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cochrane-simplification-train-300

cochrane-simplification-train-300

We identified 51 trials with 22,509 participants. Most recruited adults from the community using media or local advertising. People enrolled in the studies typically smoked an average of 23 cigarettes a day. We judged 18 of the studies to be at high risk of bias, but restricting the analysis only to the five studies at low or to the 28 studies at unclear risk of bias did not significantly alter results. We identified very low-certainty evidence, limited by risk of bias, inconsistency and imprecision, comparing the effect of reduction-to-quit interventions with no treatment on cessation rates (RR 1.74, 95% CI 0.90 to 3.38; I2 = 45%; 6 studies, 1599 participants). However, when comparing reduction-to-quit interventions with abrupt quitting (standard care) we found evidence that neither approach resulted in superior quit rates (RR 1. 01, 95% CI 0.87 to 1.17; I2 = 29%; 22 studies, 9219 participants). We judged this estimate to be of moderate certainty, due to imprecision. Subgroup analysis provided some evidence (P = 0.01, I2 = 77%) that reduction-to-quit interventions may result in more favourable quit rates than abrupt quitting if varenicline is used as a reduction aid. Our analysis comparing reduction using pharmacotherapy with reduction alone found low-certainty evidence, limited by inconsistency and imprecision, that reduction aided by pharmacotherapy resulted in higher quit rates (RR 1. 68, 95% CI 1.09 to 2.58; I2 = 78%; 11 studies, 8636 participants). However, a significant subgroup analysis (P < 0.001, I2 = 80% for subgroup differences) suggests that this may only be true when fast-acting NRT or varenicline are used (both moderate-certainty evidence) and not when nicotine patch, combination NRT or bupropion are used as an aid (all low- or very low-quality evidence). More evidence is likely to change the interpretation of the latter effects. Although there was some evidence from within-study comparisons that behavioural support for reduction to quit resulted in higher quit rates than self-help resources alone, the relative efficacy of various other characteristics of reduction-to-quit interventions investigated through within- and between-study comparisons did not provide any evidence that they enhanced the success of reduction-to-quit interventions. Pre-quit AEs, SAEs and nicotine withdrawal symptoms were measured variably and infrequently across studies. There was some evidence that AEs occurred more frequently in studies that compared reduction using pharmacotherapy versus no pharmacotherapy; however, the AEs reported were mild and usual symptoms associated with NRT use. There was no clear evidence that the number of people reporting SAEs, or changes in withdrawal symptoms, differed between trial arms. There is moderate-certainty evidence that neither reduction-to-quit nor abrupt quitting interventions result in superior long-term quit rates when compared with one another. Evidence comparing the efficacy of reduction-to-quit interventions with no treatment was inconclusive and of low certainty. There is also low-certainty evidence to suggest that reduction-to-quit interventions may be more effective when pharmacotherapy is used as an aid, particularly fast-acting NRT or varenicline (moderate-certainty evidence). Evidence for any adverse effects of reduction-to-quit interventions was sparse, but available data suggested no excess of pre-quit SAEs or withdrawal symptoms. We downgraded the evidence across comparisons due to risk of bias, inconsistency and imprecision. Future research should aim to match any additional components of multicomponent reduction-to-quit interventions across study arms, so that the effect of reduction can be isolated. In particular, well-conducted, adequately-powered studies should focus on investigating the most effective features of reduction-to-quit interventions to maximise cessation rates.

This review includes 51 studies of over 22,000 people who smoked tobacco. Most were adults, and people typically smoked at least 23 cigarettes a day at the start of the studies. All studies included at least one group of people who were asked to cut down their smoking and then quit tobacco smoking altogether. This group was compared to either a group who did not receive any treatment to stop smoking, a group who were asked to stop smoking all at once, or a group who were also asked to cut down their smoking in a different way. We did not include studies which asked people to cut down without quitting. Studies lasted for at least six months. The evidence is up to date to October 2018. There was not enough information available to decide whether cutting down before quitting helped more people to stop smoking than no stop-smoking treatment. However, people who were asked to stop smoking all of their cigarettes at once were not more likely to quit than people who were asked to cut down their smoking before quitting. This suggests that asking people to cut down their smoking first may be a useful way to help people to stop smoking. People who cut down their smoking while using varenicline or a fast-acting form of nicotine replacement therapy (NRT), such as gum or lozenge, may be more likely to quit smoking than people who cut down their smoking without using a medicine to help them. Giving people face-to-face support to cut down their smoking may help more people to quit than if they are provided with self-help materials to cut down by themselves. There was not enough information available to decide whether other features of the cutting-down-to-quit intervention improved people's chances of stopping smoking. We looked at whether being asked to cut down smoking before quitting resulted in negative effects, such as cigarette cravings, difficulty sleeping, low mood or irritability. Most studies did not provide information about this; more studies are therefore needed to answer this question. There is very low-quality evidence looking at whether cutting down smoking before quitting helps more people to quit smoking than no treatment. We rated the quality as very low, as there were problems with the design of studies, findings of studies were very different from one another, and not enough people took part, making it difficult to tell whether cutting down helps people to quit smoking. However, there is moderate-certainty evidence that cutting down before quitting may result in similar quit rates to quitting all at once, which suggests that cutting down may be a helpful approach. We rated this evidence as moderate because there is a chance that future studies may find that cutting down helps slightly more or slightly fewer people to quit than when people quit all at once. There is also moderate-quality evidence that people may be more likely to quit by cutting down first when they use a stop-smoking medicine like varenicline or a type of fast-acting NRT to help them. We rated this evidence as moderate certainty because there were not enough people taking part; more studies are needed.

10.1002/14651858.CD013183.pub2

cochrane-simplification-train-301

cochrane-simplification-train-301

Nine RCTs (N = 341 participants, 301 included in analyses) investigated various types and intensities of non pharmacological interventions for treating spasticity in adults with MS. These interventions included: physical activity programmes (such as physiotherapy, structured exercise programme, sports climbing); transcranial magnetic stimulation (Intermittent Theta Burst Stimulation (iTBS), Repetitive Transcranial Magnetic Stimulation (rTMS)); electromagnetic therapy (pulsed electromagnetic therapy; magnetic pulsing device), Transcutaneous Electrical Nerve Stimulation (TENS); and Whole Body Vibration (WBV). All studies scored 'low' on the methodological quality assessment implying high risk of bias. There is 'low level' evidence for physical activity programmes used in isolation or in combination with other interventions (pharmacological or non pharmacological), and for repetitive magnetic stimulation (iTBS/rTMS) with or without adjuvant exercise therapy in improving spasticity in adults with MS. No evidence of benefit exists to support the use of TENS, sports climbing and vibration therapy for treating spasticity in this population. There is 'low level' evidence for non pharmacological interventions such as physical activities given in conjunction with other interventions, and for magnetic stimulation and electromagnetic therapies for beneficial effects on spasticity outcomes in people with MS. A wide range of non pharmacological interventions are used for the treatment of spasticity in MS, but more robust trials are needed to build evidence about these interventions.

In this review, nine studies evaluating various non drug treatments to treat spasticity in adult with MS were included, comprising a total of 341 participants. Results from these studies suggest that all included non pharmacological therapies have low level of evidence or no evidence in improving spasticity in people with MS. However, caution should be used in the interpretation of the results, due to the poor methodological quality of all the included studies. More research is needed to determine the usefulness of these interventions before they can be recommended as routine treatments.

10.1002/14651858.CD009974.pub2

cochrane-simplification-train-302

cochrane-simplification-train-302

We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC. Interferon (IFN)-α monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence). There is probably no difference between IFN-α plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL. IFN-α alone may slightly increase one-year overall mortality compared to IFN-α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data. Treatment with IFN-α plus bevacizumab or standard targeted therapy (sunitinib) may lead to similar one-year overall mortality (RR 0.37, 95% CI 0.13 to 1.08; 1 study; 83 participants; low-quality evidence) and AEs of grade 3 or greater (RR 1.18, 95% CI 0.85 to 1.62; 1 study; 82 participants; low-quality evidence). QoL could not be evaluated due to insufficient data. Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data. In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate-quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS); 1 study, 704 participants; moderate-quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate-quality evidence). Evidence of moderate quality demonstrates that IFN-α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-α alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-α plus bevacizumab. Low-quality evidence shows no difference for IFN-α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.

A systematic search up to the end of October 2016 identified eight studies that looked at four different types of immunotherapy in 4732 people. Studies were only included if patients were randomized to a form of immunotherapy included in this review or a standard form of targeted therapy. One study was funded by a public institution whereas all the others were supported by drug companies. The study participants were generally representative of people with advanced kidney cancer. The majority of people had their kidney cancer removed before starting treatment. We compared studies of people who had previously received standard medicine (821 participants) to those of people who had not (3911 participants). All studies reported our main outcome of interest; the chance of longer survival including the survival for one year. We also focused on the frequency of severe treatment side effects, quality of life and the delay in disease worsening. Interferon-α was the most commonly used therapy option prior to the era of targeted therapies. Two studies with 1166 participants compared interferon-α alone (monotherapy) to targeted standard therapy. Interferon-α is probably inferior to tested targeted therapies called sunitinib and temsirolimus. Patients with interferon-α monotherapy probably have a shorter time to worsening of cancer. They may have similar quality of life and a slightly more severe treatment side effects. Adding temsirolimus to interferon-α probably does not improve survival compared to temsirolimus alone, but may result in more major side effects (one study). Two studies compared interferon-α to a combination of interferon-α and bevacizumab in 1381 previously untreated participants. There was a slightly increased death rate with probably fewer major side effects for people treated with interferon-α alone. Two studies evaluated vaccines. Vaccines may lead to similar death rates and side effects in people with advanced kidney cancer. For patients who had already undergone systemic treatment, one study with nivolumab, a novel checkpoint inhibitor, improved average survival by more than five months when compared to the targeted standard therapy, everolimus. The effects are probably accompanied by better quality of life and fewer major side effects. We had reduced confidence in the results of the studies we analyzed (moderate- or low-quality evidence) because patients and treating physicians were often not blinded to the treatment and involved relatively few patients.

10.1002/14651858.CD011673.pub2

cochrane-simplification-train-303

cochrane-simplification-train-303

We included 16 randomised controlled trials consisting of 2933 colonoscopies. Primary outcome measures were cecal intubation rate and adenoma detection; secondary outcomes were time needed to reach the cecum, pain experienced by participants during the procedure, completion of cecal intubation without sedation/analgesia, and adverse events. Completeness of colonoscopy, that is cecal intubation rate, was similar between water infusion and standard air insufflation (risk ratio 1.00, 95% confidence interval (CI) 0.97 to 1.03, P = 0.93). Adenoma detection rate, that is number of participants with at least one detected adenoma, was slightly improved with water infusion (risk ratio 1.16, 95% CI 1.04 to 1.30, P = 0.007). Assuming the fraction of patients undergoing screening colonoscopy who had one or more adenomas detected was 20 per 100 with standard colonoscopy, the use of water colonoscopy may increase the fraction to 23 per 100 individuals. From our findings, it is possible that up to 68,000 more of the 1.7 million outpatient screening colonoscopies performed annually in the United States, could detect adenomas if water infusion colonoscopy was used. In addition, with water infusion participants experienced significantly less pain (mean difference in pain score on a 0 to 10 scale: -1.57, 95% CI -2.00 to -1.14, P < 0.00001) and a significantly lower proportion of participants requested on-demand sedation or analgesia, or both (risk ratio 1.20, 95% CI 1.14 to 1.27, P < 0.00001). Qualitative analysis suggests that water infusion colonoscopy was not associated with a markedly increased rate of adverse events compared with the standard procedure. Completeness of colonoscopy, that is cecal intubation rate, was not improved by water infusion compared with standard air insufflation colonoscopy. However, adenoma detection, assessed with two different measures (that is adenoma detection rate and number of detected adenomas per procedure), was slightly augmented by the water infusion colonoscopy. Improved adenoma detection might be due to the cleansing effects of water infusions on the mucosa. Detection of premalignant lesions during standard colonoscopy is suboptimal, and so improvements in adenoma detection by water infusion colonoscopy, although small, may help to reduce the risk of interval colorectal carcinoma. The most obvious benefit of water infusion colonoscopy was reduction of procedure-related abdominal pain, which may enhance the acceptance of screening/surveillance colonoscopy.

We included 16 trials encompassing 2933 colonoscopies in this review. The review showed that completeness of colonoscopy was similar between water infusion and standard air insufflation, and that adenoma detection (participants with at least one adenoma detected) was improved with water colonoscopy (36% versus 31% in the air group). In addition, participants experienced significantly less pain with water colonoscopy compared with the standard procedure. Detection of cancer and precancerous lesions during standard colonoscopy is far from perfect. Improvements in adenoma detection by water infusion colonoscopy, although small, may help to increase the rate of adenoma detection. This may reduce the risk of colorectal cancer development after a colonoscopy without abnormal findings.

