%) had good grade aneurysmal subarachnoid haemorrhage. Seventy-six of 577 participants (13.1%) who received hypothermia and 93 of 581 participants (16.0%) who did not receive hypothermia were dead or dependent (RR 0.82; 95% CI 0.62 to 1.09; RD -0.03; 95% CI -0.07 to 0.01, moderate-quality evidence) after three months. Reported unfavourable outcomes did not differ between participants with or without hypothermia. The quality of evidence for these outcomes remains unclear because the outcomes were reported in a variety of ways. No decompressive craniectomy or corticectomy was reported. Thirty-six of 577 (6.2%) participants with hypothermia and 40 of 581 (6.9%) participants without hypothermia had infarction. Thirty-four of 577 (6%) participants with hypothermia and 32 of the 581 (5.5%) participants without hypothermia had clinical vasospasm (temporary deficits). Duration of hospital stay was not reported. Only one study with 112 participants reported discharge destinations: 43 of 55 (78.2%) participants with hypothermia and 39 of 57 (68.4%) participants in the control group were discharged home. The remaining participants were discharged to other facilities. Thirty-nine of 577 (6.8%) participants with hypothermia and 39 of 581 (6.7%) participants without hypothermia had infections. Six of 577 (1%) participants with hypothermia and 6 of 581 (1%) participants without hypothermia had cardiac arrhythmia. It remains possible that intraoperative mild hypothermia could prevent death or dependency in activities of daily living in people with good grade aneurysmal subarachnoid haemorrhage. However, the confidence intervals around this estimate include the possibility of both benefit and harm. There was insufficient information to draw any conclusions about the effects of intraoperative mild hypothermia in people with poor grade aneurysmal subarachnoid haemorrhage or without subarachnoid haemorrhage. We did not identify any reliable evidence to support the routine use of intraoperative mild hypothermia. A high-quality randomised clinical trial of intraoperative mild hypothermia for postoperative neurological deficits in people with poor grade aneurysmal subarachnoid haemorrhage might be feasible.

The updated evidence is current to August 2015. We found only three appropriate studies with a total of 1158 participants to include. Data primarily came from one high-quality study with 1000 participants. Our analysis showed that in good grade patients, it remains possible that cooling the brain during surgery might prevent death or dependency in everyday activities. Very limited information was available for those without bleeding or those with poor grade bleeding. Unfavourable outcomes did not differ between participants with or without hypothermia. The quality of evidence for these outcomes remains unclear because they were reported in a variety of ways. We do not have enough data to be certain about the effect of cooling on death or dependency. The evidence for other outcomes was more uncertain, since we could not combine the data due to variation in the definition and reporting of outcome data. Data in our analyses were primarily from one high quality trial on good grade participants.

10.1002/14651858.CD008445.pub3

cochrane-simplification-train-3166

cochrane-simplification-train-3166

Five trials on gabapentin and one trial on its prodrug gabapentin enacarbil met the inclusion criteria; no reports on pregabalin were identified. In total, data from 1009 patients were considered. One trial each of gabapentin 900 mg (53 patients), and gabapentin titrated to 1200 mg (63 patients) and 1800 mg (122 patients) failed to show a statistically significant reduction in headache frequency in the active treatment group as compared to the placebo group, whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (MD -0.80; 95% confidence interval (CI) -1.55 to -0.05). The pooled results of these four studies (MD -0.44; 95% CI -1.43 to 0.56; 351 patients) do not demonstrate a significant difference between gabapentin and placebo. One trial of gabapentin titrated to 1800 mg (122 patients) failed to demonstrate a significant difference between active treatment and placebo in the proportion of responders (OR 0.97; 95% CI 0.45 to 2.11), whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (OR 2.79; 95% CI 1.09 to 7.17). The pooled results of these two studies (OR 1.59; 95% CI 0.57 to 4.46; 235 patients) do not demonstrate a significant difference between gabapentin and placebo. Comparisons from one study (135 patients) suggest that gabapentin 2000 mg is no more effective than gabapentin 1200 mg. One trial of gabapentin enacarbil (523 participants) failed to demonstrate a significant difference versus placebo or between doses for gabapentin enacarbil titrated to between 1200 mg and 3000 mg with regard to proportion of responders; there was also no evidence of a dose-response trend. Adverse events, most notably dizziness and somnolence, were common with gabapentin. The pooled evidence derived from trials of gabapentin suggests that it is not efficacious for the prophylaxis of episodic migraine in adults. Since adverse events were common among the gabapentin-treated patients, it is advocated that gabapentin should not be used in routine clinical practice. Gabapentin enacarbil is not efficacious for the prophylaxis of episodic migraine in adults. There is no published evidence from controlled trials of pregabalin for the prophylaxis of episodic migraine in adults.

For the present review, researchers in The Cochrane Collaboration reviewed the evidence about the effects of gabapentin and two related drugs (pregabalin and gabapentin enacarbil) in adult patients (≥ 16 years of age) with 'episodic' migraine (headache on < 15 days per month). They examined research published up to 15 January 2013, along with three unpublished and previously confidential drug company research reports, and found six relevant studies, five of gabapentin and one of gabapentin enacarbil, both over a wide dose range. The studies showed that neither gabapentin nor gabapentin enacarbil was more effective than placebo at reducing the frequency of migraine headaches. Gabapentin commonly caused side effects, especially dizziness and somnolence (sleepiness). No studies of pregabalin were identified, and research on this drug is desirable.

10.1002/14651858.CD010609

cochrane-simplification-train-3167

cochrane-simplification-train-3167

Five studies including 523 participants reported the diagnostic accuracy of ultrasound. One studies (262 participants) compared the accuracy of ultrasound, serum bilirubin and serum alkaline phosphatase in the same participants. All the studies included people with symptoms. One study included only participants without previous cholecystectomy but this information was not available from the remaining studies. All the studies were of poor methodological quality. The sensitivities for ultrasound ranged from 0.32 to 1.00, and the specificities ranged from 0.77 to 0.97. The summary sensitivity was 0.73 (95% CI 0.44 to 0.90) and the specificity was 0.91 (95% CI 0.84 to 0.95). At the median pre-test probability of common bile duct stones of 0.408, the post-test probability (95% CI) associated with positive ultrasound tests was 0.85 (95% CI 0.75 to 0.91), and negative ultrasound tests was 0.17 (95% CI 0.08 to 0.33). The single study of liver function tests reported diagnostic accuracy at two cut-offs for bilirubin (greater than 22.23 μmol/L and greater than twice the normal limit) and two cut-offs for alkaline phosphatase (greater than 125 IU/L and greater than twice the normal limit). This study also assessed ultrasound and reported higher sensitivities for bilirubin and alkaline phosphatase at both cut-offs but the specificities of the markers were higher at only the greater than twice the normal limit cut-off. The sensitivity for ultrasound was 0.32 (95% CI 0.15 to 0.54), bilirubin (cut-off greater than 22.23 μmol/L) was 0.84 (95% CI 0.64 to 0.95), and alkaline phosphatase (cut-off greater than 125 IU/L) was 0.92 (95% CI 0.74 to 0.99). The specificity for ultrasound was 0.95 (95% CI 0.91 to 0.97), bilirubin (cut-off greater than 22.23 μmol/L) was 0.91 (95% CI 0.86 to 0.94), and alkaline phosphatase (cut-off greater than 125 IU/L) was 0.79 (95% CI 0.74 to 0.84). No study reported the diagnostic accuracy of a combination of bilirubin and alkaline phosphatase, or combinations with ultrasound. Many people may have common bile duct stones in spite of having a negative ultrasound or liver function test. Such people may have to be re-tested with other modalities if the clinical suspicion of common bile duct stones is very high because of their symptoms. False-positive results are also possible and further non-invasive testing is recommended to confirm common bile duct stones to avoid the risks of invasive testing. It should be noted that these results were based on few studies of poor methodological quality and the results for ultrasound varied considerably between studies. Therefore, the results should be interpreted with caution. Further studies of high methodological quality are necessary to determine the diagnostic accuracy of ultrasound and liver function tests.

We identified five studies including 523 participants that reported the diagnostic test accuracy of ultrasound. One of these studies, involving 262 participants, also reported the diagnostic test accuracy of serum bilirubin and serum alkaline phosphatase. All the studies included people with symptoms. One study included only participants who had not undergone previous cholecystectomy (removal of gallbladder). This information was not available from the remaining studies. Based on an average sensitivity of 73% for ultrasound, we would expect that on average 73 out of 100 people with common bile duct stones will be detected while the remaining 27 people will be missed and will not receive appropriate treatment. The average number of people with common bile duct stones detected using ultrasound may vary between 44 and 90 out of 100 people. Based on an average specificity of 91% for ultrasound, we would expect that on average 91 out of 100 people without common bile duct stones would be identified as not having common bile duct stones; 9 out of 100 would be false positives and not receive appropriate treatment. The average number of false positives could vary between 5 and 16 out of 100 people. Evidence from one study suggested that using a level of serum alkaline phosphatase higher than 125 units to distinguish between people who have and people who do not have common bile duct stones gave better diagnostic accuracy than using a level twice the normal limit (which usually ranges between 0 and 40). The study also showed better accuracy for serum alkaline phosphatase compared to serum bilirubin. The sensitivity of serum alkaline phosphatase at the 125 units cut-off was 92%, which means that 92 out of 100 people with common bile duct stones would be detected but 8 out of 100 people will be missed. The number detected could vary between 74 and 99 out of 100 people. Based on the specificity of 79%, 79 out of 100 people without common bile duct stones will be correctly identified as not having common bile duct stones while the remaining 21 people will be false positives. The number of false positives could vary between 16 and 26 out of 100 people. This suggests that further non-invasive tests may be useful to diagnose common bile duct stones prior to the use of invasive tests. All the studies were of low methodological quality, which may undermine the validity of our findings. Further studies of high methodological quality are necessary.

10.1002/14651858.CD011548

cochrane-simplification-train-3168

cochrane-simplification-train-3168

We included five trials involving 1350 participants in the original review. The updated review identified no new trials. The evidence from two small trials (one trial including infants and one including adolescents) was insufficient to allow any definitive statements to be made about the effects of the needles evaluated in the trials on vaccine immunogenicity and reactogenicity. The remaining three trials (1135 participants) contributed data to comparisons between 25 G 25 mm, 23 G 25 mm, and 25 G 16 mm needles. These trials included infants predominantly aged from two to six months undergoing intramuscular vaccination in the anterolateral thigh using the World Health Organization (WHO) injection technique (skin stretched flat, needle inserted at a 90° angle and up to the needle hub in healthy infants). The vaccines administered were combination vaccines containing diphtheria, tetanus, and whole-cell pertussis antigens (DTwP). In some trials, the vaccines also contained Haemophilus influenzae type b (DTwP-Hib) and hepatitis B (DTwP-Hib-Hep B) antigen components. Primary outcomes Incidence of vaccine-preventable diseases: No trials reported this outcome. Procedural pain and crying: Using a wider gauge 23 G 25 mm needle may slightly reduce procedural pain (low-quality evidence) and probably leads to a slight reduction in the duration of crying time immediately after vaccination (moderate-quality evidence) compared with a narrower gauge 25 G 25 mm needle (one trial, 320 participants). The effects are probably not large enough to be clinically relevant. Secondary outcomes Immune response: There is probably little or no difference in immune response, defined in terms of the proportion of seroprotected infants, between use of 25 G 25 mm, 23 G 25 mm, or 25 G 16 mm needles to administer a series of three doses of a DTwP-Hib vaccine at ages two, three, and four months (moderate-quality evidence, one trial, numbers of participants in analyses range from 309 to 402. The immune response to the pertussis antigen was not measured). Severe and non-severe local reactions: 25 mm needles (either 25 G or 23 G) probably lead to fewer severe and non-severe local reactions after DTwP-Hib vaccination compared with 25 G 16 mm needles (moderate-quality evidence, one trial, 447 to 458 participants in analyses). We estimate that one fewer infant will experience a severe local reaction (extensive redness and swelling) after the first vaccine dose for every 25 infants vaccinated with the longer rather than the shorter needle (number needed to treat for an additional beneficial outcome (NNTB) with a 25 G 25 mm needle: 25 (95% confidence interval (CI) 15 to 100); NNTB with a 23 G 25 mm needle: 25 (95% CI 17 to 100)). We estimate that one fewer infant will experience a non-severe local reaction (any redness, swelling, tenderness, or hardness (composite outcome)) at 24 hours after the first vaccine dose for every 5 or 6 infants vaccinated with a 25 mm rather than a 16 mm needle (NNTB with a 25 G 25 mm needle: 5 (95% CI 4 to 10); NNTB with a 23 G 25 mm needle: 6 (95% CI 4 to 13)). The results are similar after the second and third vaccine doses. Using a narrow gauge 25 G 25 mm needle may produce a small reduction in the incidence of local reactions after each dose of a DTwP vaccine compared with a wider gauge 23 G 25 mm needle, but the effect estimates are imprecise (low-quality evidence, two trials, 100 to 459 participants in analyses). Systemic reactions: The comparative effects of 23 G 25 mm, 25 G 25 mm, and 25 G 16 mm needles on the incidence of postvaccination fever and other systemic events such as drowsiness, loss of appetite, and vomiting are uncertain due to the very low quality of the evidence. Using 25 mm needles (either 23 G or 25 G) for intramuscular vaccination procedures in the anterolateral thigh of infants using the WHO injection technique probably reduces the occurrence of local reactions while achieving a comparable immune response to 25 G 16 mm needles. These findings are applicable to healthy infants aged two to six months receiving combination DTwP vaccines with a reactogenic whole-cell pertussis antigen component. These vaccines are predominantly used in low- and middle-income countries. The applicability of the findings to vaccines with acellular pertussis components and other vaccines with different reactogenicity profiles is uncertain.