10.1002/14651858.CD009863.pub2

cochrane-simplification-train-304

cochrane-simplification-train-304

Eleven studies (n = 927 participants) met our inclusion criteria. Eight studies compared CTA with IADSA (n = 526) and three studies compared MRA with IADSA (n = 401). Methodological quality varied considerably among studies, with partial verification bias in 7/11 (64%) and retrospective designs in 5/10 (50%). In studies of CTA, the pooled estimate of sensitivity was 0.95 (95% confidence interval (CI) 0.90 to 0.97) and specificity was 0.99 (95% CI 0.95 to 1.00). The results remained robust in a sensitivity analysis in which only studies evaluating adult patients (≥ 16 years of age) were included. In studies of MRA, the pooled estimate of sensitivity was 0.98 (95% CI 0.80 to 1.00) and specificity was 0.99 (95% CI 0.97 to 1.00). An indirect comparison of CTA and MRA using a bivariate model incorporating test type as one of the parameters failed to reveal a statistically significant difference in sensitivity or specificity between the two imaging modalities (P value = 0.6). CTA and MRA appear to have good sensitivity and specificity following ICH for the detection of intracranial vascular malformations, although several of the included studies had methodological shortcomings (retrospective designs and partial verification bias in particular) that may have increased apparent test accuracy.

This review looked at different tests used to identify blood vessel abnormalities in the brain. Intra-arterial digital subtraction angiography (IADSA) is the standard test used and involves positioning a tube, introduced through a blood vessel in the groin, into blood vessels near the brain. Dye is directly injected into the brain's blood vessels using this tube. Computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) are newer tests that may be done without any injections (MRA) or only through an injection into the arm (CTA and MRA). This review investigated the accuracy of CTA or MRA, or both, compared with IADSA after intracerebral haemorrhage. We found eight studies (involving 526 participants) that compared CTA with IADSA and three studies (involving 401 participants) that compared MRA with IADSA. Both CTA and MRA appear to have good accuracy when compared with IADSA. However, the studies were small and were limited in many cases by their design. Further research that looks at accuracy, practicality, and costs is needed.

10.1002/14651858.CD009372.pub2

cochrane-simplification-train-305

cochrane-simplification-train-305

In total, we included 28 studies with more than 83,000 participants. There were some general limitations of the evidence. Most participants were enrolled in studies which were not designed primarily to assess cognition. These studies often had no baseline cognitive assessment and used only brief cognitive assessments at follow-up. Very few studies assessed the incidence of dementia. Most study reports did not mention adverse events or made only very general statements about them. Only 10 studies had a mean follow-up > 5 years. Only two studies had participants whose mean age was < 60 years at baseline. The risk of bias in the included studies was generally low, other than a risk of attrition bias for longer-term outcomes. We considered the certainty of the evidence behind almost all results to be moderate or low. We included 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo. The majority of participants were aged over 60 years and had a history of cardio- or cerebrovascular disease. We found that giving B vitamin supplements to cognitively healthy adults, mainly in their 60s and 70s, probably has little or no effect on global cognitive function at any time point up to 5 years (SMD values from -0.03 to 0.06) and may also have no effect at 5-10 years (SMD -0.01). There were very sparse data on adverse effects or on incidence of cognitive impairment or dementia. We included 8 studies with 47,840 participants in which the active intervention was one or more of the antioxidant vitamins: ß-carotene, vitamin C or vitamin E. Results were mixed. For overall cognitive function, there was low-certainty evidence of benefit associated with ß-carotene after a mean of 18 years of treatment (MD 0.18 TICS points, 95% CI 0.01 to 0.35) and of vitamin C after 5 years to 10 years (MD 0.46 TICS points, 95% CI 0.14 to 0.78), but not at earlier time points. From two studies which reported on dementia incidence, there was low-certainty evidence of no effect of an antioxidant vitamin combination or of vitamin E, either alone or combined with selenium. One of the included studies had been designed to look for effects on the incidence of prostate cancer; it found a statistically significant increase in prostate cancer diagnoses among men taking vitamin E. One trial with 4143 participants compared vitamin D3 (400 IU/day) and calcium supplements to placebo. We found low- to moderate-certainty evidence of no effect of vitamin D3 and calcium supplements at any time-point up to 10 years on overall cognitive function (MD after a mean of 7.8 years -0.1 MMSE points, 95% CI -0.81 to 0.61) or the incidence of dementia (HR 0.94, 95% CI 0.72 to 1.24). A pilot study with 60 participants used a higher dose of vitamin D3 (4000 IU on alternate days) and found preliminary evidence that this dose probably has no effect on cognitive function over six months. We included data from one trial of zinc and copper supplementation with 1072 participants. There was moderate-certainty evidence of little or no effect on overall cognitive function (MD 0.6 MMSE points, 95% CI -0.19 to 1.39) or on the incidence of cognitive impairment after 5 years to 10 years. A second smaller trial provided no usable data, but reported no cognitive effects of six months of supplementation with zinc gluconate. From one study with 3711 participants, there was low-certainty evidence of no effect of approximately five years of selenium supplementation on the incidence of dementia (HR 0.83, 95% CI 0.61 to 1.13). Finally, we included three trials of complex supplements (combinations of B vitamins, antioxidant vitamins, and minerals) with 6306 participants. From the one trial which assessed overall cognitive function, there was low-certainty evidence of little or no effect on the TICS (MD after a mean of 8.5 years 0.12, 95% CI -0.14 to 0.38). We did not find evidence that any vitamin or mineral supplementation strategy for cognitively healthy adults in mid or late life has a meaningful effect on cognitive decline or dementia, although the evidence does not permit definitive conclusions. There were very few data on supplementation starting in midlife (< 60 years); studies designed to assess cognitive outcomes tended to be too short to assess maintenance of cognitive function; longer studies often had other primary outcomes and used cognitive measures which may have lacked sensitivity. The only positive signals of effect came from studies of long-term supplementation with antioxidant vitamins. These may be the most promising for further research.

We grouped the 28 included trials according to the kind of supplement they used and how it might work. Most of the trials were not originally designed to study cognition or dementia and used only simple measures of cognition. Very few studies investigated whether participants developed dementia. Long-term studies are probably needed to find effects on the risk of dementia or cognitive decline but only 10 studies had an average length of follow-up longer than five years. The studies were generally well-conducted although the longer trials had difficulty following up all of the participants and this could have biased some of the longer-term results. There were 14 trials of B vitamins (folic acid, vitamin B6, vitamin B12) with nearly 28,000 participants, mainly in their 60s and 70s. Most of these trials were quite short (less than two years). We found no evidence that B vitamins had any effect on cognition. There were 8 trials of antioxidant vitamins (beta-carotene/vitamin A, vitamin C, vitamin E) with approximately 47,000 participants. These trials tended to be longer than the B vitamin trials so may have had more chance of detecting effects on dementia and cognitive decline. The results were mixed. We found low-certainty evidence of better overall cognitive function after an average of 18 years taking beta-carotene and after five years to 10 years taking vitamin C, but no effects after shorter periods of treatment. There were also small benefits of beta-carotene, vitamin C, and antioxidant combinations on memory at some time points but not others. There was no evidence of any benefits from vitamin E alone. Two studies examined the risk of developing dementia. One found no effect of a combination of antioxidant vitamins and the other found no effect of vitamin E, either alone or combined with the mineral selenium. Most of the studies did not report any information about harmful effects. One included trial was designed to look for an effect on the risk of prostate cancer; it found a higher risk among the men taking vitamin E. There was a small trial of vitamin D supplements which found they probably had no effect on cognition over six months. There were longer trials of vitamin D with calcium (one trial), zinc and copper (one trial), and complex multivitamins (three trials). All lasted between five and 10 years, but none of them found any evidence of beneficial effects on cognition. One trial found no effect of selenium taken for approximately five years on the risk of developing dementia. We found no good evidence to suggest that middle-aged or older people can preserve cognitive function or prevent dementia by taking vitamin or mineral supplements. There were a few positive results associated with long-term use of antioxidant vitamins, particularly beta-carotene and vitamin C, although the effects were small. Further research into the effects of these vitamins may be worthwhile.

10.1002/14651858.CD011906.pub2

cochrane-simplification-train-306

cochrane-simplification-train-306

We identified six eligible trials including 16,135 individuals. The mean age of trial populations varied across trials; between 47.3 and 62.3 years. Four trials included individuals with diabetes mellitus type 2 only. The mean treatment duration and follow-up of participants across trials was 4.8 years. We judged the risks of selection and performance bias to be low; risks of detection bias, attrition bias, and reporting bias were unclear. Reporting of adverse effects by included trials was very limited; that is why we used discontinuation of therapy due to adverse effects as a proxy for adverse effects. Patients treated with fibrates had a reduced risk for the combined primary outcome of CVD death, non-fatal myocardial infarction, or non-fatal stroke compared to patients on placebo (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74 to 0.96; participants = 16,135; studies = 6; moderate-quality of evidence). For secondary outcomes we found RRs for fibrate therapy compared with placebo of 0.79 for combined coronary heart disease death or non-fatal myocardial infarction (95% CI 0.68 to 0.92; participants = 16,135; studies = 6; moderate-quality of evidence); 1.01 for overall mortality (95% CI 0.81 to 1.26; participants = 8471; studies = 5; low-quality of evidence); 1.01 for non-CVD mortality (95% CI 0.76 to 1.35; participants = 8471; studies = 5; low-quality of evidence); and 1.38 for discontinuation of therapy due to adverse effects (95% CI 0.71 to 2.68; participants = 4805; studies = 3; I2 = 74%; very low-quality of evidence). Data on quality of life were not available from any trial. Trials that evaluated fibrates in the background of statins (2 studies) showed no benefits in preventing cardiovascular events. Moderate-quality evidence suggests that fibrates lower the risk for cardiovascular and coronary events in primary prevention, but the absolute treatment effects in the primary prevention setting are modest (absolute risk reductions < 1%). There is low-quality evidence that fibrates have no effect on overall or non-CVD mortality. Very low-quality evidence suggests that fibrates are not associated with increased risk for adverse effects.

The evidence is current to May 2016. We identified six eligible primary prevention trials including 16,135 individuals without established cardiovascular disease that compared fibrate therapy with placebo or usual care. The mean age of the trial populations varied between 47.3 and 62.3 years; the majority of included individuals had diabetes mellitus type 2. The mean treatment duration and follow-up of participants across trials was 4.8 years. Moderate-quality evidence suggests a risk reduction of 16% with fibrate therapy for the combined outcome of death due to cardiovascular disease, heart attack, or stroke. In absolute terms, the risk for this combined outcome in patients with cardiovascular risk factors but without established cardiovascular disease was on average reduced from 5.0% to 4.3% over five years. Moderate-quality evidence also suggests a risk reduction for fatal and non-fatal heart attacks with fibrates, but there is low-quality evidence for no risk reduction for overall mortality or death from non-CVD with fibrates. Very-low quality evidence suggests that there is no increased risk for adverse effects with fibrate treatment. The reporting of adverse effects by identified trials was very limited. Data on quality of life were not available from any included study. Trials that evaluated fibrates in the background of statin treatment showed no benefits in preventing cardiovascular events.

10.1002/14651858.CD009753.pub2

cochrane-simplification-train-307

cochrane-simplification-train-307

There are 10 included trials (N = 261) published between 1973 and 2010; eight are new from the 2015 and 2017 update searches. Forty-eight studies are excluded. Participants were mostly chronically mentally ill inpatients in their 50s, and studies were primarily of short (2 to 6 weeks) duration. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment and generation of the sequence. Studies were also not clearly blinded and we are unsure if data are incomplete or selectively reported, or if other biases were operating. One small, three-arm trial found that both alpha-methyldopa (N = 20; RR 0.33, 95% CI 0.14 to 0.80; low-quality evidence) and reserpine (N = 20; RR 0.52 95% CI 0.29 to 0.96; low-quality evidence) may lead to a clinically important improvement in tardive dyskinesia symptoms compared with placebo after 2 weeks' treatment, but found no evidence of a difference between alpha-methyldopa and reserpine (N = 20; RR 0.60, 95% CI 0.19 to 1.86; very low quality evidence). Another small trial compared tetrabenazine and haloperidol after 18 weeks' treatment and found no evidence of a difference on clinically important improvement in tardive dyskinesia symptoms (N = 13; RR 0.93, 95% CI 0.45 to 1.95; very low quality evidence). No study reported on adverse events. For remaining outcomes there was no evidence of a difference between any of the interventions: alpha-methyldopa versus placebo for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence), celiprolol versus placebo for leaving the study early (1 RCT; N = 35; RR 5.28, 95% CI 0.27 to 102.58; very low quality evidence) and quality of life (1 RCT; N = 35; RR 0.87, 95% CI 0.68 to 1.12; very low quality evidence), alpha-methyldopa versus reserpine for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; not estimable, no reported events; very low quality evidence), reserpine or carbidopa/levodopa versus placebo for deterioration of tardive dyskinesia symptoms (2 RCTs; N = 37; RR 1.18, 95% CI 0.35 to 3.99; very low quality evidence), oxypertine versus placebo for deterioration of mental state (1 RCT; N = 42; RR 2.20, 95% CI 0.22 to 22.45; very low quality evidence), dopaminergic drugs (amantadine, bromocriptine, tiapride, oxypertine, carbidopa/levodopa) versus placebo for leaving the study early (6 RCTs; N = 163; RR 1.29, 95% CI 0.65 to 2.54; very low quality evidence), and tetrabenazine versus haloperidol for deterioration of tardive dyskinesia symptoms (1 RCT; N = 13; RR 1.17, 95% CI 0.09 to 14.92) and leaving the study early (1 RCT; N = 13; RR 0.23, 95% CI 0.01 to 4.00). Although there has been a large amount of research in this area, many studies were excluded due to inherent problems in the nature of their cross-over designs. Usually data are not reported before the cross-over and the nature of TD and its likely response to treatments make it imprudent to use this data. The review provides little usable information for service users or providers and more well-designed and well-reported studies are indicated.

. The review includes 10 small, short studies published mainly in the 1980s involving a total of 261 people. . One small study found that after 2 weeks' treatment both alpha-methyldopa and reserpine may lead to clinically important improvement in tardive dyskinesia symptoms compared with placebo, but the quality of evidence was low. We are uncertain about the effect of reserpine versus alpha-methyldopa; quality of evidence was very low. Another small trial compared tetrabenazine and haloperidol after 18 weeks' treatment, but again we are uncertain about the effect as the quality of evidence was very low. The included studies did not report on any harmful effects of the drugs. . Evidence is weak, limited, short term, and small scale. It is not possible to recommend these drugs as a treatment for tardive dyskinesia and their use is entirely experimental. There is a need for larger and more rigorous research in the area. This plain language summary was adapted by the review authors from a summary originally written by Ben Gray, Senior Peer Researcher, McPin Foundation (mcpin.org/).

10.1002/14651858.CD000458.pub3

cochrane-simplification-train-308

cochrane-simplification-train-308

We included 16 trials (19 articles) that enrolled 2520 adults living with HIV. All the interventions were multifaceted and included a mix of psychotherapy, relaxation, group support, and education. The included trials were conducted in the USA (12 trials), Canada (one trial), Switzerland (one trial), Uganda (one trial), and South Africa (one trial), and published between 1996 and 2016. Ten trials recruited men and women, four trials recruited homosexual men, and two trials recruited women only. Interventions were conducted with groups of four to 15 people, for 90 to 135 minutes, every week for up to 12 weeks. All interventions were conducted face-to-face except two, which were delivered by telephone. All were delivered by graduate or postgraduate trained health, psychology, or social care professionals except one that used a lay community health worker and two that used trained mindfulness practitioners. Group-based psychosocial interventions based on cognitive behavioural therapy (CBT) may have a small effect on measures of depression, and this effect may last for up to 15 months after participation in the group sessions (SMD −0.26, 95% CI −0.42 to −0.10; 1139 participants, 10 trials, low certainty evidence). Most trials used the Beck Depression Inventory (BDI), which has a maximum score of 63, and the mean score in the intervention groups was around 1.4 points lower at the end of follow-up. This small benefit was consistent across five trials where participants had a mean depression score in the normal range at baseline, but trials where the mean score was in the depression range at baseline effects were less consistent. Fewer trials reported measures of anxiety, where there may be little or no effect (four trials, 471 participants, low certainty evidence), stress, where there may be little or no effect (five trials, 507 participants, low certainty evidence), and coping (five trials, 697 participants, low certainty evidence). Group-based interventions based on mindfulness have not demonstrated effects on measures of depression (SMD −0.23, 95% CI −0.49 to 0.03; 233 participants, 2 trials, very low certainty evidence), anxiety (SMD −0.16, 95% CI −0.47 to 0.15; 62 participants, 2 trials, very low certainty evidence), or stress (MD −2.02, 95% CI −4.23 to 0.19; 137 participants, 2 trials, very low certainty evidence). No mindfulness based interventions included in the studies had any valid measurements of coping. Group-based psychosocial interventions may have a small effect on measures of depression, but the clinical importance of this is unclear. More high quality evidence is needed to assess whether group psychosocial intervention improve psychological well-being in HIV positive adults.

Cochrane researchers conducted a review of the effects of group therapy for people living with human immunodeficiency virus (HIV). After searching for relevant trials up to 14 March 2016, they included 16 trials reported in 19 articles that enrolled 2520 adults living with HIV. The included trials were conducted in the USA (12 trials), Canada (one trial), Switzerland (one trial), Uganda (one trial), and South Africa (one trial), and published between 1996 and 2016. Ten trials recruited men and women, four trials recruited homosexual men, and two trials recruited women only. What is group therapy and how might if benefit people with HIV? Group therapy aims to improve the well-being of individuals by delivering psychological therapy in a group format, which can encourage the development of peer support and social networks. Group therapy often also incorporates training in relaxation techniques and coping skills, and education on the illness and its management. Human immunodeficiency virus (HIV) causes a chronic, life threatening, and often stigmatising disease, which can impact on a person's well-being. Group therapy could help people living with HIV to adapt to knowing they have HIV, or recover from depression, anxiety, and stress. What the research says Group-based therapy based on cognitive behavioural therapy may have a small effect on measures of depression, and this effect may last for up to 15 months after participation in the group sessions (low certainty evidence). This effect was apparent in groups who did not appear to be depressed on clinical scoring systems before the therapy started. The research also showed there may be little or no effect on measures of anxiety, stress, and coping (low certainty evidence). Group-based interventions based on mindfulness have been studied in two small trials, and have not demonstrated effects on measures of depression, anxiety or stress (all very low certainty evidence). No mindfulness based interventions included in the studies had any valid measurements of coping. Overall, the review suggests that existing interventions have little to no effect in increasing psychological adjustment to living with HIV. More good quality studies are required to inform good practice and evidence.

10.1002/14651858.CD010806.pub2

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cochrane-simplification-train-309

We identified two randomised trials eligible for inclusion in the review. There was significant variability between the trials for interventions, methodology and outcome measures and therefore meta-analysis was not performed. One study suggested that the transantral approach and endoscopic transnasal technique had similar effects in reducing exophthalmos but that the endoscopic approach may be safer, relating to fewer complications. This study had short-term follow-up and lacked information on our primary outcome (success or failure of treatment). The second study provided evidence that intravenous steroids may be superior to primary surgical decompression in the management of compressive optic neuropathy requiring less secondary surgical procedures, although it relates more frequently to transient side effects. This study was weakened by a small sample size. Until more credible evidence is available recommendations as to best treatment cannot be reliably made. A single study showed that the transantral approach for orbital decompression was related to more complications than the endoscopic transnasal technique which is preferred by Ear, Nose and Throat (ENT) surgeons, usually as an adjunctive procedure. Intravenous steroids were reported in a single trial to be the most efficient intervention for dysthyroid optic neuropathy. The majority of published literature on orbital decompression for thyroid eye disease consists of retrospective, cohort, or case series studies. Although these provide useful descriptive information, clarification is required to show the relative effectiveness of each intervention for various indications. The two RCTs reviewed are not robust enough to provide credible evidence to our understanding of current decompressive surgery and to support recommendations for clinical practice. There is evidence from currently available uncontrolled studies that removal of the medial and lateral wall (balanced decompression) with or without fat removal may be the most effective surgical method related to only a few complications. There is a clear need for randomised studies evaluating the balanced two-wall, three-wall and orbital fat decompression techniques. Comparison with other surgical techniques for orbital decompression or with immunosuppression in cases of compressive optic neuropathy would also be important. These studies should primarily address the reduction of exophthalmos, disease severity, complication rates, quality of life and cost of the intervention.

Two eligible studies were included in the review. These studies vary significantly in interventions, methodology and reported outcomes. One study reported that removal of the inferior wall through the antrum and removal of the medial wall through the nose had similar effects in reducing exophthalmos but the latter had fewer complications. This study was disadvantaged by short-term follow-up and did not report on our primary outcome measure (success or failure of treatment). The second study suggested that intravenous corticosteroids achieve better visual recovery (56%) than surgical decompression (17%) as a first line treatment for optic neuropathy. It suggested that fewer secondary surgical procedures were required when treated with intravenous corticosteroids but their use related more frequently to side effects with short duration. This study was weakened by the small number of participants involved. Until more evidence is available we cannot recommend any particular intervention. This review has identified a need for more randomised controlled trials to provide further reliable evidence on the effective use of orbital decompression for thyroid ophthalmopathy. These trials should review the balanced two-wall, three-wall and orbital fat decompression techniques. These studies should address the reduction of exophthalmos, disease severity, complication rates, quality of life and cost of the intervention.

10.1002/14651858.CD007630.pub2

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Ten RCTs including 658 patients were finally included in this systematic review. Five trials compared nalbuphine with placebo. Data from one out of five studies for the outcome moderate/severe pain following nalbuphine compared to placebo gave a risk ratio (RR) 1 hour postoperatively (postop) of 0.1 (95% confidence interval (CI) 0.01 to 0.71; low quality evidence) and a RR 2 hours postop of 0.14 (95% CI 0.02 to 1.06; low quality evidence). The estimated RR based on data from a single study indicated that nalbuphine reduced the requirement for analgesia two hours postop (RR 0.47; 95% CI 0.27 to 0.84; low quality evidence). Two included trials compared nalbuphine with morphine and showed a nonsignificant lower or comparable RR for moderate/severe pain at 1 hour postop (RR 0.84; 95% CI 0.12 to 5.74; low quality evidence), and 2 hours postop (RR 1.09; 95% CI 0.59 to 2.01; low quality evidence) for nalbuphine versus morphine. Four trials compared nalbuphine with tramadol for postoperative pain; data from one trial (per outcome) revealed a lower but nonsignificant RR for the need of additional rescue analgesics in children receiving nalbuphine (RR 2 hours postop 0.75; 95% CI 0.39 to 1.43; low quality evidence) (RR 12 hours postop 0.33; 95% CI 0.04 to 2.77; low quality evidence). One out of three trials comparing nalbuphine with pethidine demonstrated that the RR was not significantly lower following nalbuphine administration compared to pethidine (RR 2 hours postop 1.07; 95% CI 0.52 to 2.23; low quality evidence) (RR 24 hours postop 1.13; 95% CI 0.52 to 2.44; very low quality evidence). The most common adverse event was postoperative nausea and vomiting (PONV). Only one included trial reported that the RR for PONV in the postoperative care unit (PACU) was not significantly higher following nalbuphine compared to placebo (RR 1.00; 95% CI 0.16 to 6.42; low quality evidence) nor to morphine (RR 1.33; 95% CI 0.64 to 2.77; low quality evidence). Because the overall quality of available evidence was low, this systematic review could not definitively show that the analgesic efficacy of nalbuphine is superior compared to placebo. Furthermore, due to the lack of significant results the comparison with other common opioids is also unclear. The same holds true for the evidence focusing on adverse events following nalbuphine compared to placebo or other opioid administration. The evidence is limited, because studies did not report conclusively all important postoperative pain outcomes (e.g. number of patients with the need for rescue analgesia, postoperative pain scores). Thus, a quantitative analysis was not possible for many major aspects (e.g. rescue analgesia, pain scores) and heterogeneity could not be further explored.

In this review, we investigated how well nalbuphine worked, compared to placebo and other opioids, in children with postoperative pain. We also looked at the side effects. We performed a systematic literature search in July 2013. Ten randomised controlled trials with 658 patients were included. The patients were children aged from 0 - 18 years and most did not have any other relevant medical conditions. The overall quality of evidence was low, so this review could not definitively show that nalbuphine is better than placebo. The same holds true for the comparison with other opioids (morphine, tramadol, pethidine, piritramid). We were not able to comment on side effects due to the small numbers of participants in the trials. Future studies need to address these issues, including more robust data for effectiveness and side effects.

10.1002/14651858.CD009583.pub2

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cochrane-simplification-train-311

We identified 28 studies (21 published, 7 unpublished): 13 from North America, 5 from the UK, 4 from continental Europe, 5 from Australia and 1 from China, comprising 1817 incident HCV infections and 8806.95 person-years of follow-up. HCV incidence ranged from 0.09 cases to 42 cases per 100 person-years across the studies. We judged only two studies to be at moderate overall risk of bias, while 17 were at serious risk and 7 were at critical risk; for two unpublished datasets there was insufficient information to assess bias. As none of the intervention effects were generated from RCT evidence, we typically categorised quality as low. We found evidence that current OST reduces the risk of HCV acquisition by 50% (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.40 to 0.63, I2 = 0%, 12 studies across all regions, N = 6361), but the quality of the evidence was low. The intervention effect remained significant in sensitivity analyses that excluded unpublished datasets and papers judged to be at critical risk of bias. We found evidence of differential impact by proportion of female participants in the sample, but not geographical region of study, the main drug used, or history of homelessness or imprisonment among study samples. Overall, we found very low-quality evidence that high NSP coverage did not reduce risk of HCV acquisition (RR 0.79, 95% CI 0.39 to 1.61) with high heterogeneity (I2 = 77%) based on five studies from North America and Europe involving 3530 participants. After stratification by region, high NSP coverage in Europe was associated with a 76% reduction in HCV acquisition risk (RR 0.24, 95% CI 0.09 to 0.62) with less heterogeneity (I2 =0%). We found low-quality evidence of the impact of combined high coverage of NSP and OST, from three studies involving 3241 participants, resulting in a 74% reduction in the risk of HCV acquisition (RR 0.26 95% CI 0.07 to 0.89). OST is associated with a reduction in the risk of HCV acquisition, which is strengthened in studies that assess the combination of OST and NSP. There was greater heterogeneity between studies and weaker evidence for the impact of NSP on HCV acquisition. High NSP coverage was associated with a reduction in the risk of HCV acquisition in studies in Europe.