We included five studies involving 1350 people. We rated the quality of the evidence from studies as very low, low, moderate, or high. Very low-quality evidence means that we are very uncertain about the results. High-quality evidence means that we are very confident in the results. There were problems with the design of some studies, and data were insufficient to answer some parts of our review question. The quality of the evidence from two studies was too low to allow us to draw any conclusions about the effects of the needles compared in the studies. However, there was sufficient evidence from the remaining three studies to allow us to reach conclusions. The three studies that allowed us to reach conclusions involved 1135 healthy infants aged mostly between two and six months. The infants were vaccinated in the thigh with either 25 G 25 mm (narrow, long needles), 23 G 25 mm (wide, long needles), or 25 G 16 mm needles (narrow, short needles). The needles were inserted at right angles (90° angle) into the skin and pushed down into the muscle of the thigh. The vaccines injected were combination vaccines designed to protect against several diseases including diphtheria (D), tetanus (T), whooping cough (pertussis), and Haemophilus influenzae type b disease (Hib). The vaccines all contained whole-cell pertussis (wP) vaccine antigens. These vaccines are commonly used in low- and middle-income countries but not in high-income countries. Our review findings are therefore most relevant to low- and middle-income countries. We found moderate-quality evidence that infants vaccinated in the thigh with 25 mm needles probably have fewer severe reactions (extensive redness and swelling in the thigh) after DTwP-Hib vaccination than infants vaccinated with 16 mm needles. We also found that the longer needles probably lead to fewer non-severe reactions such as mild swelling, tenderness, and redness after vaccination. The immune response to the vaccine is probably similar with the long and the short needles. We found low-quality evidence that the wide, long needle may slightly reduce the pain of the vaccination procedure compared with the narrow, long needle. We found moderate-quality evidence that the wide, long needle probably slightly reduces the duration of crying immediately following vaccination compared with the narrow, long needle. The differences in pain and crying between use of the wide and narrow needles are probably too small to be of any practical importance. We found low-quality evidence that infants vaccinated with the narrow, long needle may have slightly fewer non-severe reactions than infants vaccinated with the wide, long needle. We do not know if needle size has an effect on fever or other reactions that sometimes occur after vaccination including drowsiness, loss of appetite, and vomiting due to the very low quality of the evidence. The evidence in our review is current to October 2017.

10.1002/14651858.CD010720.pub3

cochrane-simplification-train-3169

cochrane-simplification-train-3169

We included 28 trials (3 of which are new trials since the original review), involving 9140 children and adolescents. Most of these trials recruited participants from schools. Most of the studies (20) were at high risk of bias, with 8 at unclear risk of bias. Twenty-five trials (8479 participants) contributed data for meta-analysis on permanent tooth surfaces: the D(M)FS pooled prevented fraction (PF) estimate was 28% (95% confidence intervals (CI) 19% to 36%; P < 0.0001; with substantial heterogeneity (P < 0.0001; I2 = 82%); moderate quality evidence). Subgroup and metaregression analyses suggested no significant association between estimates of D(M)FS prevented fractions and the prespecified trial characteristics. However, the effect of fluoride gel varied according to the type of control group used, with D(M)FS PF on average being 17% (95% CI 3% to 31%; P = 0.018) higher in non-placebo-controlled trials (the reduction in caries was 38% (95% CI 24% to 52%; P < 0.0001, 2808 participants) for the 10 trials with no treatment as control group, and 21% (95% CI 15% to 28%; P < 0.0001, 5671 participants) for the 15 placebo-controlled trials. A funnel plot of the 25 trials in the D(M)FS PF meta-analysis indicated a relationship between prevented fraction and study precision, with an apparent lack of small studies with statistically significant large effects. The d(e/m)fs pooled prevented fraction estimate for the three trials (1254 participants) that contributed data for the meta-analysis on primary teeth surfaces was 20% (95% CI 1% to 38%; P = 0.04; with no heterogeneity (P = 0.54; I2 = 0%); low quality evidence). There was limited reporting of adverse events. Only two trials reported information on acute toxicity signs and symptoms during the application of the gel (risk difference 0.01, 95% CI -0.01 to 0.02; P = 0.36; with no heterogeneity (P = 36; I2 = 0%); 490 participants; very low quality evidence). None of the trials reported information on tooth staining, mucosal irritation or allergic reaction. The conclusions of this updated review remain the same as those when it was first published. There is moderate quality evidence of a large caries-inhibiting effect of fluoride gel in the permanent dentition. Information concerning the caries-preventive effect of fluoride gel on the primary dentition, which also shows a large effect, is based on low quality evidence from only three placebo-controlled trials. There is little information on adverse effects or on acceptability of treatment. Future trials should include assessment of potential adverse effects.

We included 28 studies in which over 9000 children (aged 2 to 15 years) were randomised to treatment with fluoride gel or to a control group using placebo gel or receiving no treatment. Study duration ranged from 1 to 4 years (with 13 studies lasting around 2 years). Study reports were published between 1967 and 2005. Thirteen studies took place in the USA, seven in Europe, four in Brazil and one each in Canada, Israel, China and Venezuela. This review update confirmed that fluoride gel can reduce tooth decay in children and adolescents. We combined the results of 25 trials and found that on average there is a 28% reduction in decayed, missing and filled tooth surfaces (21% reduction in trials that used a placebo gel in the control group and 38% reduction in trials where the control group received no treatment) in permanent teeth. From the three trials looking at the effect of fluoride gel on first or baby teeth, the evidence suggests that using fluoride gel results in a 20% reduction in decayed, missing and filled tooth surfaces. We found little information about unwanted or harmful effects or how well children and young people were able to cope with the application of the gel. The application of fluoride gel results in a large reduction in tooth decay in both permanent and baby teeth. We found little information about potential unwanted or harmful effects from accidental swallowing of the gel during treatment. As children often swallow gel during application, more research is needed on these effects. The evidence available for permanent teeth is of moderate quality. The evidence on baby teeth is low quality because of the small number of studies available. The evidence available for adverse effects is very low quality.

10.1002/14651858.CD002280.pub2

cochrane-simplification-train-3170

cochrane-simplification-train-3170

Thirteen randomized double-blinded placebo-controlled trials that examined the blood pressure lowering efficacy of six partial agonists in 605 hypertensive patients were included in this review. Five of the included studies were parallel studies and the other eight were cross-over studies. The overall risk of bias is high in this review due to the small sample size and high risk of detection bias. Pindolol, celiprolol and alprenolol lowered SBP and DBP compared to placebo. Acebutolol lowered SBP but there was no clear evidence that it lowered DBP. There was no clear evidence that pindolol and oxprenolol lowered SBP or DBP. Other than for celiprolol, sample sizes were generally small increasing the uncertainty in findings for individual agents versus placebo. In patients with moderate to severe hypertension, partial agonists (considered as a subclass) lowered peak BP by an average of 8 mmHg systolic (95% CI, -10 to -6, very low quality evidence), 4 mmHg diastolic (95%CI, -5 to -3, very low quality evidence) and reduced heart rate by five beats per minute (95%CI, -6 to -4, very low quality evidence). Higher dose partial agonists did not appear to provide additional BP lowering effects compared to lower dose. The maximum BP lowering effect of the overall subclass occurred at the starting dose. Partial agonists reduced pulse pressure by 4 mmHg (95% CI, -5 to -2, very low evidence). Only one study reported withdrawal due to adverse effects, the risk ratio (95% confidence interval) was 0.72 (0.07, 7.67). There was very low quality evidence that in patients with moderate to severe hypertension, partial agonists lowered peak BP by an average of 8/4 mmHg and reduced heart rate by five beats per minute. There was no evidence of a greater effect at doses higher than the initial doses. This estimate was probably exaggerated as it was subject to a high risk of bias. Based on the indirect comparison of the results in this review and two Cochrane reviews on angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which also used similar inclusion criteria as this review, the BP lowering effect appeared to be less than the effect in patients with mild to moderate elevated BP who were taking ACE inhibitors and ARBs based on an indirect comparison. Withdrawals due to adverse effects were only reported in one trial so it is impossible to assess the harm of these drugs.

We developed a comprehensive search strategy to search relevant scientific databases for clinical trials and found 13 trials that randomly assigned 605 high blood pressure patients to either fixed-dose partial agonist treatment or placebo for up to 12 weeks. On average, partial agonists lowered blood pressure by eight points in systolic and four points in diastolic pressure in patient with moderate to severe high blood pressure. We did not find any evidence showing that doses higher than the recommended starting doses would further lower blood pressure. On average, partial agonists lowered pulse pressure by 4 mmHg. The included studies generally did not report side effects serious enough that lead to termination of treatment. It was not clear whether partial agonists provide more side effects serious enough that lead to withdrawal compared to placebo. The quality of evidence is very low due to small sample size and high risk of bias.

10.1002/14651858.CD007450.pub2

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cochrane-simplification-train-3171

Eleven studies (835 participants) compared exercise to usual care. No studies compared exercise with no treatment or non-exercise interventions. The quality of the evidence was very low for the primary outcome rates of falls, and very low to low for the secondary outcomes. We downgraded the evidence due to study limitations (risk of bias), and issues of imprecision due to small sample sizes, inconsistency and indirectness. All studies were at high risk of bias for blinding of participants and personnel due to inability to blind participants to an exercise intervention. Risk of bias was generally low or unclear for other categories. There was generally little information on the important outcomes comparing exercise to usual care. Rates of falls and number of fallers: one study (223 participants) measured accidental falls, but reported neither the rate of falls or the number of fallers; there was no difference in the number of falls between exercise and usual care (very low-quality evidence). Strength: 10 studies (813 participants) reported on strength outcomes. Two analyses favoured exercise over usual care: quadriceps strength (2 studies, 72 participants; mean difference (MD) 8.99 kg, 95% confidence interval (CI) 1.29 to 16.70; low-quality evidence), and leg press (4 studies, 388 participants; MD 21.1 kg, 95% CI 8.47 to 33.74; low-quality evidence). In one analysis of the Sit-to-Stand Test, there was no difference between exercise and usual care (4 studies, 214 participants; standardised mean difference (SMD) –0.45, 95% CI –1.05 to 0.14; very low-quality evidence). Flexibility: one study (21 participants) reported on flexibility for Sit-and-Reach Distance (MD 2.05 cm, 95% CI 0.59 to 3.51; very low-quality evidence). Balance: five studies (350 participants) measured three different balance outcomes. Two analyses favoured exercise over usual care: postural balance (4 studies, 127 participants; standardised mean difference (SMD) 0.44, 95% CI 0.08 to 0.79; very low-quality evidence), and Backward Walk Test (2 studies, 280 participants; SMD –0.24, 95% CI –0.48 to –0.01; low-quality evidence). There was no difference between exercise and usual care for the Timed Up-and-Go Test (1 study, 15 participants; MD –0.35 seconds, 95% CI –1.47 to 0.77; low-quality evidence). Number of people sustaining a fall-related fracture: the quality of the evidence for exercise reducing fall-related fractures was very low. Adverse events: a single study (223 participants) noted some temporary muscle soreness on initiation of exercise or when there was an increase in the weight lifted. As no occurrence data were reported, we could not assess this variable further. No studies reported musculoskeletal injury. Analysis indicated that there was very low-quality evidence that exercise did not increase fatigue. There is a paucity of evidence for exercise training to reduce fall rates in people living with and beyond cancer. Exercise training may improve strength, flexibility and balance for people in this population, but the evidence is very low quality.