We identified 28 research studies across Europe, Australia, North America and China. On average across the studies, the rate of new hepatitis C infections per year was 19.0 for every 100 people. Data from 11,070 people who inject drugs who were not infected with hepatitis C at the start of the study were combined in the analysis. Of the sample, 32% were female, 50% injected opioids, 51% injected daily, and 40% had been homeless. Our study was funded by the National Institute of Health Research's (NIHR) Public Health Research Programme, the Health Protection Research Unit in Evaluation of Interventions, and the European Commission Drug Prevention and Information Programme (DIPP), Treatment as Prevention in Europe: Model Projections. Current use of OST (defined as use at the time of survey or within the previous six months) may reduce risk of acquiring hepatitis C by 50%. We are uncertain whether high coverage NSP (defined as regular attendance at an NSP or all injections being covered by a new needle/syringe) reduces the risk of becoming infected with hepatitis C across all studies globally, but there was some evidence from studies in Europe that high NSP coverage may reduce the risk of hepatitis C infection by 76%. The combined use of high coverage NSP with OST may reduce risk of hepatitis C infection by 74%. Quality of evidence ranged from moderate to very low because none of the studies used the gold standard design of randomised controlled trials.

10.1002/14651858.CD012021.pub2

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We identified one randomised controlled trial that included 226 people with high-risk neuroblastoma who were pre-treated with autologous HSCT. The study randomised 113 participants to receive immunotherapy including isotretinoin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and ch14.18, a type of anti-GD2 antibody also known as dinutuximab. The study randomised another 113 participants to receive standard therapy including isotretinoin. The results on overall survival favoured the dinutuximab-containing immunotherapy group (hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31 to 0.80; P = 0.004). The results on event-free survival also favoured the dinutuximab-containing immunotherapy group (HR 0.61, 95% CI 0.41 to 0.92; P = 0.020). Randomised data on adverse events were not reported separately. The study did not report progression-free survival, late non-haematological toxicity, and health-related quality of life as separate endpoints. We graded the quality of the evidence as moderate. The evidence base favours dinutuximab-containing immunotherapy compared to standard therapy concerning overall survival and event-free survival in people with high-risk neuroblastoma pre-treated with autologous HSCT. Randomised data on adverse events are lacking, therefore more research is needed before definitive conclusions can be made regarding this outcome.

The evidence is current to 20 September 2018. We included a single randomised trial (a type of study in which participants are assigned to one of two or more treatment groups using a random method) with 113 people allocated to immunotherapy including isotretinoin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and ch14.18, a distinct type of anti-GD2 antibody also known as dinutuximab. Another 113 people were allocated to receive standard therapy including isotretinoin. The results on overall survival and event-free survival favoured the dinutuximab-containing immunotherapy group. Other outcomes including those on adverse events were not adequately reported; more research is needed before definitive conclusions can be made regarding these outcomes. We assessed the quality of the evidence as moderate.

10.1002/14651858.CD012442.pub2

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cochrane-simplification-train-313

Six trials were included and five trials contributed to this review with data. A total of 2904 participants were randomly assigned to IFNs (1704) and GA (1200). The treatment duration was three years for one study, two years for the other four RCTs while one study was stopped early (after one year). The IFNs analysed in comparison with GA were IFN-beta 1b 250 mcg (two trials, 933 participants), IFN-beta 1a 44 mcg (three trials, 466 participants) and IFN-beta 1a 30 mcg (two trials, 305 participants). Enrolled participants were affected by active RRMS. All studies were at high risk for attrition bias. Three trials are still ongoing, one of them completed. Both therapies showed similar clinical efficacy at 24 months, given the primary outcome variables (number of participants with relapse (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.87 to 1.24) or progression (RR 1.11, 95% CI 0.91 to 1.35). However at 36 months, evidence from a single study suggests that relapse rates were higher in the group given IFNs than in the GA group (RR 1.40, 95% CI 1.13 to 1.74, P value 0.002). Secondary magnetic resonance imaging (MRI) outcomes analysis showed that effects on new or enlarging T2- or new contrast-enhancing T1 lesions at 24 months were similar (mean difference (MD) −0.15, 95% CI −0.68 to 0.39, and MD −0.14, 95% CI −0.30 to 0.02, respectively). However, the reduction in T2- and T1-weighted lesion volume was significantly greater in the groups given IFNs than in the GA groups (MD −0.58, 95% CI −0.99 to −0.18, P value 0.004, and MD −0.20, 95% CI −0.33 to −0.07, P value 0.003, respectively). The number of participants who dropped out of the study because of adverse events was similar in the two groups (RR 0.95, 95% CI 0.64 to 1.40). The quality of evidence for primary outcomes was judged as moderate for clinical end points, but for safety and some MRI outcomes (number of active T2 lesions), quality was judged as low. The effects of IFNs-beta and GA in the treatment of people with RRMS, including clinical (e.g. people with relapse, risk to progression) and MRI (Gd-enhancing lesions) measures, seem to be similar or to show only small differences. When MRI lesion load accrual is considered, the effect of the two treatments differs, in that IFNs-beta were found to limit the increase in lesion burden as compared with GA. Evidence was insufficient for a comparison of the effects of the two treatments on patient-reported outcomes, such as quality-of-life measures.

Study characteristicsWe searched medical databases for studies in which neither participants nor researchers were told which treatment was given (randomised double-blind trials). The efficacy of the two therapies was considered in terms of occurrence of relapse and progression of disease.Key results and quality of evidenceUp to August 2016, we found six studies comprising 2904 participants (1704 treated with IFNs; 1200 with GA) that met our inclusion criteria requirements. We found that the two therapies seemed to have similar effects or only small differences in the occurrence of relapse or progression.The quality of evidence was moderate overall, although in terms of the safety profile the quality of evidence was low. The risk for incomplete outcome data was found to be high, as some studies present incomplete reporting of adverse events and numbers of participants who dropped out.It is worth noting that all studies but one were sponsored by the drug industry. Furthermore, all of the studies were short-term, with a treatment duration of three years for one study and two years for the other four, while one study was stopped early after one year.

10.1002/14651858.CD009333.pub3

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cochrane-simplification-train-314

We included seven new RCTs (536 participants) in the update. In total, we included 19 studies in the review (776 participants in the low tidal volume group and 772 in the high volume group). There are four studies awaiting classification and three are ongoing. All included studies were at some risk of bias. Participants were scheduled for abdominal surgery, heart surgery, pulmonary thromboendarterectomy, spinal surgery and knee surgery. Low tidal volumes used in the studies varied from 6 mL/kg to 8.1 mL/kg while high tidal volumes varied from 10 mL/kg to 12 mL/kg. Based on 12 studies including 1207 participants, the effects of low volume ventilation on 0- to 30-day mortality were uncertain (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.42 to 1.53; I2 = 0%; low-quality evidence). Based on seven studies including 778 participants, lower tidal volumes probably reduced postoperative pneumonia (RR 0.45, 95% CI 0.25 to 0.82; I2 = 0%; moderate-quality evidence; NNTB 24, 95% CI 16 to 160), and it probably reduced the need for non-invasive postoperative ventilatory support based on three studies including 506 participants (RR 0.31, 95% CI 0.15 to 0.64; moderate-quality evidence; NNTB 13, 95% CI 11 to 24). Based on 11 studies including 957 participants, low tidal volumes during surgery probably decreased the need for postoperative invasive ventilatory support (RR 0.33, 95% CI 0.14 to 0.77; I2 = 0%; NNTB 39, 95% CI 30 to 166; moderate-quality evidence). Based on five studies including 898 participants, there may be little or no difference in the intensive care unit length of stay (standardized mean difference (SMD) –0.06, 95% CI –0.22 to 0.10; I2 = 33%; low-quality evidence). Based on 14 studies including 1297 participants, low tidal volumes may have reduced hospital length of stay by about 0.8 days (SMD –0.15, 95% CI –0.29 to 0.00; I2 = 27%; low-quality evidence). Based on five studies including 708 participants, the effects of low volume ventilation on barotrauma (pneumothorax) were uncertain (RR 1.77, 95% CI 0.52 to 5.99; I2 = 0%; very low-quality evidence). We found moderate-quality evidence that low tidal volumes (defined as less than 10 mL/kg) decreases pneumonia and the need for postoperative ventilatory support (invasive and non-invasive). We found no difference in the risk of barotrauma (pneumothorax), but the number of participants included does not allow us to make definitive statement on this. The four studies in 'Studies awaiting classification' may alter the conclusions of the review once assessed.

We searched medical databases up to 19 May 2017. We included 19 studies with 1548 adults of both sexes. The participants had had operations on the abdomen (tummy), heart, blood vessels of the lungs, back, lower limbs or various surgeries. Two studies mentioned financial support from the pharmaceutical industry or from medical equipment manufacturers. We do not think that this had an effect on the results as high or low volumes may be administered with any machine. We did not find a difference in 0- to 30-day mortality (death within one month). We found that using a volume lower than 10 millilitres per kilogram of body weight reduced the risk of pneumonia (lung infection) and increased the chances that people would be able to get back to their normal respiratory status immediately after surgery. Low volumes should be used preferentially during surgery. For every 1000 people operated on, 84 would have pneumonia after the operation if high volumes were used during surgery. This number was reduced to 43 if low volumes were used instead. Likewise, the number of people needing additional non-invasive ventilatory support (through a mask applied to the face) would be reduced from 115 to 36 if volumes lower than 10 millilitres per kilogram of body weight were used during surgery and the need invasive ventilatory support (through a tube inserted in the person's windpipe) would be reduced from 39 to 13. Hospital length of stay may be slightly reduced (equivalent to almost one day). We identified no possible harmful effects of using low volumes. We judged the reliability of the evidence as moderate for pneumonia and reduced need for ventilatory support (non-invasive or invasive). Results on these three outcomes may be affected with additional data.

10.1002/14651858.CD011151.pub3

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We included 75 studies (36 from the original review and 39 from our updated review) enrolling a total of 7200 participants. Among primary outcomes, 36% of participants receiving IV paracetamol/propacetamol experienced at least 50% pain relief over four hours compared with 16% of those receiving placebo (number needed to treat to benefit (NNT) = 5; 95% confidence interval (CI) 3.7 to 5.6, high quality evidence). The proportion of participants in IV paracetamol/propacetamol groups experiencing at least 50% pain relief diminished over six hours, as reflected in a higher NNT of 6 (4.6 to 7.1, moderate quality evidence). Mean pain intensity at four hours was similar when comparing IV paracetamol and placebo, but was seven points lower on a 0 to 100 visual analog scale (0 = no pain, 100 = worst pain imaginable, 95% CI -9 to -6, low quality evidence) in those receiving paracetamol at six hours. For secondary outcomes, participants receiving IV paracetamol/propacetamol required 26% less opioid over four hours and 16% less over six hours (moderate quality evidence) than those receiving placebo. However, this did not translate to a clinically meaningful reduction in opioid-induced adverse events. Meta-analysis of efficacy comparisons between IV paracetamol/propacetamol and active comparators (e.g., opioids or nonsteroidal anti-inflammatory drugs) were either not statistically significant, not clinically significant, or both. Adverse events occurred at similar rates with IV paracetamol or IV propacetamol and placebo. However, pain on infusion occurred more frequently in those receiving IV propacetamol versus placebo (23% versus 1%). Meta-analysis did not demonstrate clinically meaningful differences between IV paracetamol/propacetamol and active comparators for any adverse event. Since the last version of this review, we have found 39 new studies providing additional information. Most included studies evaluated adults only. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides high quality evidence that a single dose of either IV paracetamol or IV propacetamol provides around four hours of effective analgesia for about 36% of patients with acute postoperative pain. Low to very low quality evidence demonstrates that both formulations are associated with few adverse events, although patients receiving IV propacetamol have a higher incidence of pain on infusion than both placebo and IV paracetamol.

Our updated review included data from 75 studies of 7200 patients with moderate-to-severe pain after an operation. We found high quality evidence that IV paracetamol or IV propacetamol provided pain relief for four hours for about 36% of people versus 16% of those receiving placebo. Direct comparisons with other painkillers, such as morphine and anti-inflammatories, did not show large differences (if any) in effectiveness, although this may have been due to the small numbers of patients studied. Low quality evidence showed that IV paracetamol and IV propacetamol produced few side effects. However, patients receiving IV propacetamol complained of pain at the site their medication was infused at more often than those receiving placebo or IV paracetamol. Due to the amount of data already included in our review, we think it is unlikely that any new studies will change our conclusions. However, we found very few studies that included children, so this is an area that requires further investigation.

10.1002/14651858.CD007126.pub3

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We included seven trials involving 1,020 participants. Mean time to cessation of vomiting in one study was 0.34 days less with dimenhydrinate suppository compared to placebo (P value = 0.036). Pooled data from three studies comparing oral ondansetron with placebo showed: a reduction in the immediate hospital admission rate (RR 0.40, NNT 17, 95% CI 10 to 100) but no difference between the hospitalization rates at 72 hours after discharge from the Emergency Department (ED); a reduction in IV rehydration rates both during the ED stay (RR 0.41, NNT 5, 95% CI 4 to 8), and in follow-up to 72 hours after discharge from the ED stay (worst-best scenario for ondansetron RR 0.57, NNT 6, 95% CI 4 to 13) and an increase in the proportion of patients with cessation of vomiting (RR 1.34, NNT 5, 95% CI 3 to 7)). No significant difference was noted in the revisit rates or adverse events, although diarrhea was reported as a side effect in four of the five ondansetron studies. In one study the proportion of patients with cessation of vomiting in 24 hours was (58%) with IV ondansetron, (17%) placebo and (33%) in the metoclopramide group (P value = 0.039). Oral ondansetron increased the proportion of patients who had ceased vomiting and reduced the number needing intravenous rehydration and immediate hospital admission. Intravenous ondansetron and metoclopramide reduced the number of episodes of vomiting and hospital admission, and dimenhydrinate as a suppository reduced the duration of vomiting.

The small number of included trials provided evidence which appeared to favour the use of antiemetics over placebo to reduce the number of episodes of vomiting due to gastroenteritis in children. A single oral dose of ondansetron given to children with mild to moderate dehydration can control vomiting, avoid hospitalization and intravenous fluid administration which would otherwise be needed. There were no major side effects other than a few reports of increased frequency of diarrhea.

10.1002/14651858.CD005506.pub5

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Only one trial met the inclusion criteria for this review which was a small, open-label, unblinded, randomised trial of the safety and feasibility of switching from phenytoin to levetiracetam monotherapy or continuing phenytoin for glioma-related seizure control following craniotomy (Lim 2009). Levetiracetam (a non enzyme-inducing antiepileptic drug) appears to have been at least as well tolerated and as effective as phenytoin (an enzyme-inducing antiepileptic drug) for the treatment of seizures in people with brain tumours. Eighty-seven per cent of participants treated with levetiracetam were free of seizures at six months compared with 75% of participants treated with phenytoin. There is one ongoing study of levetiracetam versus pregabalin for the treatment of seizures in adults undergoing chemotherapy, radiotherapy,or both for primary brain tumours. No data from this study were available at the time of preparing this review. There is a lack of robust, randomised, controlled evidence to support the choice of antiepileptic drug for the treatment of seizures in adults with brain tumours. While some authors support the use of non enzyme-inducing antiepileptic drugs, reliable, comparative evidence to provide clinical justification for this is limited. There is a need for further large, randomised, controlled trials in this area.

There is a lack of good quality evidence to support the choice of any particular antiepileptic drug for the treatment of seizures in adults with brain tumours. Our searches identified one small randomised trial directly comparing two different antiepileptic drugs (phenytoin and levetiracetam) for the treatment of seizures in adults with brain tumours. No significant difference was identified between the effectiveness of these two drugs. This small study was intended as a feasibility study for a larger trial that was not carried out. We also identified one ongoing study of levetiracetam versus pregabalin for the treatment of seizures in adults undergoing chemotherapy, radiotherapy,or both for primary brain tumours although no data from this study were available at the time of preparing this review. We identified a number of other small studies but we excluded them from the review as they were not randomised controlled trials. There is a clear need for larger randomised controlled trials to study the effectiveness of different antiepileptic drugs in the treatment of seizures in adults with brain tumours.

10.1002/14651858.CD008586.pub2

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We included a total of 24 randomised controlled trials (reported in 39 published research articles or abstracts) in this review. The trials included 2352 participants with lumbar spinal stenosis with symptoms of neurogenic claudication. None of the included trials compared surgery with no treatment, placebo or sham surgery. Therefore, all included studies compared two or more surgical techniques. We judged all trials to be at high risk of bias for the blinding of care provider domain, and most of the trials failed to adequately conceal the randomisation process, blind the participants or use intention-to-treat analysis. Five trials compared the effects of fusion in addition to decompression surgery. Our results showed no significant differences in pain relief at long-term (mean difference (MD) -0.29, 95% confidence interval (CI) -7.32 to 6.74). Similarly, we found no between-group differences in disability reduction in the long-term (MD 3.26, 95% CI -6.12 to 12.63). Participants who received decompression alone had significantly less perioperative blood loss (MD -0.52 L, 95% CI -0.70 L to -0.34 L) and required shorter operations (MD -107.94 minutes, 95% CI -161.65 minutes to -54.23 minutes) compared with those treated with decompression plus fusion, though we found no difference in the number of reoperations (risk ratio (RR) 1.25, 95% CI 0.81 to 1.92). Another three trials investigated the effects of interspinous process spacer devices compared with conventional bony decompression. These spacer devices resulted in similar reductions in pain (MD -0.55, 95% CI -8.08 to 6.99) and disability (MD 1.25, 95% CI -4.48 to 6.98). The spacer devices required longer operation time (MD 39.11 minutes, 95% CI 19.43 minutes to 58.78 minutes) and were associated with higher risk of reoperation (RR 3.95, 95% CI 2.12 to 7.37), but we found no difference in perioperative blood loss (MD 144.00 mL, 95% CI -209.74 mL to 497.74 mL). Two trials compared interspinous spacer devices with decompression plus fusion. Although we found no difference in pain relief (MD 5.35, 95% CI -1.18 to 11.88), the spacer devices revealed a small but significant effect in disability reduction (MD 5.72, 95% CI 1.28 to 10.15). They were also superior to decompression plus fusion in terms of operation time (MD 78.91 minutes, 95% CI 30.16 minutes to 127.65 minutes) and perioperative blood loss (MD 238.90 mL, 95% CI 182.66 mL to 295.14 mL), however, there was no difference in rate of reoperation (RR 0.70, 95% CI 0.32 to 1.51). Overall there were no differences for the primary or secondary outcomes when different types of surgical decompression techniques were compared among each other. The quality of evidence varied from 'very low quality' to 'high quality'. The results of this Cochrane review show a paucity of evidence on the efficacy of surgery for lumbar spinal stenosis, as to date no trials have compared surgery with no treatment, placebo or sham surgery. Placebo-controlled trials in surgery are feasible and needed in the field of lumbar spinal stenosis. Our results demonstrate that at present, decompression plus fusion and interspinous process spacers have not been shown to be superior to conventional decompression alone. More methodologically rigorous studies are needed in this field to confirm our results.

We included all trials that compared any surgical technique with no surgery or placebo surgery, and also trials comparing different surgical techniques with each other, including fusion and spinal implants. All the patients included in these studies were diagnosed with lumbar spinal stenosis and had symptoms in the leg or thigh that worsened by walking or standing and were generally relieved by a change in position, such as bending forward or sitting. The main measure we used to compare how well the different types of surgery worked was how much less pain people felt as they went about their daily lives. We also looked at whether their leg pain improved, how much blood they lost during surgery, how long the surgery took, how long they had to stay in hospital, how many patients had to have another operation for the problem and how much the treatment cost. Twenty-four randomised controlled trials were included with a total of 2352 people. We did not find trials that compared surgery with no treatment or placebo surgery, so all included trials compared different surgical techniques. The quality of the evidence from these studies varied from very low quality to high quality. This large variation was mainly due to different study protocols, surgical techniques and quality of reporting according to the 'Risk of bias' assessment. We found that patients who had decompression plus fusion fared no better than those who underwent decompression surgery alone. In fact, decompression plus fusion resulted in more blood loss during surgery than decompression alone. Although the spinal spacers were slightly better than decompression plus fusion in terms of improvements on daily activities, there were no differences when they were compared with decompression alone. Finally, we found no differences between different forms of decompression.

10.1002/14651858.CD012421

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Fifteen trials were included which tested two treatment regimes, 90 and 180 mg/day of nimodipine for 12, 24 weeks and 52 weeks. Two trials included only patients with Alzheimer's disease (AD), 10 trials included only patients with cerebrovascular dementia (CVD), and three trials included patients with AD, CVD and mixed disease. Available outcome data from nine trials (2492 patients) cover the domains of cognitive function, activities of daily living, global clinical state, safety and tolerability. By pooling available data from all trials, whatever the diagnosis of the patients included, this review found benefit associated with nimodipine (90 mg/day at 12 weeks) compared with placebo on the SCAG scale (WMD -7.59, 95% CI -9.87 to -5.31, P<0.00001), on clinical global impression (WMD -0.87, 95% CI -1.07 to -0.67, P<0.00001) and cognitive function (SMD 0.61, 95% CI 0.42 to 0.81, P<0.00001) but not on scales assessing activities of daily living. When the AD trials and the VD trials were pooled separately, similar significant results were found for the 90 mg/day dose of nimodipine at 12 weeks. Drop-out rates were low in the trials, affecting similar proportions of treatment and placebo groups. Nimodipine is well tolerated with a low rate of adverse effects similar to that associated with placebo. There were slightly more adverse cerebrovascular events, and adverse events due to blood problems, associated with placebo than with nimodipine, and adverse autonomic events were slightly more common with nimodipine than with placebo. Nimodipine can be of some benefit in the treatment of patients with features of dementia due to unclassified disease or to Alzheimer's disease, cerebrovascular disease, or mixed Alzheimer's and cerebrovascular disease. It appears to be well tolerated with few side effects. Data were not available from several trials, a total of more than 500 patients. A meta-analysis of individual patient data from all trials is desirable. Dementia is a chronic disorder and the short-term benefits of nimodipine demonstrated in the trials reviewed do not justify its use as a long-term anti-dementia drug. New research must focus on longer term outcomes.

The efficacy of nimodipine, a calcium channel blocker, has been tested in randomized controlled trials for the treatment of dementia, particularly Alzheimer's disease and multi-infarct dementia, the commonest forms of dementia in older people. The rationale for its use is to restrict the influx of calcium ions into neurons, and, by vasodilatation, to improve blood flow to the brain. This review found evidence of some short-term benefit attributable to nimodipine, mainly in measures of cognitive function and global impression, but not in activities on daily living, for patients with degenerative and multi-infarct dementia, and mixed dementia. Nimodipine is well tolerated with a low rate of adverse effects similar to that associated with placebo.

10.1002/14651858.CD000147

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Three studies (313 participants) met the inclusion criteria. One study compared INF versus intramuscular morphine (IMM); another study compared INF versus intravenous morphine (IVM); and another study compared standard concentration INF (SINF) versus high concentration INF (HINF). All three studies reported a reduction in pain score following INF administration. INF produced a greater reduction in pain score at 10 minutes post administration when compared with IMM (INF group pain score: 1/5 vs IMM group pain score: 2/5; P value 0.014). No other statistically significant differences in pain scores were reported at any other time point. When INF was compared with IVM and HINF, no statistically significant differences in pain scores were noted between treatment arms, before analgesia or at 5, 10, 20 and 30 minutes post analgesia. Specifically, when INF was compared with IVM, both agents were seen to produce a statistically significant reduction in pain score up to 20 minutes post analgesia. No further reduction in pain score was noted after this time. When SINF was compared with HINF, a statistically and clinically significant reduction in pain scores over study time was observed (median decrease for both groups 40 mm, P value 0.000). No adverse events (e.g. opiate toxicity, death) were reported in any study following INF administration. One study described better patient tolerance to INF compared with IMM, which achieved statistical significance. The other studies described reports of a “bad taste” and vomiting with INF. Overall the risk of bias in all studies was considered low. INF may be an effective analgesic for the treatment of patients with acute moderate to severe pain, and its administration appears to cause minimal distress to children. However, this review of published studies does not allow any definitive conclusions regarding whether INF is superior, non-inferior or equivalent to intramuscular or intravenous morphine. Limitations of this review include the following: few eligible studies for inclusion (three); no study examined the use of INF in children younger than three years of age; no study included children with pain from a "medical" cause (e.g. abdominal pain seen in appendicitis); and all eligible studies were conducted in Australia. Consequently, the findings may not be generalizable to other healthcare settings, to children younger than three years of age and to those with pain from a "medical" cause.

We included studies with children (younger than 18 years of age) suffering from acute severe pain as a result of injury or medical illness. The target intervention was INF administered for pain relief compared with any other drug intervention for pain relief (e.g. intravenous morphine) or non-drug intervention (e.g. limb splinting, wound dressing) provided in the emergency setting. The evidence is current to January 2014. We identified three studies that included 313 children with acute severe pain resulting from broken bones of the upper and lower limbs. These trials compared INF versus morphine administered by a needle into a muscle (intramuscular morphine) or via a drip into a vein (intravenous morphine), as well as standard concentration INF versus high concentration INF. The collective study population in these trials consisted of children three to 15 years of age. Males accounted for approximately two-thirds of the overall study population. The review concluded that INF may be an effective analgesic for the treatment of children in acute moderate to severe pain, and its administration appears to cause minimal distress to children; however, the evidence is insufficient to permit judgement of the effects of INF compared with intramuscular or intravenous morphine. No serious adverse events (e.g. opiate toxicity, death) were reported. Limitations of this review include the following: Few studies (three) were eligible for inclusion; no study examined the use of INF in children younger than three years of age; no study included children with pain resulting from a "medical" cause (e.g. abdominal pain seen in appendicitis); and all eligible studies were conducted in Australia. Consequently, the findings may not be generalizable to other healthcare settings, to children younger than three years of age and to those with pain from a "medical" cause.

10.1002/14651858.CD009942.pub2

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The review now includes 13 poorly reported randomised trials (total 478 people), all participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. There was no clear difference between vitamin E and placebo for the outcome of TD: not improved to a clinically important extent (6 RCTs, N = 264, RR 0.95, 95% CI 0.89 to 1.01, low-quality evidence). However, people allocated to placebo may show more deterioration of their symptoms compared with those given vitamin E (5 RCTs, N = 85, RR 0.23, 95% CI 0.07 to 0.76, low-quality evidence). There was no evidence of a difference in the incidence of any adverse effects (9 RCTs, N = 205, RR 1.21, 95% CI 0.35 to 4.15, very low-quality evidence), extrapyramidal adverse effects (1 RCT, N = 104, MD 1.10, 95% CI -1.02 to 3.22, very low-quality evidence), or acceptability of treatment (measured by participants leaving the study early) (medium term, 8 RCTs, N = 232, RR 1.07, 95% CI 0.64 to 1.80, very low-quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes designated important to patients. There is no trial-based information regarding the effect of vitamin E for those with early onset of TD. Small trials of limited quality suggest that vitamin E may protect against deterioration of TD. There is no evidence that vitamin E improves symptoms of this problematic and disfiguring condition once established. New and better trials are indicated in this under-researched area, and, of the many adjunctive treatments that have been given for TD, vitamin E would be a good choice for further evaluation.