In July 2018, we searched for clinical trials about exercise to reduce falls in adults living with and beyond cancer. We found 11 studies of variable quality and size, including a total of 835 people, that compared exercise to usual care. Most of the studies were very small, four with fewer than 30 people. Only one study reported on accidental falls. All 11 studies reported on one or more measures that are risk factors for falling (e.g. strength, flexibility and balance). We rated the quality of the evidence from the studies using four levels: very low, low, moderate or high. Very low-quality evidence means that we are very uncertain about the results. High-quality evidence means that we are very confident in the results. The quality of the evidence was very low to low across all of the measures of interest. There were several weaknesses identified in the design of all studies including small numbers of participants. No study could prevent participants knowing their treatment and so there could have been bias. Only one study looked at the effect of exercise on accidental falls and found no difference in number of falls between people who exercised and people who did not (very low-quality evidence). Therefore, there were insufficient data for conclusions to be drawn regarding the effects of exercise on reducing accidental falls for people living with and beyond cancer. There was improvement in some factors that are known to affect falls; we found improvement in some measures of strength, flexibility and balance, although the overall quality of this evidence was very low to low.

10.1002/14651858.CD011687.pub2

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cochrane-simplification-train-3172

We included two eligible studies with a total of 287 participants; both had good methodological quality. There was no difference in the duration of catheter patency between heparin-bonded and non-heparin bonded catheters (median duration seven days versus six days) reported in one study. There was no difference in the risk of catheter-related thrombosis (two studies, RR 0.34, 95% CI 0.01 to 7.68; I2 = 80%; RD -0.06, 95% CI -0.17 to 0.06). Data from one study revealed a statistically significant reduction in the risk of catheter occlusion (RR 0.06, 95% CI 0.00 to 1.07; RD -0.08, 95% CI -0.13 to -0.02; NNT 13, 95% CI 8 to 50), catheter-related blood stream infections (RR 0.06, 95% CI 0.01 to 0.41; RD -0.17, 95% CI -0.25 to -0.10; NNT 6, 95% CI 4 to 10) and catheter colonization (RR 0.21, 95% CI 0.06 to 0.71; RD -0.11, 95% CI -0.19 to -0.04; NNT 9, 95% CI 5 to 25) in the heparin-bonded catheter group. The second study did not report on these outcomes. There was no significant difference in risk of thrombocytopenia after catheter placement (RR 0.73, 95% CI 0.38 to 1.39; RD -0.02, 95% CI -0.10 to 0.07). Two eligible studies on the use of heparin-bonded catheters versus placebo in children were identified. Meta-analysis of the two studies revealed no reduction in catheter-related thrombosis with heparin-bonded catheters. One study reported a reduction in catheter-related blood stream infection and colonization following the use of heparin-bonded catheters. The strength of evidence is low and further well-designed multicenter randomized controlled trials are warranted.

The review authors identified two good quality controlled trials that randomized 287 children aged one day to 16 years to either a heparin-bonded catheter or a standard catheter. The median duration of time that the catheter could be used to give fluids (its patency) was not clearly different with the two types of catheter. This was seven days in the heparin-bonded catheter group and six days in the standard catheter group. There was a no difference between the two groups for risk of catheter-related thrombosis over the time the catheter was in. There was a trend towards a reduction in the risk of catheter occlusion in the first week after catheter placement, reported in one study only. The risks of catheter-related blood stream infections and bacterial colonization of the catheter were significantly reduced using the heparin-bonded catheter, with a longer time to develop infection (delayed in the heparin-bonded catheter group); however, it was reported in one study only and the strength of evidence was low. There was no significant difference in risk of thrombocytopenia after catheter placement.

10.1002/14651858.CD005983.pub3

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cochrane-simplification-train-3173

We identified four new studies for the review update; the review now includes seven studies with 420 participants. Four small studies with 20 to 30 children each, and two larger studies of 80 children each, showed an improvement of congestive heart failure with beta-blocker therapy. A larger study with 161 participants showed no evidence of benefit over placebo in a composite measure of heart failure outcomes. The included studies showed no significant difference in mortality or heart transplantation rates between the beta-blocker and control groups. No significant adverse events were reported with beta-blockers, apart from one episode of complete heart block. A meta-analysis of left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) data showed a very small improvement with beta-blockers. However, there were vast differences in the age, age range, and health of the participants (aetiology and severity of heart failure; heterogeneity of diagnoses and co-morbidities); there was a range of treatments across studies (choice of beta-blocker, dosing, duration of treatment); and a lack of standardised methods and outcome measures. Therefore, the primary outcomes could not be pooled in meta-analyses. There is not enough evidence to support or discourage the use of beta-blockers in children with congestive heart failure, or to propose a paediatric dosing scheme. However, the sparse data available suggested that children with congestive heart failure might benefit from beta-blocker treatment. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are also required to provide effective dosing in future trials.

This review summarises and discusses the available information on the use of beta-blockers in children with congestive heart failure. Seven studies, with a total of 420 children were included in the review. Beta-blocker therapy improved heart failure in four small studies with less than 30 participants each, and two larger studies with 80 participants each. However, the largest trial, with 161 participants, did not show a significant effect of the investigated beta-blocker over placebo. None of the studies reported any severe beta-blocker-related adverse events, apart from one child who had a heart rhythm disturbance. There were not enough data to recommend or discourage the use of beta-blockers in children with congestive heart failure. However, the current available data suggest that children with heart failure might benefit from beta-blocker treatment. Further investigations are required to establish guidelines for therapy.

10.1002/14651858.CD007037.pub3

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cochrane-simplification-train-3174

We identified two randomised controlled trials that met our inclusion criteria, and we found no new trials when we updated the searches in 2012. The first, a study with overall unclear risk of bias, examined the effects of a twice-daily exercise program of moderate load endurance exercise versus "usual activities" in 25 people with ALS. The second, a study with overall low risk of bias, examined the effects of thrice weekly moderate load and moderate intensity resistance exercises compared to usual care (stretching exercises) in 27 people with ALS. After three months, when the results of the two trials were combined (43 participants), there was a significant mean improvement in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) measure of function in favour of the exercise groups (mean difference 3.21, 95% confidence interval 0.46 to 5.96). No statistically significant differences in quality of life, fatigue or muscle strength were found. In both trials adverse effects, investigators reported no adverse effects such as increased muscle cramping, muscle soreness or fatigue The included studies were too small to determine to what extent strengthening exercises for people with ALS are beneficial, or whether exercise is harmful. There is a complete lack of randomised or quasi-randomised clinical trials examining aerobic exercise in this population. More research is needed.

This review found only two randomised studies of exercise in people with ALS. The trials compared an exercise program with usual care (stretching exercises). Combining the results from the two trials (43 participants), exercise produced a greater average improvement in function (measured using an ALS-specific measurement scale) than usual care. There were no other differences between the two groups. There were no reported adverse events due to exercise. The studies were too small to determine to what extent exercise for people with ALS is beneficial or whether exercise is harmful. We found no new trials when we updated the searches in 2012. More research is needed.

10.1002/14651858.CD005229.pub3

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cochrane-simplification-train-3175

Two RCTs were identified. One compared warfarin, aspirin and no antithrombotic therapy and the second compared warfarin with placebo in patients with idiopathic dilated cardiomyopathy. Three small prospective controlled studies of warfarin in heart failure were also identified, but they were over 50 years old with methods not considered reliable by modern standards. In both WASH 2004 and HELAS 2006, there were no significant differences in the incidence of myocardial infarction, non-fatal stroke and death between patients taking oral anticoagulation and those taking placebo. Four retrospective non-randomised cohort analyses and four observational studies of oral anticoagulation in heart failure included differing populations of heart failure patients and reported contradictory results. Based on the two major randomised trials (HELAS 2006; WASH 2004), there is no convincing evidence that oral anticoagulant therapy modifies mortality or vascular events in patients with heart failure and sinus rhythm. Although oral anticoagulation is indicated in certain groups of patients with heart failure (for example those with atrial fibrillation), the available data does not support the routine use of anticoagulation in heart failure patients who remain in sinus rhythm.

Although anticoagulants such as warfarin are of proven benefit in patients in certain subgroups of patients with heart failure, such as those with atrial fibrillation, there is little evidence that warfarin works well in the wider heart failure population. There may also be serious side effects such as bleeding (causing ulcers and haemorrhagic stroke). At present there are no data to recommend the routine use of anticoagulants to prevent thromboembolism in patients with heart failure who are in normal heart rhythm.

10.1002/14651858.CD003336.pub3

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cochrane-simplification-train-3176

This review examined 16 trials lasting four weeks to two years involving 1391 participants receiving 15 different Chinese herbal medicines in eight different comparisons. No trial reported on mortality, morbidity or costs. No serious adverse events like severe hypoglycaemia were observed. Meta-analysis of eight trials showed that those receiving Chinese herbal medicines combined with lifestyle modification were more than twice as likely to have their fasting plasma glucose levels return to normal levels (i.e. fasting plasma glucose <7.8 mmol/L and 2hr blood glucose <11.1 mmol/L) compared to lifestyle modification alone (RR 2.07; 95% confidence intervall (CI) 1.52 to 2.82). Those receiving Chinese herbs were less likely to progress to diabetes over the duration of the trial (RR 0.33; 95% CI 0.19 to 0.58). However, all trials had a considerable risk of bias and none of the specific herbal medicines comparison data was available from more than one study. Moreover, results could have been confounded by rates of natural reversion to normal glucose levels. The positive evidence in favour of Chinese herbal medicines for the treatment of IGT or IFG is constrained by the following factors: lack of trials that tested the same herbal medicine, lack of details on co-interventions, unclear methods of randomisation, poor reporting and other risks of bias.

This review examined 16 randomised controlled trials of 15 different Chinese herbal medicines. The trials lasted from four weeks to two years (average nine months) and involved altogether 1391 participants. Death from any cause, diabetic complications and economic outcomes were not investigated. No serious adverse events were reported. The available evidence suggests that Chinese herbal medicines are able to lower and normalise high blood glucose. Due to considerable distortions (bias) in the trials, further high-quality and rigorously evaluated studies are required before any conclusions can confidently be reached about the effects of Chinese herbal medicines for the treatment of impaired glucose tolerance and the delay of diabetes onset.

10.1002/14651858.CD006690.pub2

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cochrane-simplification-train-3177

Fourteen trials compared escitalopram with another SSRI and eight compared escitalopram with a newer antidepressive agent (venlafaxine, bupropion and duloxetine). Escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR 0.67, 95% CI 0.50 to 0.87). Escitalopram was also more effective than citalopram in terms of remission (OR 0.53, 95% CI 0.30 to 0.93). Significantly fewer patients allocated to escitalopram withdrew from trials compared with patients allocated to duloxetine, for discontinuation due to any cause (OR 0.62, 95% CI 0.38 to 0.99). Some statistically significant differences favouring escitalopram over other antidepressive agents for the acute phase treatment of major depression were found, in terms of efficacy (citalopram and fluoxetine) and acceptability (duloxetine). There is insufficient evidence to detect a difference between escitalopram and other antidepressants in early response to treatment (after two weeks of treatment). Cost-effectiveness information is also needed in the field of antidepressant trials. Furthermore, as with most standard systematic reviews, the findings rely on evidence from direct comparisons. The potential for overestimation of treatment effect due to sponsorship bias should also be borne in mind.

In the present review we assessed the evidence for the efficacy, acceptability and tolerability of escitalopram in comparison with all other antidepressants in the acute-phase treatment of major depression. Twenty-two randomised controlled trials (about 4000 participants) were included in the present review. Escitalopram appears to be suitable as first-line antidepressant treatment for people with moderate to severe major depression. It has been compared with only a few other antidepressants and so we are unable to say whether it is better, worse or the same as many of the other drugs used in practice. However, it did perform better than citalopram when we brought together the results of six studies in nearly two thousand patients

10.1002/14651858.CD006532.pub2

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cochrane-simplification-train-3178

We included eight studies in the review and seven in the meta-analysis. Of those seven studies, only two were judged to be at low risk of bias. Overall, no strong evidence exists that etomidate increases mortality in critically ill patients when compared to other bolus dose induction agents (odds ratio (OR) 1.17; 95% confidence interval (CI) 0.86 to 1.60, 6 studies, 772 participants, moderate quality evidence). Due to a large number of participants lost to follow-up, we performed a post hoc sensitivity analysis. This gave a similar result (OR 1.15; 95% CI 0.86 to 1.53). There was evidence that the use of etomidate in critically ill patients was associated with a positive adrenocorticotropic hormone (ACTH) stimulation test, and this difference was more pronounced at between 4 to 6 hours (OR 19.98; 95% CI 3.95 to 101.11) than after 12 hours (OR 2.37; 95% CI 1.61 to 3.47) post-dosing. Etomidate's use in critically ill patients was associated with a small increase in SOFA score, indicating a higher risk of multisystem organ failure (mean difference (MD) 0.70; 95% CI 0.01 to 1.39, 2 studies, 591 participants, high quality evidence), but this difference was not clinically meaningful. Etomidate use did not have an effect on ICU LOS (MD 1.70 days; 95% CI -2.00 to 5.40, 4 studies, 621 participants, moderate quality evidence), hospital LOS (MD 2.41 days; 95% CI -7.08 to 11.91, 3 studies, 152 participants, moderate quality evidence), duration of mechanical ventilation (MD 2.14 days; 95% CI -1.67 to 5.95, 3 studies, 621 participants, moderate quality evidence), or duration of vasopressor use (MD 1.00 day; 95% CI -0.53 to 2.53, 1 study, 469 participants). Although we have not found conclusive evidence that etomidate increases mortality or healthcare resource utilization in critically ill patients, it does seem to increase the risk of adrenal gland dysfunction and multi-organ system dysfunction by a small amount. The clinical significance of this finding is unknown. This evidence is judged to be of moderate quality, owing mainly to significant attrition bias in some of the smaller studies, and new research may influence the outcomes of our review. The applicability of these data may be limited by the fact that 42% of the patients in our review were intubated for "being comatose", a population less likely to benefit from the haemodynamic stability inherent in etomidate use, and less at risk from its potential negative downstream effects of adrenal suppression.

We looked at the evidence up to February 2013 and found 1666 studies. We included eight studies in our review and seven studies (involving 772 patients) in our meta-analysis. The studies involved people who were in an unstable condition and critically ill. They were given one dose of etomidate or another sedative agent for endotracheal intubation. We reran the search in August 2014. We will deal with any studies of interest when we update the review. No strong evidence exists to suggest that etomidate, when compared to other bolus dose induction agents, increases mortality in critically ill patients. We must be careful in interpreting this finding because only large studies would be able to show a difference in mortality. So far, no such study has been completed. Etomidate does seem to impair adrenal gland functioning. Functioning is impaired most between four and six hours after etomidate is given. Sequential Organ Failure Assessment (SOFA) scores are used to find out how badly someone’s organs are failing. Using etomidate results in worse SOFA scores but this difference is small and not clinically meaningful. The effects of impaired adrenal gland functioning and higher SOFA scores on people’s health is unknown. Using etomidate does not seem to increase the length of time someone is in hospital (including an intensive care unit), the length of time a person is connected to a mechanical ventilator (a machine to assist with breathing), or the use of vasopressors (medicines to increase blood pressure). Most of the evidence was moderate quality. This is mainly because some small studies we looked at did not check up on people adequately after they were intubated. Most people that were involved in one study were intubated because they were in a coma. These people comprise 42% of those involved in the studies we looked at. People in a coma are unlike other critically ill people because they may not benefit to the same extent from having stable blood pressure during endotracheal intubation, which etomidate provides, nor are they at high risk from impaired adrenal gland function compared to other critically ill patients, for example those with severe infection.

10.1002/14651858.CD010225.pub2

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cochrane-simplification-train-3179

We included 10 trials that involved 390 children with ASD. The age range was three to 18 years and the treatment duration ranged from four weeks to nine months. The studies were carried out in Hong Kong, mainland China and Egypt. Two trials compared needle acupuncture with sham acupuncture and found no difference in the primary outcome of core autistic features (RFRLRS total score: MD 0.09; 95% CI -0.03 to 0.21, P = 0.16), although results suggested needle acupuncture might be associated with improvement in some aspects of the secondary outcomes of communication and linguistic ability, cognitive function and global functioning. Six trials compared needle acupuncture plus conventional treatment with conventional treatment alone. The trials used different primary outcome measures and most could not demonstrate effectiveness of acupuncture in improving core autistic features in general, though one trial reported patients in the acupuncture group were more likely to have improvement on the Autism Behavior Checklist (RR 1.53; 95% CI 1.09 to 2.16, P = 0.02) and had slightly better post-treatment total scores (MD -5.53; 95% CI -10.76 to -0.31, P = 0.04). There was no evidence that acupuncture was effective for the secondary outcome of communication and linguistic ability, though there seemed to be some benefit for the secondary outcomes of cognitive function and global functioning. Two trials compared acupressure plus conventional treatment with conventional treatment alone and did not report on the primary outcome. Individual study results suggested there may be some benefit from acupressure for certain aspects of the secondary outcomes of communication and linguistic ability, cognitive function and global functioning. Four trials reported some adverse effects, though there was little quantitative information, and at times both intervention and control groups experienced them. Adverse effects noted included bleeding, crying due to fear or pain, irritability, sleep disturbance and increased hyperactivity. None of the trials reported on quality of life. There are a number of problems with the evidence base: the trials were few in number and included only children; six of the trials were at high risk of bias; they were heterogeneous in terms of participants and intervention; they were of short duration and follow-up; they reported inconsistent and imprecise results, and, due to carrying out large numbers of analyses, they were at risk of false positivity. Current evidence does not support the use of acupuncture for treatment of ASD. There is no conclusive evidence that acupuncture is effective for treatment of ASD in children and no RCTs have been carried out with adults. Further high quality trials of larger size and longer follow-up are needed.

We wanted to evaluate the effectiveness and safety of acupuncture for ASD by systematically reviewing all studies of acupuncture for ASD where people were randomly allocated to a treatment or control group (placebo, sham or no treatment), i.e. randomized controlled trials (RCTs). We searched through 15 databases, most recently in September 2010, and read over the titles and abstracts to make sure we identified everything relevant. We found10 RCTs to include in this review. These studies, which were carried out in Hong Kong, mainland China and Egypt, involved 390 children aged between three and 18 years. Two studies compared needle acupuncture with sham acupuncture and found no difference in core autistic features. Results did suggest that needle acupuncture might be associated with improvement in other areas of communication and linguistic ability, cognitive function and global functioning. Six studies compared needle acupuncture plus conventional treatment with conventional treatment alone. They used a range of tools to measure core autistic features and most could not show that acupuncture led to improvement in these. One trial did report, though, that needle acupuncture led to an improvement in scores on Autism Behavior Checklist. There was no evidence for improvement due to acupuncture on communication and linguistic ability but it might be beneficial for cognitive function and global functioning. Two studies compared acupressure plus conventional treatment with conventional treatment alone and found no difference in core autistic features, although acupressure seemed to improve some aspects of the secondary outcomes. Problems that were noted by parents of study participants included crying due to fear or pain, bleeding, sleep disturbance and increased hyperactivity. It is unclear if these were due to the acupuncture treatment. Half of the trials reported some negative effects but did not report how often or how severe these were and sometimes the problems occurred in both the treatment and control groups. None of the studies used measures of quality of life. Overall, acupuncture did not seem to be effective in improving core features of ASD but it might have improved certain developmental and functioning outcomes, at least in the short term. There are problems with assessing acupuncture due to the quality of the evidence. There were a small number of studies and they were all conducted with children. Moreover, there is a high likelihood that they may have been biased due to the methods used not being rigorous enough, the wide variety in the people and interventions in the studies, the inconsistent and imprecise reporting of results and the large number of analyses carried out, which make it more likely a significant result will be found just by chance. In conclusion, current evidence does not support the use of acupuncture for the treatment of ASD. We need high quality trials of larger size and longer follow-up as the evidence base at present has many limitations.

10.1002/14651858.CD007849.pub2

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cochrane-simplification-train-3180

For this update we included one RCT with 17,802 participants that assessed rosuvastatin compared with placebo for the prevention of VTE. The quality of the evidence was moderate because of imprecision, as the required sample size for the outcomes of this review was not achieved. Analysis showed that when compared with placebo rosuvastatin reduced the incidence of VTE (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.37 to 0.86) and deep vein thrombosis (DVT) (OR 0.45, 95% CI 0.25 to 0.79), the risk of any (fatal and non-fatal) myocardial infarction (MI) (OR 0.45, 95% CI 0.30 to 0.69), and any (fatal and non-fatal) stroke (OR 0.51, 95% CI 0.34 to 0.78). There was no difference in the incidence of pulmonary embolism (PE) (OR 0.77, 95% CI 0.41 to 1.46), fatal MI (OR 1.50, 95% CI 0.53 to 4.22), fatal stroke (OR 0.30, 95% CI 0.08 to 1.09) or death after VTE (OR 0.50, 95% CI 0.20 to 1.24). The incidence of any serious adverse events was no different between the rosuvastatin and placebo groups (OR 1.07, 95% CI 0.95 to 1.20). Available evidence showed that rosuvastatin was associated with a reduced incidence of VTE, but the evidence was limited to a single RCT and any firm conclusions and suggestions could be not drawn. Randomised controlled trials of statins (including rosuvastatin) are needed to evaluate their efficacy in the prevention of VTE.

Our review included one published randomised controlled trial, involving 17,802 participants, which reported outcomes of VTE. This trial investigated rosuvastatin compared with placebo for the primary prevention of VTE. Analysis showed that, compared with placebo, rosuvastatin reduced the incidence of VTE and DVT, the risk of any (fatal and non-fatal) myocardial infarction, and any (fatal and non-fatal) stroke. There were no differences between rosuvastatin and placebo in the incidence of pulmonary embolism, fatal myocardial infarction, fatal stroke, and death after VTE. The incidence of any serious adverse events was not different between rosuvastatin and placebo. No firm conclusions or suggestions could be made from these findings. More randomised controlled trials of statins (including rosuvastatin) are needed to evaluate the efficacy of statins in the prevention of VTE. Quality of the evidence The quality of the evidence was moderate because of imprecision, as the required sample size for the outcomes of this review was not achieved.

10.1002/14651858.CD008203.pub3

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cochrane-simplification-train-3181

Three cohort studies were included in the review. They examined 484 patients with HIV infection who received YF immunisation. Patients with HIV infection developed significantly lower concentrations of neutralising antibodies in the first year post immunisation compared to uninfected patients, though decay patterns were similar for recipients regardless of HIV infection. No study patient with HIV infection suffered serious adverse events as a result of YF vaccination. YF vaccination can produce protective levels of neutralising antibodies in HIV patients. Immunogenicity of YF vaccine is slightly less in HIV-infected patients compared to HIV-uninfected patients. No serious adverse events related to YF vaccine were observed in HIV-infected study participants. At time of immunisation, higher CD4 cell counts and lower HIV RNA levels in patients with HIV infection seem to be key determinants for development of protective titres of neutralising antibodies. The quality of the evidence for all outcomes was low to very low. YF vaccine may potentially be used safely in HIV-infected patients, although our conclusions are limited by small numbers of patients who have been reported. To assure maximum effectiveness YF vaccine should be given to HIV-infected patients after HIV replication has been suppressed.

The purpose of this review was to assess the risks and benefits of YF vaccine for people living with HIV. We found three cohort studies that addressed this question. One study in children, from a time before effective widespread use of antiretroviral drugs, found that YF vaccine worked much less well in children with HIV than it did in those without HIV. Two studies in adults found that the immune response to yellow fever vaccine was slightly lower in HIV-infected patients. No severe adverse events were observed in patients in these studies. However, because the numbers of people with HIV who have received YF vaccine is small, and serious side effects are uncommon in people without HIV infection, we are not positive about its safety. When it does need to be used, it should be given to people whose viral loads are low and CD4 counts are high.

10.1002/14651858.CD010929.pub2

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cochrane-simplification-train-3182

Only one randomised trial was identified and included in the review. The bias risk in the trial was high. The trial compared chlorambucil versus no intervention in 24 patients with primary biliary cirrhosis. Fisher's exact test did not show a significant reduction of mortality when comparing chlorambucil with no treatment (0/13 (0%) versus (2/11 (18.2%); P = 0.20). There was no significant difference regarding adverse events for chlorambucil compared with no treatment, but all patients receiving chlorambucil experienced adverse events (13/13 (100%) versus (3/11 (27%); P = 0.1). According to the authors of the trial, chlorambucil led to a significant improvement in mean serum levels of bilirubin (P < 0.05), albumin (P < 0.05), immunoglobulin M (P < 0.01), serum aspartate aminotransferase activity (P < 0.01), and hepatic inflammatory infiltrates (P < 0.01). There is not sufficient evidence to support or reject the use of chlorambucil for patients with primary biliary cirrhosis. Chlorambucil may show benefit in some unvalidated surrogate outcome measures (for example, serum bilirubin and immunoglobulin M levels). Chlorambucil is, however, connected with a number of adverse events. Bone marrow suppression should be noted in particular. Further randomised clinical trials are necessary to assess the benefits and harms of chlorambucil in this indication.

This review aimed to assess the beneficial or harmful effects of chlorambucil for primary biliary cirrhosis. The authors identified only one randomised trial, with 24 participants included. This trial compared chlorambucil with no intervention. The trial is small and at a high risk of bias, which suggests that the results may not be reliable. Meta-analyses were not possible because of the inclusion of one trial only. Fisher's exact test and t-test were used instead. Chlorambucil was not associated with significantly lower mortality when compared with no intervention. All patients on chlorambucil experienced adverse events, especially bone marrow suppression. Chlorambucil led to a significant improvement in mean serum levels of bilirubin, albumin, immunoglobulin M, serum aspartate aminotransferase activity, and hepatic inflammatory infiltrates. However, these outcomes are unvalidated surrogate outcomes for patient-relevant outcomes. This means that improvement of these biochemistry measures cannot be taken as proof of improvement of patient-relevant outcomes. It remains unclear whether chlorambucil can be supported or rejected for use in patients with primary biliary cirrhosis.