We searched for trials, July 2015 and April 2017, using the Cochrane Schizophrenia Group's register of trials. The review includes 13 poorly reported randomised trials investigating the effects of vitamin E for people with schizophrenia or other chronic mental illnesses who also developed TD as a result of taking antipsychotics. The trials randomised a total of 478 participants who had been ill for a long time. Vitamin E may protect against tardive dyskinesia. However, there is no clear evidence that vitamin E improves this problematic and disfiguring condition. Available evidence is weak, limited and poor and we are unable to make any conclusions regarding the use of Vitamin E for antipsychotic-induced tardive dyskinesia. Well-designed trials involving a large number of participants investigating the effects of vitamin E over long periods of time are needed to determine whether this vitamin provides an effective treatment option for tardive dyskinesia. This plain language summary was adapted by the review authors from a summary originally written by Ben Gray, Senior Peer Researcher, McPin Foundation (http://mcpin.org/).

10.1002/14651858.CD000209.pub3

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This is an update of a Cochrane review from 2011, which included five trials. This update includes seven studies on treadmill intervention in 175 children: 104 were allocated to treadmill groups, and 71 were controls. The studies varied in population (children with Down syndrome, cerebral palsy, developmental delay or at moderate risk for neuromotor delay); comparison type (treadmill versus no treadmill; treadmill with versus without orthoses; high- versus low-intensity training); study duration, and assessed outcomes. Due to the diversity of the studies, only data from five studies were used in meta-analyses for five outcomes: age of independent walking onset, overall gross motor function, gross motor function related to standing and walking, and gait velocity. GRADE assessments of quality of the evidence ranged from high to very low. The effects of treadmill intervention on independent walking onset compared to no treadmill intervention was population dependent, but showed no overall effect (mean difference (MD) -2.08, 95% confidence intervals (CI) -5.38 to 1.22, 2 studies, 58 children; moderate-quality evidence): 30 children with Down syndrome benefited from treadmill training (MD -4.00, 95% CI -6.96 to -1.04), but 28 children at moderate risk of developmental delay did not (MD -0.60, 95% CI -2.34 to 1.14). We found no evidence regarding walking onset in two studies that compared treadmill intervention with and without orthotics in 17 children (MD 0.10, 95% CI -5.96 to 6.16), and high- versus low-intensity treadmill interventions in 30 children with Down syndrome (MD -2.13, 95% -4.96 to 0.70). Treadmill intervention did not improve overall gross motor function (MD 0.88, 95% CI -4.54 to 6.30, 2 studies, 36 children; moderate-quality evidence) or gross motor skills related to standing (MD 5.41, 95% CI -1.64 to 12.43, 2 studies, 32 children; low-quality evidence), and had a negligible improvement in gross motor skills related to walking (MD 4.51, 95% CI 0.29 to 8.73, 2 studies, 32 children; low-quality evidence). It led to improved walking skills in 20 ambulatory children with developmental delay (MD 7.60, 95% CI 0.88 to 14.32, 1 study) and favourable gross motor skills in 12 children with cerebral palsy (MD 8.00, 95% CI 3.18 to 12.82). A study which compared treadmill intervention with and without orthotics in 17 children with Down syndrome suggested that adding orthotics might hinder overall gross motor progress (MD -8.40, 95% CI -14.55 to -2.25). Overall, treadmill intervention showed a very small increase in walking speed compared to no treadmill intervention (MD 0.23, 95% CI 0.08 to 0.37, 2 studies, 32 children; high-quality evidence). Treadmill intervention increased walking speed in 20 ambulatory children with developmental delay (MD 0.25, 95% CI 0.08 to 0.42), but not in 12 children with cerebral palsy (MD 0.18, 95% CI -0.09 to 0.45). This update of the review from 2011 provides additional evidence of the efficacy of treadmill intervention for certain groups of children up to six years of age, but power to find significant results still remains limited. The current findings indicate that treadmill intervention may accelerate the development of independent walking in children with Down syndrome and may accelerate motor skill attainment in children with cerebral palsy and general developmental delay. Future research should first confirm these findings with larger and better designed studies, especially for infants with cerebral palsy and developmental delay. Once efficacy is established, research should examine the optimal dosage of treadmill intervention in these populations.

We included seven studies on treadmill intervention on 175 children with Down syndrome, cerebral palsy, general developmental delay or children with moderate risk for delay. Studies used home-based or clinic-based treadmill protocols, ranging in duration from six weeks to several months, or until the children walked independently. Treadmill training versus no treadmill training was compared in five studies, including 117 children with one of the above mentioned risks. Treadmill training with or without orthotics (braces) was examined in 22 children with Down syndrome. High-intensity versus low-intensity treadmill training was compared in 36 children with Down syndrome. Compared to no treadmill intervention, treadmill training helped 30 children with Down syndrome to walk earlier, but did not help 28 infants at moderate risk for developmental delay. Overall, treadmill intervention did not improve overall gross motor function or gross motor skills related to standing. One study, which compared treadmill intervention with and without orthotics in 17 children with Down syndrome, suggested that adding orthotics might hinder gross motor progress. However, 20 ambulatory children with developmental delay, who engaged in treadmill training at preschool, improved walking skills. Twelve children with cerebral palsy, who received intensive treadmill training, showed faster achievement of motor milestones than children without treadmill training. None of the studies reported problems or injuries from the treadmill training. Overall, support for the intervention is limited. Confirmation from larger studies is necessary. Once efficacy of the intervention is established, optimal dosage research is needed. Statistical analysis was only performed on similar outcomes across studies. Standardized assessment for quality of evidence ranged from high to very low. Quality of evidence was determined by the number of children studied, completeness of the data, and random group assignment.

10.1002/14651858.CD009242.pub3

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We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs). Compared with placebo, PCSK9 inhibitors decreased LDL-C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors decreased LDL-C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 inhibitors decreased LDL-C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors decreased the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a stronger protective effect on CVD risk, although with considerable uncertainty (RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; GRADE: very low). No data were available for the ezetimibe only comparison. Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 participants; GRADE: low). Similar effects were observed for the comparison of ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 5376 participants; GRADE: low. Clinical event data were unavailable for the ezetimibe only comparison. Over short-term to medium-term follow-up, PCSK9 inhibitors reduced LDL-C. Studies with medium-term follow-up time (longest median follow-up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE-1 and -2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow-up times were short and events were few. Large trials with longer follow-up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high-risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%).

Review authors identified 20 studies that evaluated the effects of PCSK9 inhibitors in participants at high risk of CVD; studies were conducted in outpatient clinic settings. Review authors identified the studies included in this review through electronic literature searches conducted up to May 2016, and added three large trials published in March 2017. PCSK9 inhibitors constitute a class of drugs that decrease LDL-C and therefore may decrease the incidence of CVD. We examined the results of 20 studies, which showed beneficial effects on blood cholesterol concentrations of PCSK9 inhibitors at both six months and one year of follow-up. Although the magnitude of this beneficial effect differed between studies, all showed beneficial effects. In comparisons of PCSK9 inhibitors versus no PCSK9 inhibitors, current evidence suggests that PCSK9 inhibitors decrease CVD incidence without affecting the incidence of all-cause mortality. In comparisons of PCSK9 inhibitors versus alternative (more established) treatments such as statins or ezetimibe, high-quality evidence is lacking. Differences in risk between people treated with and without PCKS9 inhibitors suggest the absolute treatment benefit will likely be modest (e.g. < 1% change in risk). Most of the included randomised controlled trials (RCTs) were designed to explore biomarker associations; however, as all trials were industry funded, GRADE assessment revealed that the quality of the evidence was moderate. For associations with clinical endpoints (mortality and CVD), the quality of the evidence was moderate (placebo comparison) to very low (ezetimibe and statin comparisons).

10.1002/14651858.CD011748.pub2

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One cluster-RCT (with 157,259 participants) and four RCTs of individuals (1917 participants) met the inclusion criteria. The cluster-RCT from the former USSR showed that, compared with no vaccine, a live-attenuated vaccine (called STI) protected against clinical anthrax whether given by a needleless device (RR 0.16; 102,737 participants, 154 clusters) or the scarification method (RR 0.25; 104,496 participants, 151 clusters). Confidence intervals were statistically significant in unadjusted calculations, but when a small amount of association within clusters was assumed, the differences were not statistically significant. The four RCTs (of individuals) of inactivated vaccines (anthrax vaccine absorbed and recombinant protective antigen) showed a dose response relationship for the anti-protective antigen IgG antibody titre. Intramuscular administration was associated with fewer injection site reactions than subcutaneous injection, and injection site reaction rates were lower when the dosage interval was longer. One cluster-RCT provides limited evidence that a live-attenuated vaccine is effective in preventing cutaneous anthrax. Vaccines based on anthrax antigens are immunogenic in most vaccinees with few adverse events or reactions. Ongoing randomized controlled trials are investigating the immunogenicity and safety of anthrax vaccines.

The authors of this review wanted to evaluate the benefits and harms of vaccines for preventing anthrax. They identified four recent smaller randomized controlled trials of individuals and an older large cluster-randomized controlled trial with over 150,000 participants. The cluster trial provided limited evidence that a vaccine, based on a strain of live anthrax organisms incapable of causing disease, was effective in preventing cutaneous anthrax. More recent types of vaccines tested in the smaller trials, also based on inactivated components of the anthrax bacterium, appear to have few adverse events and to stimulate a good immune response. Several randomized controlled trials testing these newer vaccines are currently in progress. They will provide further information on the immunogenicity and safety of different vaccine regimens to be used for people at risk of anthrax exposure.

10.1002/14651858.CD006403.pub2

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Apart from the five studies in the original review, this update included one additional RCT. In total, the analysis included 171 participants, all during treatment for childhood acute lymphoblastic leukaemia (ALL). The duration of the training sessions ranged from 15 to 60 minutes per session. Both the type of intervention and intervention period varied in all the included studies. However, the control group always received usual care. All studies had methodological limitations, such as small numbers of participants, unclear randomization methods, and single-blind study designs in case of one RCT and all results were of moderate to very low quality (GRADE). Cardiorespiratory fitness was evaluated by the 9-minute run-walk test, timed up-and-down stairs test, the timed up-and-go time test, and the 20-m shuttle run test. Data of the 9-minute run-walk test and the timed up-and-down stairs test could be pooled. The combined 9-minute run-walk test results showed significant differences between the intervention and the control groups, in favour of the intervention group (standardized mean difference (SMD) 0.69; 95% confidence interval (CI) 0.02 to 1.35). Pooled data from the timed up-and-down stairs test showed no significant differences in cardiorespiratory fitness (SMD -0.54; 95% CI -1.77 to 0.70). However, there was considerable heterogeneity (I2 = 84%) between the two studies on this outcome. The other two single-study outcomes, 20-m shuttle run test and the timed up-and-go test, also showed positive results for cardiorespiratory fitness in favour of the intervention group. Only one study assessed the effect of exercise on bone mineral density (total body), showing a statistically significant positive intervention effect (SMD 1.07; 95% CI 0.48 to 1.66). The pooled data on body mass index showed no statistically significant end-score difference between the intervention and control group (SMD 0.59; 95% CI -0.23 to 1.41). Three studies assessed flexibility. Two studies assessed ankle dorsiflexion. One study assessed active ankle dorsiflexion, while the other assessed passive ankle dorsiflexion. There were no statistically significant differences between the intervention and control group with the active ankle dorsiflexion test; however, in favour of the intervention group, they were found for passive ankle dorsiflexion (SMD 0.69; 95% CI 0.12 to 1.25). The third study assessed body flexibility using the sit-and-reach distance test, but identified no statistically significant difference between the intervention and control group. Three studies assessed muscle strength (knee, ankle, back and leg, and inspiratory muscle strength). Only the back and leg strength combination score showed statistically significant differences on the muscle strength end-score between the intervention and control group (SMD 1.41; 95% CI 0.71 to 2.11). Apart from one sub-scale of the cancer scale (Worries; P value = 0.03), none of the health-related quality of life scales showed a significant difference between both study groups on the end-score. For the other outcomes of fatigue, level of daily activity, and adverse events (all assessed in one study), there were no statistically significant differences between the intervention and control group. None of the included studies evaluated activity energy expenditure, time spent on exercise, anxiety and depression, or self efficacy as an outcome. The effects of physical exercise training interventions for childhood cancer participants are not yet convincing. Possible reasons are the small numbers of participants and insufficient study designs, but it can also be that this type of intervention is not as effective as in adult cancer patients. However, the first results show some positive effects on physical fitness in the intervention group compared to the control group. There were positive intervention effects for body composition, flexibility, cardiorespiratory fitness, muscle strength, and health-related quality of life (cancer-related items). These were measured by some assessment methods, but not all. However, the quality of the evidence was low and these positive effects were not found for the other assessed outcomes, such as fatigue, level of daily activity, and adverse events. There is a need for more studies with comparable aims and interventions, using a higher number of participants that also include diagnoses other than ALL.