10.1002/14651858.CD008714.pub2

cochrane-simplification-train-3183

cochrane-simplification-train-3183

We included 23 trials (8 parallel-group and 15 cross-over trials), with 2675 children aged three years to 17 years. All studies compared amphetamines to placebo. Study durations ranged from 14 days to 365 days, with the majority lasting less than six months. Most studies were conducted in the United States; three studies were conducted across Europe. We judged 11 included studies to be at a high risk of bias due to insufficient blinding methods, failing to account for dropouts and exclusions from the analysis, and failing to report on all outcomes defined a priori. We judged the remaining 12 studies to be at unclear risk of bias due to inadequate reporting. Amphetamines improved total ADHD core symptom severity according to parent ratings (SMD -0.57; 95% confidence interval (CI) -0.86 to -0.27; 7 studies; 1247 children/adolescents; very low quality evidence), teacher ratings (SMD -0.55; 95% CI -0.83 to -0.27; 5 studies; 745 children/adolescents; low quality evidence), and clinician ratings (SMD -0.84; 95% CI -1.32 to -0.36; 3 studies; 813 children/adolescents; very low quality evidence). In addition, the proportion of responders as rated by the Clinical Global Impression - Improvement (CGI-I) scale was higher when children were taking amphetamines (RR 3.36; 95% CI 2.48 to 4.55; 9 studies; 2207 children/adolescents; very low quality evidence). The most commonly reported adverse events included decreased appetite, insomnia/trouble sleeping, abdominal pain, nausea/vomiting, headaches, and anxiety. Amphetamines were associated with a higher proportion of participants experiencing decreased appetite (RR 6.31; 95% CI 2.58 to 15.46; 11 studies; 2467 children/adolescents), insomnia (RR 3.80; 95% CI 2.12 to 6.83; 10 studies; 2429 children/adolescents), and abdominal pain (RR 1.44; 95% CI 1.03 to 2.00; 10 studies; 2155 children/adolescents). In addition, the proportion of children who experienced at least one adverse event was higher in the amphetamine group (RR 1.30; 95% CI 1.18 to 1.44; 6 studies; 1742 children/adolescents; low quality evidence). We performed subgroup analyses for amphetamine preparation (dexamphetamine, lisdexamphetamine, mixed amphetamine salts), amphetamine release formulation (long acting versus short acting), and funding source (industry versus non industry). Between-group differences were observed for proportion of participants experiencing decreased appetite in both the amphetamine preparation (P < 0.00001) and amphetamine release formulation (P value = 0.008) subgroups, as well as for retention in the amphetamine release formulation subgroup (P value = 0.03). Most of the included studies were at high risk of bias and the overall quality of the evidence ranged from low to very low on most outcomes. Although amphetamines seem efficacious at reducing the core symptoms of ADHD in the short term, they were associated with a number of adverse events. This review found no evidence that supports any one amphetamine derivative over another, and does not reveal any differences between long-acting and short-acting amphetamine preparations. Future trials should be longer in duration (i.e. more than 12 months), include more psychosocial outcomes (e.g. quality of life and parent stress), and be transparently reported.

As of August 2015, we identified 23 randomized controlled trials (RCTs: a type of scientific experiment in which people are randomly assigned to one of two or more treatments), which included 2675 children and adolescents between three years and 17 years of age. These studies compared amphetamines to placebo. Three different kinds of amphetamines were investigated: dexamphetamine, lisdexamphetamine and mixed amphetamine salts. The duration of the included studies ranged from 14 days to 365 days. The RCTs were conducted in the United States and Europe.Key resultsWe found that amphetamines were effective at improving the core symptoms of ADHD in the short term, but that they were also linked to a higher risk of experiencing adverse events such as sleep problems, decreased appetite, and stomach pain. We found no evidence that one kind of amphetamine was better than another, and found no difference between amphetamines that act for longer periods of time versus those that act for shorter periods of time. The quality of the included studies was low to very low because of problems in their design and large differences between the studies. Well-designed and clearly reported RCTs that are longer in duration are needed, so we may better understand the long-term effects (both positive and negative) of amphetamines.

10.1002/14651858.CD009996.pub2

cochrane-simplification-train-3184

cochrane-simplification-train-3184

We included 1 RCT and 9 CCTs (total number of participants = 770). None of the included studies reported clinical outcomes. All included studies reported on influenza immunity and adverse reactions to vaccination. In five studies, immune responses to influenza vaccine were compared in 272 children receiving chemotherapy and 166 children not receiving chemotherapy. In four studies, responses to influenza vaccine were assessed in 236 children receiving chemotherapy compared with responses in 142 healthy children. Measures used to assess immune responses included a four-fold rise in antibody titre after vaccination, development of a haemagglutination inhibition (HI) titre > 32 and pre- and post-vaccination geometric mean titres (GMTs). Immune responses in children receiving chemotherapy were consistently weaker (four-fold rise of 38% to 65%) than those in children who had completed chemotherapy (50% to 86%) and in healthy children (53% to 89%). In terms of adverse effects, 391 paediatric oncology patients received influenza vaccine, and the adverse effects described included mild local reactions and low-grade fever. No life-threatening or persistent adverse effects were reported. Paediatric oncology patients receiving chemotherapy are able to generate an immune response to the influenza vaccine, but it remains unclear whether this immune response protects them from influenza infection or its complications. We are awaiting results from well-designed RCTs addressing the clinical benefit of influenza vaccination in these patients.

This review therefore focused on the efficacy of influenza vaccination in children with cancer. We identified no studies that assessed the clinical efficacy of influenza vaccination; however, we identified one additional controlled clinical trial in our update, which brings the total to nine studies that assessed immune responses after vaccination in children with cancer. It was shown that children receiving chemotherapy mount poorer immune responses than healthy children, but that the vaccine can be safely administered. On the basis of this updated review, it is not possible to recommend or discourage influenza vaccination in children with cancer who are treated with chemotherapy. A future trial should address the clinical benefits of influenza vaccination in children with cancer who are treated with chemotherapy.

10.1002/14651858.CD006484.pub3

cochrane-simplification-train-3185

cochrane-simplification-train-3185

Eleven studies met the inclusion criteria of the review (1021 participants). Five studies on 833 participants compared inhaled mannitol with placebo but poor outcome reporting meant we could pool very little data and most outcomes were reported by only one study. One 12-month trial on 461 participants provided results for exacerbations and demonstrated an advantage for mannitol in terms of time to first exacerbation (median time to exacerbation 165 versus 124 days for mannitol and placebo respectively (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63 to 0.96, P = 0.022) and number of days on antibiotics for bronchiectasis exacerbations was significantly better with mannitol (risk ratio (RR) 0.76, 95%CI 0.58 to 1.00, P = 0.0496). However, exacerbation rate per year was not significantly different between mannitol and placebo (RR 0.92 95% CI 0.78 to 1.08). The quality of this evidence was rated as moderate. There was also an indication, from only three trials, again based on moderate quality evidence, that mannitol improves health-related quality of life (mean difference (MD) -2.05; 95% CI -3.69 to -0.40). An analysis of adverse events data, also based on moderate quality evidence, revealed no difference between mannitol and placebo (OR 0.96; 95% CI 0.61 to 1.51). Two additional small trials on 25 participants compared mannitol versus no treatment and the data from these studies were inconclusive. Four studies (combined N = 113) compared hypertonic saline versus isotonic saline. On most outcomes there were conflicting results and the opportunities for the statistical aggregation of data from studies was very limited. It is not possible to draw robust conclusions for this comparison and judgments should be reserved until further data are available. There is an indication from a single, large, unpublished study that inhaled mannitol increases time to first exacerbation in patients with bronchiectasis. In patients with near normal lung function, spirometry does not change dramatically with mannitol and adverse events are not more frequent than placebo. Further investigation is required in a patient population with impaired lung function. It is not possible to draw firm conclusions regarding the effect of nebulised hypertonic saline due to significant differences in the methodology, patient groups, and findings amongst the limited data available. The data suggest that it is unlikely to have benefit over isotonic saline in patients with milder disease, and hence future studies should test its use in those with more severe disease

We found 11 randomised controlled trials on 1021 participants that compared inhaled hyperosmolar agents versus no mucolytic treatment. Five studies compared inhaled mannitol versus placebo (with a total of 883 participants) and two very small studies (with a total of just 25 participants) compared inhaled mannitol with no treatment. We also found four studies (with a total of 113 participants) that compared hypertonic saline with isotonic (normal) saline. For the comparison between mannitol and placebo only one study (a 12-month trial with 461 participants) provided information on the number of people who had an exacerbation (or flare up) over the course of a year. This study showed that people who were treated with mannitol had 8% fewer exacerbations on average compared with placebo. Overall, we felt the quality of this evidence was moderate and new trials would be likely to change either how effective we think the treatment is or how confident we are about it. Three trials assessed the effect of mannitol on health-related quality of life, and again the quality of the evidence was rated as moderate. An analysis of adverse events data, also based on moderate quality evidence, revealed no difference between mannitol and placebo The trials comparing hypertonic saline with isotonic saline had conflicting results for most of the outcomes of interest. Because we were unable to combine the data, it is not possible to draw robust conclusions for this comparison and judgments should be reserved until further data are available. Our analysis of adverse events between hypertonic saline versus isotonic saline showed no significant difference however this was based on a single study and the quality of the evidence was moderate. Details of how the patients in the trials were allocated to receive mannitol or not was clearly described in only one of the studies, and similarly only one of the hypertonic saline versus isotonic saline studies provided this information. The general lack of information on this point was considered carefully in the review in relation to our level of uncertainty in interpreting the results. Taking this into account, the quality of evidence was generally regarded as moderate both for the mannitol and hypertonic saline studies.

10.1002/14651858.CD002996.pub3

cochrane-simplification-train-3186

cochrane-simplification-train-3186

Nine studies involving 804 participants (IM = 402 participants; oral = 402 participants) met our review inclusion criteria. Four studies enrolled children (n = 245 participants), while five studies enrolled adults (n = 559 participants). All of the studies recruited participants presenting to an ED, except one study which recruited participants attending a primary care clinic. All of the paediatric studies compared intramuscular (IM) dexamethasone to oral prednisone/prednisolone. In the adult studies, the IM corticosteroid provided ranged from methylprednisolone, betamethasone, dexamethasone, or triamcinolone, while the regimen of oral corticosteroids provided consisted of prednisone, methylprednisolone, or dexamethasone. Only five studies were placebo controlled. For the purposes of this review, we did not take corticosteroid dose equivalency into account in the analysis. The most common co-intervention provided to participants during the acute care visit included short-acting beta₂-agonists (SABA), methylxanthines, and ipratropium bromide. In some instances, some studies reported providing some participants with supplemental oral or IV corticosteroids during their stay in the ED. Co-interventions provided to participants at discharge consisted primarily of SABA, methylxanthine, long-acting beta₂-agonists (LABA), and ipratropium bromide. The risk of bias of the included studies ranged from unclear to high across various domains. The primary outcome of interest was relapse to additional care defined as an unscheduled visit to a health practitioner for worsening asthma symptoms, or requiring subsequent treatment with corticosteroids which may have occurred at any time point after discharge from the ED. We found intramuscular and oral corticosteroids to be similarly effective in reducing the risk for relapse (RR 0.94, 95% CI 0.72 to 1.24; 9 studies, 804 participants; I² = 0%; low-quality evidence). We found no subgroup differences in relapse rates between paediatric and adult participants (P = 0.71), relapse occurring within or after 10 days post-discharge (P = 0.22), or participants with mild/moderate or severe exacerbations (P = 0.35). While we found no statistical difference between participants receiving IM versus oral corticosteroids regarding the risk for adverse events (RR 0.83, 95% CI 0.64 to 1.07; 5 studies, 404 participants; I² = 0%; moderate-quality evidence), an estimated 50 fewer patients per 1000 receiving IM corticosteroids reported experiencing adverse events (95% from 106 fewer to 21 more). We found inconsistent reporting of specific adverse events across the studies. There were no differences in the frequency of specific adverse events including nausea and vomiting, pain, swelling, redness, insomnia, or personality changes. We did not seek additional adverse events data. Participants receiving IM corticosteroids or oral corticosteroids both reported decreases in peak expiratory flow (MD −7.78 L/min, 95% CI −38.83 L/min to 23.28 L/min; 4 studies, 272 participants; I² = 33%; moderate-quality evidence), similar symptom persistence (RR 0.41, 95% CI 0.14 to 1.20; 3 studies, 80 participants; I² = 44%; low-quality evidence), and 24-hour beta-agonist use (RR 0.54, 95% CI 0.21 to 1.37; 2 studies, 48 participants; I² = 0%; low-quality evidence). There is insufficient evidence to identify whether IM corticosteroids are more effective in reducing relapse compared to oral corticosteroids among children or adults discharged from an ED or equivalent acute care setting for acute asthma. While we found no statistical differences, patients receiving IM corticosteroids reported fewer adverse events. Additional studies comparing the effectiveness of IM versus oral corticosteroids could provide further evidence clarity. Furthermore, there is a need for studies comparing different IM corticosteroids (e.g. IM dexamethasone versus IM methylprednisone) and different oral corticosteroids (e.g. oral dexamethasone versus oral prednisone), with consideration for dosing and pharmacokinetic properties, to better identify the optimal IM or oral corticosteroid regimens to improve patient outcomes. Other factors, such as patient preference and potential issues with adherence, may dictate practitioner prescribing.