We searched scientific databases for studies of comparing the effects of physical exercise training within the first five years following the diagnosis of childhood cancer compared with no training. Participants were under 19 years of age with any type of childhood cancer. The evidence is current to November 2014. This review included five randomized controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) and one clinical controlled trial (clinical studies where people are put into one of two or more treatment groups but this is not done in a random way) that evaluated the effects of a physical exercise training programme in children during cancer treatment. Childhood acute lymphoblastic leukaemia (ALL) is a cancer of the white blood cells and is the most common type of childhood cancer. For that reason, researchers often focus on this type of cancer since it will provide the largest number of patients in the shortest time-span. In total, our analysis included 171 participants with ALL. The results of the review showed that there were some small benefits of physical exercise training on body composition (percentage of fat mass, muscles, and bones), flexibility, cardiorespiratory fitness (how effective your heart and lungs are at delivering oxygen to your body), muscle strength and quality of life, but the evidence was limited. This can be related to an unsuitable programmes for children with cancer, or due to poorly designed studies. More studies assessing the effects of exercise are needed in a variety of childhood cancer populations. Furthermore, the current findings do not provide enough evidence to identify an optimal physical exercise training programme for children with cancer, neither do they provide information on the characteristics of people who will, or will not, benefit from such a programme. These important issues still need to be clarified.

10.1002/14651858.CD008796.pub3

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We could only include five studies conducted between 1965 and 1980. Most of the included studies did not report details of randomisation, allocation concealment, details of blinding and we could not assess the impact of attrition due to poor reporting. For the primary outcome of Global state - not improved, the confidence interval was compatible with a small benefit and increased risk of not improving with pericyazine compared with typical antipsychotics (2 RCTs, n = 122, RR 1.24 CI 0.93 to 1.66, very low quality of evidence) or atypical antipsychotics (1 RCT, n = 93, RR 0.97 CI 0.67 to 1.42, very low quality of evidence). When compared with typical antipsychotics relapse was only experienced by one person taking pericyazine (1 RCT, n = 80, RR 2.59 CI 0.11 to 61.75, very low quality of evidence). Pericyazine was associated with more extrapyramidal side effects than typical antipsychotics (3 RCTs, n = 163, RR 0.52 CI 0.34 to 0.80, very low quality of evidence) and atypical antipsychotics (1 RCT, n = 93, RR 2.69 CI 1.35 to 5.36, very low quality of evidence). The estimated risk of leaving the study early for specific reasons was imprecise for the comparisons of pericyazine with typical antipsychotics (2 RCTs, n = 71, RR 0.46 CI 0.11 to 1.90, very low quality of evidence), and with atypical antipsychotics (1 RCT, n = 93, RR 0.13 CI 0.01 to 2.42, very low quality of evidence). On the basis of very low quality evidence we are unable to determine the effects of pericyazine in comparison with typical or atypical antipsychotics for the treatment of schizophrenia. However, there is some evidence that pericyazine may be associated with a higher incidence of extrapyramidal side effects than other antipsychotics, and again this was judged to be very low quality evidence. Large, robust studies are still needed before any firm conclusions can be drawn.

This review aims to assess the effectiveness of pericyazine in the treatment of schizophrenia compared to older and newer antipsychotics.A search for studies was carried out in 2013 and five studies conducted between 1965 and 1980 were found and included in the review. The quality of evidence was rated by the authors to be very low, and their results were imprecise for many outcomes where they compared pericyazine and other older and newer antipsychotic drugs. The evidence is inadequate to determine whether pericyazine is better than other antipsychotics. The results of the analysis for the outcome of improvement were imprecise and the authors could not be certain that more people who took pericyazine were found to have not improved compared with those who took typical antipsychotics. More side effects, such as involuntary shaking, tremors, restlessness and spasms, were experienced by people who took pericyazine than other typical or atypical antipsychotics. These side effects are very unpleasant and the increased occurrence of them compared to other antipsychotics is an important finding considering pericyazine may not have additional benefits for the symptoms of schizophrenia. No studies reported outcomes on satisfaction of treatment or cost effectiveness, which require attention. This lack of evidence leaves people with schizophrenia, mental health professionals and policy makers with little information on the benefits, hazards or problems of pericyazine. Outcomes on the cost of care and satisfaction with treatment should be included in future trials which should also be larger, better conducted, and fully reported. (This plain language summary has been written by Ben Gray from Rethink Mental Illness).

10.1002/14651858.CD007479.pub2

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Thirty studies met our inclusion criteria. From 11 studies on osteoporosis, meta-analysis of five studies (high-certainty evidence) showed that a combination of a GP alerting system on a patient's increased risk of osteoporosis and a patient-directed intervention (including patient education and a reminder to see their GP) improves GP behaviour with regard to diagnostic bone mineral density (BMD) testing and osteoporosis medication prescribing (RR 4.44; (95% confidence interval (CI) 3.54 to 5.55; 3 studies; 3,386 participants)) for BMD and RR 1.71 (95% CI 1.50 to 1.94; 5 studies; 4,223 participants) for osteoporosis medication. Meta-analysis of two studies showed that GP alerting on its own also probably improves osteoporosis guideline-consistent GP behaviour (RR 4.75 (95% CI 3.62 to 6.24; 3,047 participants)) for BMD and RR 1.52 (95% CI 1.26 to 1.84; 3.047 participants) for osteoporosis medication) and that adding the patient-directed component probably does not lead to a greater effect (RR 0.94 (95% CI 0.81 to 1.09; 2,995 participants)) for BMD and RR 0.93 (95% CI 0.79 to 1.10; 2,995 participants) for osteoporosis medication. Of the 10 studies on low back pain, seven showed that guideline dissemination and educational opportunities for GPs may lead to little or no improvement with regard to guideline-consistent GP behaviour. Two studies showed that the combination of guidelines and GP feedback on the total number of investigations requested may have an effect on GP behaviour and result in a slight reduction in the number of tests, while one of these studies showed that the combination of guidelines and GP reminders attached to radiology reports may result in a small but sustained reduction in the number of investigation requests. Of the four studies on osteoarthritis, one study showed that using educationally influential physicians may result in improvement in guideline-consistent GP behaviour. Another study showed slight improvements in patient outcomes (pain control) after training GPs on pain management. Of three studies on shoulder pain, one study reported that there may be little or no improvement in patient outcomes (functional capacity) after GP education on shoulder pain and injection training. Of two studies on other musculoskeletal conditions, one study on pain management showed that there may be worse patient outcomes (pain control) after GP training on the use of validated assessment scales. The 12 remaining studies across all musculoskeletal conditions showed little or no improvement in GP behaviour and patient outcomes. The direction of the targeted behaviour (i.e. increasing or decreasing a behaviour) does not seem to affect the effectiveness of an intervention. The majority of the studies did not investigate the potential adverse effects of the interventions and only three studies included a cost-effectiveness analysis. Overall, there were important methodological limitations in the body of evidence, with just a third of the studies reporting adequate allocation concealment and blinded outcome assessments. While our confidence in the pooled effect estimate of interventions for improving diagnostic testing and medication prescribing in osteoporosis is high, our confidence in the reported effect estimates in the remaining studies is low. There is good-quality evidence that a GP alerting system with or without patient-directed education on osteoporosis improves guideline-consistent GP behaviour, resulting in better diagnosis and treatment rates. Interventions such as GP reminder messages and GP feedback on performance combined with guideline dissemination may lead to small improvements in guideline-consistent GP behaviour with regard to low back pain, while GP education on osteoarthritis pain and the use of educationally influential physicians may lead to slight improvement in patient outcomes and guideline-consistent behaviour respectively. However, further studies are needed to ascertain the effectiveness of such interventions in improving GP behaviour and patient outcomes.

Eleven studies evaluated interventions aiming to improve the management of osteoporosis by GPs. Five of these studies were sufficiently similar that we were able to combine their results. Our findings suggest that alerting the GP that a patient is at risk of osteoporosis and educating the patient, reminding them to visit their GP, leads to improved GP behaviour (diagnostic testing and medication prescribing). We determined that the quality or certainty of the evidence from these studies is high, so we are confident in these results. GP alerting on its own is also probably effective according to two studies and adding the patient-directed component probably does not lead to a greater effect. Of the ten studies on low back pain, seven showed that GP education and distribution of guidelines may lead to little or no improvement with regards to GPs' clinical behaviour. Two studies showed that providing GPs with guidelines and information on the total number of tests they request may have an effect on GP behaviour (resulting in a slight reduction in the number of tests). One study showed that using a combination of guidelines and GP reminders attached to test reports may result in a small but sustained reduction in the number of tests. Of the four studies on osteoarthritis, one found that GP behaviour may improve when prominent GPs are recruited to educate their colleagues. A second study showed slight improvements in patient outcomes (pain control) after training GPs on pain management. Of the three studies on shoulder pain, one study showed that there may be little or no improvement in patient outcomes (functional capacity) after GP education on shoulder pain and injection training. Of the two studies on other musculoskeletal conditions, one study on pain management showed worse patient outcomes (pain control) after GP training on the use of tools to measure pain. The 12 remaining studies across all musculoskeletal conditions showed little or no improvement in GP behaviour and patient outcomes. The majority of the studies did not investigate the potential adverse effects of the interventions and only three studies included a cost-effectiveness analysis. The direction of the targeted behaviour (i.e. increasing or decreasing a behaviour) does not seem to affect the effectiveness of an intervention. The certainty of the evidence was high from studies that examined the effectiveness of interventions to improve the management of osteoporosis by GPs, so we are confident in these findings. There were important limitations in how most of the remaining studies were conducted or reported, and we are less certain of the likely effects of these interventions to improve the management of musculoskeletal conditions.

10.1002/14651858.CD007495.pub2

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Our search strategies led to 699 potentially relevant references. Of these, one RCT involving 79 patients was included. We judged the quality of the trial as moderate. The study was reported as a randomised open-label study and published as a full-text article. Even though PFS was statistically significantly improved for patients treated with HD-MTX plus cytarabine (HR 0.54; 95% CI 0.31 to 0.92; P = 0.01), this did not translate to a statistical significant OS benefit (HR 0.65; 95% CI 0.38 to 1.13; P = 0.07). AEs, especially infective complications, hepatotoxicity and haematological toxicities, were assessed more often in patients undergoing HD-MTX therapy combined with cytarabine. However, there were no statistically significant differences in terms of TRM (RR 3.08; 95% CI 0.33 to 28.32; P = 0.35). Owing to the small number of included trials and patients, the findings in this review remain uncertain. In summary, the presently available evidence (one small trial) showed a benefit in terms of PFS, ORR and CRR but no statistically significant difference regarding OS for patients with PCNSL treated with HD-MTX plus cytarabine compared to HD-MTX alone. However, the risk of severe infections and toxicity was significantly higher in patients treated with combined chemotherapy. More RCTs with additional chemotherapy to HD-MTX therapy with higher numbers of patients and longer follow-up periods are needed to confirm the results of this review and determine whether the PFS benefit will translate into an OS advantage. At least the one included study shows that RCTs of moderate quality and with valuable outcomes for this malignant disease are feasible.

In this systematic review we summarised and analysed the evidence from randomised controlled trials (RCTs) on efficacy and safety of methotrexate combined with additional chemotherapy in the treatment of adult, immunocompetent PCNSL patients regarding overall survival, progression-free survival, response rate, adverse events, treatment-related mortality and quality of life. We searched several important medical databases such as CENTRAL and MEDLINE and found one RCT with 79 patients that fulfilled our inclusion criteria. As a result, this review shows that patients treated with methotrexate plus cytarabine compared to high-dose methotrexate alone have a statistically significant improvement in progression-free survival and response rate. No statistically significant difference is shown for overall survival. Adverse events, especially infections, hepatotoxicity and haematological toxicities are more common in patients undergoing therapy with methotrexate plus cytarabine, although there are no differences in terms of treatment-related mortality. Owing to the small number of included trials and patients, the findings in this review remain uncertain and more RCTs with enlarged numbers of patients and longer follow-up periods are needed. However, the one analysed study demonstrated that RCTs are feasible on patients with this rare disease and should concentrate on overall survival.

10.1002/14651858.CD009355.pub2

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Six randomised controlled trials met the inclusion criteria for this review. Four studies compared LED and halogen light sources. Two studies compared LED and compact fluorescent light sources. The duration of phototherapy (six studies, 630 neonates) was comparable in LED and non-LED phototherapy groups (mean difference (hours) -0.43, 95% CI -1.91 to 1.05). The rate of decline of serum total bilirubin (STB) (four studies, 511 neonates) was also similar in the two groups (mean difference (mg/dL/hour) 0.01, 95% CI -0.02 to 0.04). Treatment failure, defined as the need of additional phototherapy or exchange blood transfusion (1 study, 272 neonates), was comparable (RR 1.83, 95% CI 0.47 to 7.17). Side effects of phototherapy such as hypothermia (RR 6.41, 95% CI 0.33 to 122.97), hyperthermia (RR 0.61, 95% CI 0.18 to 2.11) and skin rash (RR 1.83, 95% CI 0.17 to 19.96) were rare and occurred with similar frequency in the two groups. LED light source phototherapy is efficacious in bringing down levels of serum total bilirubin at rates that are similar to phototherapy with conventional (compact fluorescent lamp (CFL) or halogen) light sources. Further studies are warranted for evaluating efficacy of LED phototherapy in neonates with haemolytic jaundice or in the presence of severe hyperbilirubinaemia (STB ≥ 20 mg/dL).