We included nine studies that compared the effectiveness of an intramuscular injection compared to corticosteroid tablets in patients presenting to an ED or similar acute care setting with acute asthma. The studies enrolled a total of 804 paediatric and adult participants. Most studies investigated the injectable corticosteroids dexamethasone or methylprednisolone compared to the corticosteroid tablets prednisone or methylprednisolone. Most studies did not report sources of funding (5 studies). Two studies received funding from general health research grants. One study was funded by a pharmaceutical company (Pfizer); however, reported that the company was not involved in any aspect of the study or manuscript preparation. One study reported being unfunded. Intramuscular injections of corticosteroids appear to be as effective as corticosteroids tablets in preventing relapse. We did not find any differences in the risk of relapse between participants receiving intramuscular injections and corticosteroid tablets. Although not all studies reported adverse effects in their study groups, we found no differences between participants receiving intramuscular injections and corticosteroid tablets. At follow-up, we found no differences in pulmonary function tests between participants who had received an intramuscular injection or corticosteroid tablets. In the studies that reported symptom scores and duration, we did not identify any differences between participants receiving corticosteroids by injection or by tablets. The quality of the evidence regarding the effectiveness of intramuscular injections of corticosteroids in improving health outcomes ranged from low to moderate. We had only moderate confidence about the estimated effects of intramuscular steroids on hospital admissions, improvement in respiratory function and relapse because of the risk of bias among included studies.

10.1002/14651858.CD012629.pub2

cochrane-simplification-train-3187

cochrane-simplification-train-3187

For the purpose of this review, STI strategies were classified either as a timed-cycle STI strategy or a CD4-guided STI strategy. In timed-cycle STI strategy, a predetermined period of fixed duration (e.g. one week, one month) off ART was attempted followed by resumption of ART, while closely monitoring changes in CD4 levels and viral load levels. Predetermined criteria for interruption and resumption were laid out in this strategy. Timed-cycle STI fell out of favor due to reports of development of resistance in many studies. Moreover, there were no significant immunological and virological benefits, and no reduction in toxicities, reported in these studies. In CD4-guided STI strategy, ART was interrupted for variable durations guided by CD4 levels. Participants with high nadir CD4 levels qualified for this approach. A reduction in costs of ART, a reduction in mutation, and a better tolerability of this CD4-guided STI strategy was reported. However, concerns about long-term safety of this strategy on immunological, virological, and clinical outcomes were also raised. Timed-cycle STI have not been proven to be safe in the short term. Although CD4-guided STI strategy has reported favorable outcomes in the short term, the long-term safety, efficacy and tolerability of this strategy has not been fully investigated. Based on the studies we reviewed, the evidence to support the use of timed-cycle STI and CD4-guided STI cycles as a standard of care in the management of chronic suppressed HIV infection is inconclusive.

This systematic review aims to synthesize the evidence for use of STI as an alternative strategy in the management of chronic suppressed HIV infection. STI is a planned, experimental intervention, and the evidence from 33 available intervention trials has been summarized. Currently, several large STI trials are underway, investigating long-term effects of STI strategies. Their results will be available in a few years. Based on the studies we reviewed, we find that there is insufficient evidence to support the use of STI as a standard of care in the management of chronic suppressed HIV infection.

10.1002/14651858.CD005482

cochrane-simplification-train-3188

cochrane-simplification-train-3188

Overall, 102 studies have been included in this review. Interventions explored were: 'positive distracters', to include aromas (two studies), audiovisual distractions (five studies), decoration (one study), and music (85 studies); interventions to reduce environmental stressors through physical changes, to include air quality (three studies), bedroom type (one study), flooring (two studies), furniture and furnishings (one study), lighting (one study), and temperature (one study); and multifaceted interventions (two studies). We did not find any studies meeting the inclusion criteria to evaluate: art, access to nature for example, through hospital gardens, atriums, flowers, and plants, ceilings, interventions to reduce hospital noise, patient controls, technologies, way-finding aids, or the provision of windows. Overall, it appears that music may improve patient-reported outcomes such as anxiety; however, the benefit for physiological outcomes, and medication consumption has less support. There are few studies to support or refute the implementation of physical changes, and except for air quality, the included studies demonstrated that physical changes to the hospital environment at least did no harm. Music may improve patient-reported outcomes in certain circumstances, so support for this relatively inexpensive intervention may be justified. For some environmental interventions, well designed research studies have yet to take place.

The review identified 102 relevant studies, 85 of which were on the use of music in hospital. Other environmental aspects considered were: aromas (two studies), audiovisual distractions (five studies), decoration (one study), air quality (three studies), bedroom type (one study), flooring (two studies), furniture and furnishings (one study), lighting (one study), temperature (one study), and multiple design changes (two studies). No studies meeting the inclusion criteria were found to evaluate: art, access to nature for example through hospital gardens, atriums, flowers, and plants, ceilings, interventions to reduce hospital noise, patient controls, technologies, way-finding aids, or the provision of windows. Overall, it appears that music in hospital may help improve patient-reported outcomes such as anxiety; however, there is less evidence to support the use of music for physiological outcomes (such as reducing heart rate and blood pressure) and for reducing the use of medications. For other aspects of hospital environments, there are not very many well designed studies to help with making evidence-based design decisions. The studies that have been included in this review show that physical changes made to 'improve' the hospital environment on the whole do no harm.

10.1002/14651858.CD005315.pub2

cochrane-simplification-train-3189

cochrane-simplification-train-3189

Twenty trials were included. These involved a total of 2562 mostly young active adult males. All trials had methodological weaknesses. Specifically, concealment of allocation was confirmed in only one trial. Data for pooling individual outcomes were only available for a maximum of 12 trials and under 60% of participants. The findings of statistically significant differences in favour of the surgical treatment group for the four primary outcomes (non-return to pre-injury level of sports; ankle sprain recurrence; long-term pain; subjective or functional instability) when using the fixed-effect model were not robust when using the random-effects model, nor on the removal of one low quality (quasi-randomised) trial that had more extreme results. A corresponding drop in the I² statistics showed the remaining trials to be more homogeneous. The functional implications of the statistically significantly higher incidence of objective instability in conservatively treated trial participants are uncertain. There was some limited evidence for longer recovery times, and higher incidences of ankle stiffness, impaired ankle mobility and complications in the surgical treatment group. There is insufficient evidence available from randomised controlled trials to determine the relative effectiveness of surgical and conservative treatment for acute injuries of the lateral ligament complex of the ankle. High quality randomised controlled trials of primary surgical repair versus the best available conservative treatment for well-defined injuries are required.

Twenty trials were included. These involved a total of 2562 mostly young active adult males. All trials had methodological flaws that could have affected their results. Data for pooling individual outcomes were only available for a maximum of 12 trials. Additionally, there was one low quality and potentially biased trial with very positive results in favour of surgery. When this trial was excluded, the findings of better results for surgery in terms of return to sports, re-injury, persistent pain and ankle instability as judged by the patient were no longer statistically significant. Thus, the trend to a better result from surgery remains unproven. Ankle stability, as judged by the clinician using standard tests, was better after surgery than with conservative treatment. Conversely, there was some limited evidence for longer recovery times, and higher incidences of ankle stiffness, impaired ankle mobility and complications in the surgical treatment group. We concluded that there was not enough evidence from randomised controlled trials to say whether surgery gives a better result than conservative treatment for acute ankle sprain in adults.

10.1002/14651858.CD000380.pub2

cochrane-simplification-train-3190

cochrane-simplification-train-3190

The 2011 update search yielded three further randomised controlled trials. The review currently includes 34 studies with 2657 participants. Most studies were characterised by a small sample size, short duration, and incomplete outcome data reporting. Benzodiazepine monotherapy is compared with placebo in eight trials. The proportion of participants with no clinically important response did not significantly differ between those given benzodiazepines or placebo (N = 382, 6 RCTs, RR 0.67 CI 0.44 to 1.02). The results from the various rating scales applied to assess global and mental state were inconsistent. Fourteen studies examined benzodiazepine monotherapy in comparison with antipsychotic monotherapy. Clinically important treatment response assessment revealed no statistically significant difference between the study groups (30 minutes: N = 44, 1 RCT, RR 0.91 CI 0.58 to 1.43; 60 minutes: N = 44,1 RCT, RR 0.61 CI 0.20 to 1.86; 12 hours: N = 66, 1 RCT, RR 0.75 CI 0.44 to 1.30; pooled short-term studies: N = 112, 2 RCTs, RR 1.48 CI 0.64 to 3.46). Desired sedation occurred significantly more often among participants in the benzodiazepine group than in the antipsychotic group at 20 and 40 minutes. No significant between-group differences could be identified for global and mental state or occurrence of adverse effects. Twenty trials compared benzodiazepine augmentation of antipsychotics with antipsychotic monotherapy. Referring to clinically important response, statistically significant improvement could be demonstrated only for the first 30 minutes of augmentation treatment (30 minutes: 1 RCT, N = 45, RR 0.38 CI 0.18 to 0.80; 60 minutes: N = 45,1 RCT, RR 0.07 CI 0.00 to 1.13; 12 hour: N = 67,1 RCT, RR 0.85 CI 0.51 to 1.41; pooled short-term studies: N = 511, 6 RCTs, RR 0.87 CI 0.49 to 1.54). Analyses of the global and mental state yielded no between-group differences except for desired sedation at 30 as well as 60 minutes (30 minutes: N = 45, 1 RCT, RR 2.25 CI 1.18 to 4.30; 60 minutes: N = 45, 1 RCT, RR 1.39 CI 1.06 to 1.83). There is currently no convincing evidence to confirm or refute the practise of administering benzodiazepines as monotherapy or in combination with antipsychotics for the pharmacological treatment of schizophrenia and schizophrenia-like psychosis. Low-quality evidence suggests that benzodiazepines are effective for very short-term sedation and could be considered for calming acutely agitated people with schizophrenia. Measured by the overall attrition rate, the acceptability of benzodiazepine treatment appears to be adequate. Adverse effects were generally poorly reported. High-quality future research projects with large sample sizes are required to clarify the evidence of benzodiazepine treatment in schizophrenia, especially regarding long-term augmentation strategies.

This review found 34 studies with 2657 people. It compared benzodiazepines when used alone as the only medication or when used in combination with another drug for people with schizophrenia. Information from the 34 studies was generally poor, incomplete and badly reported. The 34 studies were of short duration and were small in size. The review suggests that there is little evidence to support the use of benzodiazepines either alone or in combination. However, benzodiazepines do have sedative properties that can calm people down and help them become less agitated for short periods of time. More research, particularly involving benzodiazepines as add-on treatment used in combination with traditional antipsychotic drugs, is required. This plain language summary has been written by Benjamin Gray, Service User and Service User Expert, Rethink Mental Illness, Email: [email protected]

10.1002/14651858.CD006391.pub2

cochrane-simplification-train-3191

cochrane-simplification-train-3191

We included one quasi-RCT (with data from 73 women) in the review. The trial, which was conducted in a public hospital in Brazil, compared oral chloramphenicol 500 mg four times daily for 72 hours after episiotomy repair (N = 34) and no treatment (N = 39). We assessed most of the domains at high risk of bias because women were randomised according to even and odd numbers, allocation concealment was based on protocol number, there was no treatment or placebo administered in the control group, we were unclear about the blinding of outcome assessments, and outcomes were incompletely reported. We considered the other domains to be at low risk of bias. We downgraded the quality of the evidence for very serious design limitations (related to lack of random sequence generation, allocation concealment, and blinding) and imprecision of effect estimates (small sample sizes and wide confidence intervals (CI) of effect estimates). We found very low-quality evidence, from one trial of 73 women, that there was no clear indication that prophylactic antibiotics reduced the incidence of episiotomy wound dehiscence with infection (risk ratio (RR) 0.13, 95% CI 0.01 to 2.28), or without infection (RR 0.82, 95% CI 0.29 to 2.34). No cases of other puerperal infections (e.g. endometritis) were reported in either the antibiotic or control group. The trial did not report on any of the secondary outcomes of interest for this review, including severe maternal infectious morbidity, discomfort or pain at the episiotomy wound site, sexual function postpartum, adverse effects of antibiotics, costs of care, women's satisfaction with care, and individual antimicrobial resistance. There was insufficient evidence to assess the clinical benefits or harms of routine antibiotic prophylaxis for episiotomy repair after normal birth. The only trial included in this review had several methodological limitations, with very serious limitations in design, and imprecision of effect estimates. In addition, the trial tested an antibiotic with limited application in current clinical practice. There is a need for a careful and rigorous assessment of the comparative benefits and harms of prophylactic antibiotics on infection morbidity after episiotomy, in well-designed randomised controlled trials, using common antibiotics and regimens in current obstetric practice.

The review assessed whether routine use of antibiotics at the time of an episiotomy prevented infection for women with an uncomplicated vaginal birth, compared with either placebo, or no antibiotics. We searched for evidence (24 July 2017) from randomised controlled trials in the medical literature. We only identified one small trial that was conducted in a public hospital in Brazil and provided very low-quality data from 73 women. The trial showed no clear difference between the groups, with or without antibiotics, of the number of women who experienced infection or breakdown of the episiotomy wound. No women developed infection of the lining of the uterus in either group. The trial did not report on any other outcomes of interest for this review. The current evidence on the impact of prophylactic antibiotics for prevention of infection after episiotomy is from one small trial with design limitations. The relatively low incidence of episiotomy infection, when infection control measures are well observed, raises questions about the potential added benefit of antibiotic prophylaxis, particularly when balanced against the risk of antibiotic-related side effects for the mother, and her baby, and in terms of emerging antibiotic resistance. There is a need for a careful and rigorous assessment of the comparative benefits and harms of prophylactic antibiotics on infection morbidity after episiotomy, in well-designed randomised controlled trials, using common antibiotics and regimens in current obstetric practice.

10.1002/14651858.CD012136.pub2

cochrane-simplification-train-3192

cochrane-simplification-train-3192

The search update identified 273 new references, of which none fulfilled our inclusion criteria. We included four studies (643 participants) in this updated review, which were all included in the previous (2004) update. The quality of the evidence was very low for all outcomes. As data were too clinically heterogeneous to be pooled, we described individual trial results. The results indicate that there is very low quality evidence that back schools are no more effective than a placebo (or sham or attention control) or another treatment (physical therapies, myofascial therapy, joint manipulations, advice) on pain, disability, work status and adverse events at short-term, intermediate-term and long-term follow-up. There is very low quality evidence that shows a statistically significant difference between back schools and a placebo (or sham or attention control) for return to work at short-term follow-up in favour of back school. Very low quality evidence suggests that back school added to a back care programme is more effective than a back care programme alone for disability at short-term follow-up. Very low quality evidence also indicates that there is no difference in terms of adverse events between back school and myofascial therapy, joint manipulation and combined myofascial therapy and joint manipulation. It is uncertain if back schools are effective for acute and subacute non-specific LBP as there is only very low quality evidence available. While large well-conducted studies will likely provide more conclusive findings, back schools are not widely used interventions for acute and subacute LBP and further research into this area may not be a priority.

We included four studies in this review, which we included in the previous version of this review, which means that we did not identify any new relevant studies for inclusion in this update. The treatment comparisons were too dissimilar to be pooled and half of the studies were at high risk of bias. The quality of the evidence was very low for all outcomes. One study compared back school with a placebo (sham treatment) and found no difference between groups for pain at short-term follow-up. Concerning work status, people in the back school group had a significantly shorter duration of sick-leave than people in the placebo group at short-term follow-up. Four studies compared back school with another treatment (physical therapies, myofascial therapy, joint manipulations, advice). Overall, there were no differences between groups for pain, disability, work status and adverse events at any time of follow-up. Only one study showed that back school added to a back care programme was more effective than back school alone for disability at short-term follow-up. The included studies are insufficient to clearly answer our question and the inclusion of other well-designed studies is very likely to change the conclusions. However, back schools do not seem to be a treatment widely used nowadays for people with acute and subacute non-specific low-back pain and are not endorsed by guidelines. The quality of the evidence was very low for all the outcomes according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. This was due to poor study designs and imprecision in the results.

10.1002/14651858.CD008325.pub2

cochrane-simplification-train-3193

cochrane-simplification-train-3193

We included in the review 37 studies representing 6128 adult and adolescent participants (most with mild to moderate asthma). Investigators in these studies used three leukotriene receptor antagonists (LTRAs): montelukast (n = 24), zafirlukast (n = 11) and pranlukast (n = 2); studies lasted from four weeks to five years. Anti-leukotrienes and ICS versus same dose of ICS Of 16 eligible studies, 10 studies, representing 2364 adults and adolescents, contributed data. Anti-leukotriene agents given as adjunct therapy to ICS reduced by half the number of participants with exacerbations requiring oral corticosteroids (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.29 to 0.86; 815 participants; four studies; moderate quality); this is equivalent to a number needed to treat for additional beneficial outcome (NNTB) over six to 16 weeks of 22 (95% CI 16 to 75). Only one trial including 368 participants reported mortality and serious adverse events, but events were too infrequent for researchers to draw a conclusion. Four trials reported all adverse events, and the pooled result suggested little difference between groups (RR 1.06, 95% CI 0.92 to 1.22; 1024 participants; three studies; moderate quality). Investigators noted between-group differences favouring the addition of anti-leukotrienes for morning peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1), asthma symptoms and night-time awakenings, but not for reduction in β2-agonist use or evening PEFR. Anti-leukotrienes and ICS versus higher dose of ICS Of 15 eligible studies, eight studies, representing 2008 adults and adolescents, contributed data. Results showed no statistically significant difference in the number of participants with exacerbations requiring oral corticosteroids (RR 0.90, 95% CI 0.58 to 1.39; 1779 participants; four studies; moderate quality) nor in all adverse events between groups (RR 0.96, 95% CI 0.89 to 1.03; 1899 participants; six studies; low quality). Three trials reported no deaths among 834 participants. Results showed no statistically significant differences in lung function tests including morning PEFR and FEV1 nor in asthma control measures including use of rescue β2-agonists or asthma symptom scores. Anti-leukotrienes and ICS versus tapering dose of ICS Seven studies, representing 1150 adults and adolescents, evaluated the combination of anti-leukotrienes and tapering-dose of ICS compared with tapering-dose of ICS alone and contributed data. Investigators observed no statistically significant difference in % change from baseline ICS dose (mean difference (MD) -3.05, 95% CI -8.13 to 2.03; 930 participants; four studies; moderate quality), number of participants with exacerbations requiring oral corticosteroids (RR 0.46, 95% CI 0.20 to 1.04; 542 participants; five studies; low quality) or all adverse events (RR 0.95, 95% CI 0.83 to 1.08; 1100 participants; six studies; moderate quality). Serious adverse events occurred more frequently among those taking anti-leukotrienes plus tapering ICS than in those taking tapering doses of ICS alone (RR 2.44, 95% CI 1.52 to 3.92; 621 participants; two studies; moderate quality), but deaths were too infrequent for researchers to draw any conclusions about mortality. Data showed no improvement in lung function nor in asthma control measures. For adolescents and adults with persistent asthma, with suboptimal asthma control with daily use of ICS, the addition of anti-leukotrienes is beneficial for reducing moderate and severe asthma exacerbations and for improving lung function and asthma control compared with the same dose of ICS. We cannot be certain that the addition of anti-leukotrienes is superior, inferior or equivalent to a higher dose of ICS. Scarce available evidence does not support anti-leukotrienes as an ICS sparing agent, and use of LTRAs was not associated with increased risk of withdrawals or adverse effects, with the exception of an increase in serious adverse events when the ICS dose was tapered. Information was insufficient for assessment of mortality.

We found 37 studies (representing 6128 adults and adolescents). The people in these trials had mild to moderate asthma. Most (24) studies used the LTRA called montelukast, 11 studies used zafirlukast and only two studies used pranlukast. We divided all studies into three categories to help us make sense of the evidence. • Anti-leukotrienes and ICS versus same dose of ICS: Ten studies (representing 2364 adults and adolescents) contributed data for analysis. Anti-leukotrienes given with ICS reduced by half the number of patients with exacerbations requiring oral steroids (from 9% to 5% over three months), but we are unsure about effects of this treatment on quality of life or serious side effects. Anti-leukotrienes given with ICS improved lung function and asthma control measures. • Anti-leukotrienes and ICS versus higher dose of ICS: Eight studies (representing 2008 adults and adolescents) contributed data for analysis. Results showed no reduction in the number of patients with exacerbations requiring oral steroids and no difference in quality of life nor in side effects. Data showed no improvement in lung function nor in asthma control measures. • Anti-leukotrienes and gradual reduction of ICS dose versus gradual reduction of ICS dose alone: Seven studies (representing 1150 adults and adolescents) evaluated anti-leukotrienes given with a gradually reduced dose of ICS compared with a gradually reduced dose of ICS without use of anti-leukotriene agents. This approach was not beneficial for % reduction in the amount of ICS over time. More people receiving anti-leukotriene and ICS compared with ICS alone experienced increased serious side effects and showed no improvement in lung function nor in asthma control measures. For adolescents and adults with asthma not controlled with daily low-dose ICS, adding anti-leukotriene agents to ICS reduced by half the number of patients with asthma exacerbations requiring an oral corticosteroid. Anti-leukotrienes and ICS also improved lung function and asthma control. However, we are not sure whether the combination of anti-leukotrienes and ICS is superior to higher-dose ICS. Limited available evidence does not support use of anti-leukotrienes as a way to decrease ICS dose. In general, addition of anti-leukotrienes to ICS therapy was not associated with increased side effects, if the dose of ICS was maintained. Our confidence in the evidence was moderate or low for most outcomes.

10.1002/14651858.CD010347.pub2

cochrane-simplification-train-3194

cochrane-simplification-train-3194

Three trials met the inclusion criteria. Two trials (n = 20,451) assessed the effect of TXA. The larger of these (CRASH-2, n = 20,211) was conducted in 40 countries and included patients with a variety of types of trauma; the other (n = 240) restricted itself to those with traumatic brain injury (TBI) only. One trial (n = 77) assessed aprotinin in participants with major bony trauma and shock. The pooled data show that antifibrinolytic drugs reduce the risk of death from any cause by 10% (RR 0.90, 95% CI 0.85 to 0.96; P = 0.002) (quality of evidence: high). This estimate is based primarily on data from the CRASH-2 trial of TXA, which contributed 99% of the data. There is no evidence that antifibrinolytics have an effect on the risk of vascular occlusive events (quality of evidence: moderate), need for surgical intervention or receipt of blood transfusion (quality of evidence: high). There is no evidence for a difference in the effect by type of antifibrinolytic (TXA versus aprotinin) however, as the pooled analyses were based predominantly on trial data concerning the effects of TXA, the results can only be confidently applied to the effects of TXA. The effects of aprotinin in this patient group remain uncertain. There is some evidence from pooling data from one study (n = 240) and a subset of data from CRASH-2 (n = 270) in patients with TBI which suggest that TXA may reduce mortality although the estimates are imprecise, the quality of evidence is low, and uncertainty remains. Stronger evidence exists for the possibility of TXA reducing intracranial bleeding in this population. TXA safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events.  TXA should be given as early as possible and within three hours of injury, as further analysis of the CRASH-2 trial showed that treatment later than this is unlikely to be effective and may be harmful. Although there is some promising evidence for the effect of TXA in patients with TBI, substantial uncertainty remains. Two ongoing trials being conducted in patients with isolated TBI should resolve these remaining uncertainties.

Two trials assessed the effect of TXA in patients aged 16 and over. The largest (n = 20,211) involved patients suffering from a variety of types of trauma, and the other (n = 240) only those who had suffered traumatic brain injury. Results The trial assessing the effect of aprotinin was too small to provide reliable data. Results for TXA suggest that, when given early, TXA reduces the risk of death compared to patients who do not receive TXA without increasing the risk of side effects. However, there is still some uncertainty about the effect of TXA in patients who have bleeding inside the brain from a head injury, but are not bleeding from injuries elsewhere. It is possible that the effects of TXA are different in this specific patient group. We have found two ongoing trials that are trying to answer this question. The authors of this review conclude that TXA can safely reduce death in trauma patients with bleeding and should be given as soon as possible after injury. However, they cannot conclude whether or not TXA is also effective in patients with traumatic brain injury with no other trauma, until the ongoing trials have been completed. Quality of the evidence Evidence for important outcomes including mortality, need for further surgery and blood transfusion, came from high-quality evidence, meaning we have confidence in the findings. There was moderate-quality evidence for important adverse events including vascular occlusive events (including heart attacks, deep vein thrombosis, stroke and pulmonary embolism).

10.1002/14651858.CD004896.pub4

cochrane-simplification-train-3195

cochrane-simplification-train-3195

We included 13 trials (1135 participants, 1923 eyes) in this review. Nine of these trials randomised eyes to treatment, two trials randomised people to treatment and treated both eyes, and two trials randomised people to treatment and treated one eye. None of the paired trials reported an appropriate paired analysis. We considered the overall quality of evidence to be low for most outcomes because of the risk of bias in the included trials. There was evidence that LASIK gives a faster visual recovery than PRK and is a less painful technique. Results at one year after surgery were comparable: most analyses favoured LASIK but they were not statistically significant. LASIK gives a faster visual recovery and is a less painful technique than PRK. The two techniques appear to give similar outcomes one year after surgery. Further trials using contemporary techniques are required to determine whether LASIK and PRK as currently practised are equally safe. Randomising eyes to treatment is an efficient design, but only if analysed properly. In future trials, more efforts could be made to mask the assessment of outcome.

This review analyses the results from 13 clinical trials where 1923 eyes of 1135 participants were randomly treated with either LASIK or PRK. We considered the overall quality of evidence from these studies to be low. There was some evidence that LASIK gives a faster visual recovery than PRK, and is a less painful technique, although visual results one year after surgery were comparable. Surgical techniques are improving all the time and further trials are needed to see whether LASIK and PRK, as currently practised, are equally safe.

10.1002/14651858.CD005135.pub3

cochrane-simplification-train-3196

cochrane-simplification-train-3196

We included 14 studies with 2966 randomised men across five comparisons. The studies recruited from urology outpatients clinics and defined nocturia as two or more voids per night. The average age of study participants ranged between 57 and 74 years. Desmopressin versus placebo: based on short-term follow-up (up to three months), desmopressin may result in a small, possibly unimportant effect on the number of nocturnal voids (mean difference (MD) -0.61, 95% confidence interval (CI) -0.96 to -0.27; low-quality evidence). We are uncertain about the effect of desmopressin on major adverse events at short-term follow-up (risk ratio (RR) 0.97, 95% CI 0.10 to 9.03; very low-quality evidence). For intermediate-term follow-up (three to 12 months), desmopressin may reduce the number of nocturnal voids in an appreciable number of men (MD -0.85, 95% CI -1.17 to -0.53; low-quality evidence). There was one major adverse event in the desmopressin group at intermediate-term follow-up in one trial of 115 men (RR 3.05, 95% CI 0.13 to 73.39 for both outcomes; low-quality evidence). We found no evidence on quality of life. Subgroup analyses suggest a larger effect on nocturnal voiding with oral, higher-dose formulations of desmopressin and in men with documented nocturnal polyuria. Desmopressin versus behaviour modification: there were no data regarding the effect on the number of nocturnal voids, quality of life, or major adverse events. Desmopressin versus alpha-blocker: based on short-term follow-up in one small trial, desmopressin likely has a similar effect on the number of nocturnal voids (MD 0.30, 95% CI -0.20 to 0.80; moderate-quality evidence) and quality of life measured on the International Prostate Symptom Score (IPSS) scale (MD 0.00, 95% CI -0.35 to 0.35; moderate-quality evidence). There were no major adverse events in either group. Desmopressin plus alpha-blocker versus alpha-blocker alone: based on short-term follow-up, combination therapy likely results in a small, unimportant effect on the number of nocturnal voids (MD -0.47, 95% CI -0.73 to -0.21; moderate-quality evidence) and quality of life (MD -0.29, 95% CI -0.51 to -0.07; moderate-quality evidence). The risk of major adverse events may be similar (0.5% versus 0.3%; RR 0.30, 95% CI 0.01 to 7.32; low-quality evidence). Desmopressin plus alpha-blocker versus alpha-blocker plus an anticholinergic: based on short-term follow-up, combination therapy likely results in little or no difference in the number of nocturnal voids (MD -0.43, 95% CI -0.97 to 0.11; moderate-quality evidence). We found no evidence on quality of life or sleep duration. There were no major adverse events in either study group. Desmopressin may reduce the number of nocturnal voids by a small amount compared to placebo in intermediate-term (three to 12 months) follow-up without increasing major adverse events. We found insufficient evidence to determine the effects of desmopressin when compared with behaviour modification. The effect on the number of nocturnal voids in the short term is likely to be similar to that of alpha-blockers, with very infrequent major adverse events. There appears to be little added benefit in the combined use of desmopressin with an alpha-blocker. The findings of this review were limited by short-term follow-up, study limitations, and imprecision.

The search is up-to-date to 1 August 2017. We identified 14 clinical trials including 2966 men. We compared desmopressin alone or in combination with other medicines used for urinary problems (such as alpha-blockers or anticholinergics) against placebo (pretend treatment), behaviour changes, or medicines used for urinary problems alone or in combination. Most of the included studies enrolled only older men. Treatment with desmopressin for three to 12 months may reduce how often men urinate at night in a small number of men compared to placebo. Serious side effects were not increased. We do not know how the use of desmopressin compares to changes in behaviour. The effect of desmopressin on how often men urinate at night is likely to be similar to that of alpha-blockers when given for up to three months (i.e. short-term treatment) without major side effects. Adding desmopressin to an alpha-blocker seems to work little better than an alpha-blocker alone or an alpha-blocker combined with an anticholinergic. We rated the quality of the evidence to be low in most cases, meaning that we cannot fully trust the results. The included studies were poorly designed, small, and only followed people for a short time (usually three months or less).

10.1002/14651858.CD012059.pub2

cochrane-simplification-train-3197

cochrane-simplification-train-3197

Nineteen studies of 2033 initially randomly assigned participants were included, of which 11 used a second injected agent, five used a mechanical method (haemoclips) and three employed thermal methods. The risk of further bleeding after initial haemostasis was lower in the combination therapy groups than in the epinephrine alone group, regardless of which second procedure was applied (RR 0.53, 95% CI 0.35 to 0.81). Adding any second procedure significantly reduced the overall bleeding rate (persistent and recurrent bleeding) (RR 0.57, 95% CI 0.43 to 0.76) and the need for emergency surgery (RR 0.68, 95% CI 0.50 to 0.93). Mortality rates were not significantly different when either method was applied. Rebleeding in the 10 studies that scheduled a reendoscopy showed no difference between epinephrine and combined therapy; without second-look endoscopy, a statistically significant difference was observed between epinephrine and epinephrine and any second endoscopic method, with fewer participants rebleeding in the combined therapy group (nine studies) (RR 0.32, 95% CI 0.21 to 0.48). For ulcers of the Forrest Ia or Ib type (oozing or spurting), the addition of a second therapy significantly reduced the rebleeding rate (RR 0.66, 95% CI 0.49 to 0.88); this difference was not seen for type IIa (visible vessel) or type IIb (adherent clot) ulcers. Few procedure-related adverse effects were reported, and this finding was not statistically significantly different between groups. Few adverse events occurred, and no statistically significant difference was noted between groups. The addition of a second injected method reduced recurrent and persistent rebleeding rates and surgery rates in the combination therapy group, but these findings were not statistically significantly different. Significantly fewer participants died in the combined therapy group (RR 0.50, 95% CI 0.25 to 1.00). Epinephrine and a second mechanical method decreased recurrent and persistent bleeding (RR 0.31, 95% CI 0.18 to 0.54) and the need for emergency surgery (RR 0.20, 95% CI 0.06 to 0.62) but did not affect mortality rates. Epinephrine plus thermal methods decreased the rebleeding rate (RR 0.49, 95% CI 0.30 to 0.78) and the surgery rate (RR 0.20, 95% CI 0.06 to 0.62) but did not affect the mortality rate. Our risk of bias estimates show that risk of bias was low, as, although the type of study did not allow a double-blind trial, rebleeding, surgery and mortality were not dependent on subjective observation. Although some studies had limitations in their design or implementation, most were clear about important quality criteria, including randomisation and allocation concealment, sequence generation and blinding. Additional endoscopic treatment after epinephrine injection reduces further bleeding and the need for surgery in patients with high-risk bleeding peptic ulcer. The main adverse events include risk of perforation and gastric wall necrosis, the rates of which were low in our included studies and favoured neither epinephrine therapy nor combination therapy. The main conclusion is that combined therapy seems to work better than epinephrine alone. However, we cannot conclude that a particular form of treatment is equal or superior to another.

We performed an extensive search for randomised trials comparing epinephrine alone versus epinephrine plus a second method. We found 19 clinical trials involving 2033 randomly assigned participants We found that adding a second procedure reduced the further bleeding rate and the need for emergency surgery, but the effect of this approach on death rates has not been proven. In conclusion, additional endoscopic treatment after epinephrine injection reduces further bleeding and the need for surgery in patients with high-risk bleeding peptic ulcer. Our risk of bias estimates show that the overall quality of the included studies was moderate or high. Although some studies had limitations in their design or implementation, most were clear about important quality criteria including randomisation and allocation concealment, sequence generation and blinding. We rated the quality of evidence as moderate for most outcomes. Further research is likely to have an impact on our confidence in the estimate of effect and may change the conclusions of this review.

10.1002/14651858.CD005584.pub3

cochrane-simplification-train-3198

cochrane-simplification-train-3198

We included 24 studies (2,610 patients) in this review. Teicoplanin reduced the risk of nephrotoxicity compared to vancomycin (RR 0.66, 95% CI 0.48 to 0.90).The effects of teicoplanin or vancomycin were similar for clinical cure (RR 1.03, 95% CI 0.98 to 1.08), microbiological cure (RR 0.98, 95% CI 0.93 to 1.03) and mortality (RR 1.02, 95% CI 0.79 to1.30). Six studies reported no cases of acute kidney injury (AKI) needing dialysis. Adverse events were less frequent with teicoplanin including cutaneous rash (RR 0.57, 95% CI 0.35 to 0.92), red man syndrome (RR 0.21, 95% CI 0.08 to 0.59) and total adverse events (RR 0.73, 95% CI 0.53 to 1.00). A lower risk of nephrotoxicity with teicoplanin was observed in patients either with (RR 0.51, 95% CI 0.30 to 0.88) or without aminoglycosides (RR 0.31, 95% 0.07 to 1.50), and also when vancomycin dosing was guided by serum levels (RR 0.22, 95% CI 0.10 to 0.52). Teicoplanin and vancomycin are both effective in treating those with proven or suspected infection; however the incidence of adverse effects including nephrotoxicity was lower with teicoplanin. There were no cases of AKI needing dialysis. It remains unclear whether the differential effect on kidney function should influence which antibiotic be prescribed, although it may be reasonable to consider teicoplanin for patients at higher risk for AKI needing dialysis.

This review identified 24 studies enrolling 2,610 patients comparing teicoplanin and vancomycin in those with either proven or suspected infection. Teicoplanin was as effective as vancomycin for treating infections caused by Staphylococcus aureus with similar results for clinical cure, microbiological cure and death. However, there were less adverse events (skin rash and red man syndrome) and it caused significantly less damage to the kidneys.

10.1002/14651858.CD007022.pub2

cochrane-simplification-train-3199

cochrane-simplification-train-3199

Seven low quality randomised trials were included. All studies included a total of 310 patients, but due to selective outcome reporting bias, less patients could be included in our analyses. Pooled analysis of three homogenous trials showed that needle aspiration did not significantly increase the proportion of patients with fever resolution (RR 0.60, 95% confidence interval (CI) 0.22 to 1.61). Sensitivity analysis according to trial quality preserved these findings. Trials that evaluated resolution of abdominal pain, days to resolution of fever, pain, resolution of abscess cavities, reduction in liver size, and duration of hospitalisation were heterogeneous. The benefits in the number of days to resolution of pain (MD -1.59, 95%CI -2.73 to -0.42), number of days to resolution of abdominal tenderness (MD -1.70, 95%CI -2.86 to -0.54), and duration of hospitalisation (MD -1.31, 95%CI -2.05 to -0.57) were observed in the needle aspiration group only. Therapeutic aspiration in addition to metronidazole to hasten clinical or radiologic resolution of uncomplicated amoebic liver abscesses cannot be supported or refuted by the present evidence. The trials lack methodological rigour and adequate sample size to conclude on the presence of effectiveness of adjunctive image-guided aspiration plus metronidazole versus metronidazole alone. Further randomised trials are necessary.

This review compares the standard treatment with a more invasive alternative, where pus-filled mass is drained by image-guided percutaneous procedure (performed through the skin). Seven low quality randomised trials were included. All the seven studies included a total of 310 patients, but due to selective outcome reporting bias, less patients could be included in our analyses. Pooled analysis of three homogenous trials showed that needle aspiration did not significantly increase the proportion of patients with fever resolution. Benefits could be observed in resolution time of pain and tenderness. No additional benefit has been found with percutaneous needle aspiration plus metronidazole versus metronidazole alone for uncomplicated amoebic liver abscesses in hastening clinical and radiologic resolution. However, this conclusion is based on trials with methodological flaws and with insufficient sample sizes, and requires further confirmation in larger well-designed, randomised trials.

10.1002/14651858.CD004886.pub2