In this systematic review, the efficacy of LED phototherapy was compared with conventional (non-LED) phototherapy. LED phototherapy was observed to be efficacious in bringing down the levels of serum total bilirubin, at rates similar to phototherapy with conventional light sources.

10.1002/14651858.CD007969.pub2

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Twenty studies (1150 women) were included. Women who had caesarean section performed under regional analgesia and had wound infiltration had a decrease in morphine consumption at 24 hours (SMD -1.70mg; 95% confidence interval (CI) -2.75 to -0.94) compared to placebo. In women under general anaesthesia, with caesarean section wound infiltration and peritoneal spraying with local anaesthetic (one study, 100 participants), the need for opioid rescue was reduced (risk ratio (RR) 0.51; 95% CI 0.38 to 0.69). The numerical pain score (0 to10) within the first hour was also reduced (mean difference (MD) -1.46; 95% CI -2.60 to -0.32). Women with regional analgesia who had local anaesthetic and non-steriodal anti-inflammatory cocktail wound infiltration consumed less morphine (one study, 60 participants; MD -7.40 mg; 95% CI -9.58 to -5.22) compared to local anaesthetic control. Women who had regional analgesia with abdominal nerves blocked had decreased opioid consumption (four studies, 175 participants; MD -25.80 mg; 95% CI -50.39 to -5.37). For the outcome of visual analogue scale 0 to 10 over 24 hours, no advantage was demonstrated in the single study of 50 participants who had wound infiltrated with a mixture of local analgesia and narcotics versus local analgesia. Addition of ketamine to the local analgesia in women who had regional analgesia does not confer any advantage. Local analgesia infiltration and abdominal nerve blocks as adjuncts to regional analgesia and general anaesthesia are of benefit in caesarean section by reducing opioid consumption. Nonsteroidal anti-inflammatory drugs as an adjuvant may confer additional pain relief.

The authors identified twenty randomised controlled trials of sufficient quality involving 1150 women. These trials were carried out in both developed and developing countries. In general, local anaesthesia wound infiltration was of benefit in women having a caesarean section requiring regional anaesthetics because of a reduction in the use of opioid analgesia. Women undergoing general anaesthesia who had wound infiltration with local anaesthetics and peritoneal spraying required lower amounts of opioids in the first 24 hours post-operation compared to saline control. Those who had a general anaesthetic and the abdominal wall nerves blocked had reduced pain scores within the first 24 hours postoperative. Women who had regional anaesthesia and abdominal nerves blocked also benefited by decrease in opioid requirements. Non-steroidal anti-inflammatory drugs provided additional pain relief but with more side effects of pruritus. The commonly used local anaesthetic agents do have side effects but these are very rare, ranging from allergy to cardiovascular and central nervous system effects. There was no report of side effects in infants following local anaesthetic infiltration but the number of women studied was small. The longer theatre time and cost of the local anaesthetic may be offset by less use of postoperative analgesia. The effect on the development of chronic pelvic pain should be an important area of research.

10.1002/14651858.CD006954.pub2

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We identified 16 eligible trials. Four trials are ongoing and two have been completed but the results have not yet been published (trial completion dates: April 2012 to February 2017). Therefore, the review included 10 trials in eight references with 554 participants. Six trials (336 participants) only included participants with acute myeloid leukaemia undergoing intensive chemotherapy, two trials (38 participants) included participants with lymphoma undergoing intensive chemotherapy and two trials (180 participants) reported participants undergoing allogeneic stem cell transplantation. Men and women were equally well represented in the trials. The age range of participants included in the trials was from 16 years to 81 years. All trials took place in high-income countries. The manufacturers of the agent sponsored eight trials that were under investigation, and two trials did not report their source of funding. No trials assessed artificial platelet substitutes, fibrinogen concentrate, recombinant activated factor VII or desmopressin. Nine trials compared a TPO mimetic to placebo or standard care; seven of these used pegylated recombinant human megakaryocyte growth and differentiation factor (PEG-rHuMGDF) and two used recombinant human thrombopoietin (rhTPO). One trial compared platelet-poor plasma to platelet transfusion. We considered that all the trials included in this review were at high risk of bias and meta-analysis was not possible in seven trials due to problems with the way data were reported. We are very uncertain whether TPO mimetics reduce the number of participants with any bleeding episode (odds ratio (OR) 0.40, 95% confidence interval (CI) 0.10 to 1.62, one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce the risk of a life-threatening bleed after 30 days (OR 1.46, 95% CI 0.06 to 33.14, three trials, 209 participants, very low quality evidence); or after 90 days (OR 1.00, 95% CI 0.06 to 16.37, one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce platelet transfusion requirements after 30 days (mean difference -3.00 units, 95% CI -5.39 to -0.61, one trial, 120 participants, very low quality evidence). No deaths occurred in either group after 30 days (one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce all-cause mortality at 90 days (OR 1.00, 95% CI 0.24 to 4.20, one trial, 120 participants, very low quality evidence). No thromboembolic events occurred for participants treated with TPO mimetics or control at 30 days (two trials, 209 participants, very low quality evidence). We found no trials that looked at: number of days on which bleeding occurred, time from randomisation to first bleed or quality of life. One trial with 18 participants compared platelet-poor plasma transfusion with platelet transfusion. We are very uncertain whether platelet-poor plasma reduces the number of participants with any bleeding episode (OR 16.00, 95% CI 1.32 to 194.62, one trial, 18 participants, very low quality evidence). We are very uncertain whether platelet-poor plasma reduces the number of participants with severe or life-threatening bleeding (OR 4.00, 95% CI 0.56 to 28.40, one trial, 18 participants, very low quality evidence). We found no trials that looked at: number of days on which bleeding occurred, time from randomisation to first bleed, number of platelet transfusions, all-cause mortality, thromboembolic events or quality of life. There is insufficient evidence to determine if platelet-poor plasma or TPO mimetics reduce bleeding for participants with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation. To detect a decrease in the proportion of participants with clinically significant bleeding from 12 in 100 to 6 in 100 would require a trial containing at least 708 participants (80% power, 5% significance). The six ongoing trials will provide additional information about the TPO mimetic comparison (424 participants) but this will still be underpowered to demonstrate this level of reduction in bleeding. None of the included or ongoing trials include children. There are no completed or ongoing trials assessing artificial platelet substitutes, fibrinogen concentrate, recombinant activated factor VII or desmopressin in people undergoing intensive chemotherapy or stem cell transplantation for haematological malignancies.

The evidence is current to May 2016. We identified 16 clinical trials: 10 completed trials and six ongoing trials. We included the 10 completed trials in this review. Six trials included adults with acute myeloid leukaemia undergoing intensive chemotherapy, two trials included adults with lymphoma undergoing intensive chemotherapy and two trials included adults undergoing allogeneic stem cell transplantation. The age range of participants was between 16 and 81 years. Men and women were equally well represented. All trials took place in high-income countries. The manufacturer of the agent that was under investigation sponsored eight trials, and two trials did not report their source of funding. We identified nine trials (536 participants) assessing thrombopoietin mimetics and one trial (18 participants) assessing platelet-poor plasma. These trials were conducted between 1974 and 2015. No trial assessed artificial platelets, fibrinogen concentrate, recombinant activated factor VII or desmopressin). For adults treated with thrombopoietin mimetics, we are very uncertain whether there is a difference in the number of participants with: any bleeding, risk of life-threatening bleeding, number of platelet transfusions, overall risk of death or thromboembolic events because the quality of the evidence was very low. We found no trials of thrombopoietin mimetics that looked at: the number of days on which bleeding occurred, time from start of trial to first bleed or quality of life. For adults treated with platelet-poor plasma, we are very uncertain whether there is a difference in the number of participants with: any bleeding or risk of life-threatening bleeding. We found no trials that looked at: the number of days on which bleeding occurred, time from start of trial to first bleeding episode, number of platelet transfusions, overall risk of death, thromboembolic events or quality of life. The quality of the evidence was very low, making it difficult to draw conclusions or make recommendations regarding the usefulness and safety of thrombopoietin mimetics or platelet-poor plasma. There was no trial evidence for artificial platelets, fibrinogen concentrate, recombinant activated factor VII or desmopressin.

10.1002/14651858.CD010982.pub2

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We included eight RCTs that fulfilled our criteria, with a total of 3680 participants. The quality of evidence, according GRADE, varied by outcome and ranged from low to moderate. We found an incidence of DVT ranging from 4.3% to 40% in patients who had a leg injury that had been immobilized in a plaster cast or a brace for at least one week, and who received no prophylaxis, or placebo. This number was significantly lower in patients who received daily subcutaneous injections of LMWH during immobilization, with event rates ranging from 0% to 37% (odds ratio (OR) 0.45, 95% confidence interval (CI) 0.33 to 0.61; with minimal evidence of heterogeneity: I² = 26%, P = 0.23; seven studies; 1676 participants, moderate-quality evidence). Comparable results were seen in the following groups of participants: patients with below-knee casts, conservatively treated patients (non-operated patients), operated patients, patients with fractures, patients with soft-tissue injuries, and patients with distal or proximal thrombosis. No clear differences were found between the LMWH and control groups for pulmonary embolism (OR 0.50, 95% CI 0.17 to 1.47; with no evidence of heterogeneity: I² = 0%, P = 0.56; five studies, 2517 participants; low-quality evidence). The studies also showed less symptomatic VTE in the LMWH groups compared with the control groups (OR 0.40, 95% CI 0.21 to 0.76; with minimal evidence of heterogeneity: I² = 16%, P = 0.31; six studies; 2924 participants; low-quality evidence). One death was reported in the included studies, but no deaths due to pulmonary embolism were reported. Complications of major adverse events were rare, with minor bleeding the main adverse events reported. Moderate-quality evidence showed that the use of LMWH in outpatients reduced DVT when immobilization of the lower limb was required, when compared with no prophylaxis or placebo. The quality of the evidence was reduced to moderate because of risk of selection and attrition bias in the included studies. Low-quality evidence showed no clear differences in PE between the LMWH and control groups, but less symptomatic VTE in the LMWH groups. The quality of the evidence was downgraded due to risk of bias and imprecision.

We included eight studies in this review (current until April 2017). The studies included a total of 3680 participants. Participants received either LMWH subcutaneously once daily, or no preventive treatment or placebo. New cases of DVT ranged from 4.3% to 40% in the control groups and ranged from 0% to 37% in the LMWH groups. The risk of DVT was lower in participants who received LMWH. Further analysis also showed a reduction in the occurrence of DVT when the use of LMWH was compared to no treatment or placebo in the following groups of participants: patients with below-knee casts, conservatively treated patients (patients not operated), operated patients, patients with fractures, patients with soft-tissue injuries, patients with above-knee thrombosis, and patients with below-knee thrombosis. No clear differences were found between the LMWH and control groups for pulmonary embolism. The studies showed less symptomatic venous thromboembolism in the LMWH groups compared with the control groups. No cases of death due to pulmonary embolism were reported. One study reported one death in the control group. There were few reported adverse effects in the treated patients. The main adverse events reported were cases of minor bleeding such as nose bleeds, blood in urine and dark stool. The use of LMWH in adult patients reduced DVT when immobilization of the lower limb was required, compared with no prevention or placebo. The quality of the evidence was downgraded to moderate due to risks of bias in some trials, such as lack of blinding of participants, or unclear reasons for excluding participants from the analyses. Low-quality evidence showed no clear differences in pulmonary embolism between LMWH and the control groups, but fewer symptomatic venous thromboemboli in the LMWH groups. The quality of evidence was downgraded due to methodological issues and imprecision of the results.

10.1002/14651858.CD006681.pub4

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A total of 10 RCTs and four quasi-randomised trials with 6466 participants met the inclusion criteria. Six studies involved minor procedures conducted in an outpatient or emergency department setting; eight studies involved major surgery conducted in theatre. Nine different topical antibiotics were included. We included two three-arm trials, two four-arm trials and 10 two-arm trials. The control groups comprised; an alternative topical antibiotic (two studies), topical antiseptic (six studies) and no topical antibiotic (10 studies), which comprised inert ointment (five studies) no treatment (four studies) and one study with one arm of each. The risk of bias of the 14 studies varied. Seven studies were at high risk of bias, five at unclear risk of bias and two at low risk of bias. Most risk of bias concerned risk of selection bias. Twelve of the studies (6259 participants) reported infection rates, although we could not extract the data for this outcome from one study. Four studies (3334 participants) measured allergic contact dermatitis as an outcome. Four studies measured positive wound swabs for patterns of antimicrobial resistance, for which there were no outcomes reported. No episodes of anaphylaxis were reported. Topical antibiotic versus no topical antibiotic We pooled the results of eight trials (5427 participants) for the outcome of SSI. Topical antibiotics probably reduce the risk of SSI in people with surgical wounds healing by primary intention compared with no topical antibiotic (RR 0.61, 95% CI 0.42 to 0.87; moderate-quality evidence downgraded once for risk of bias). This equates to 20 fewer SSIs per 1000 patients treated with topical antibiotics (95% CI 7 to 29) and a number needed to treat for one additional beneficial outcome (NNTB) (i.e. prevention of one SSI) of 50. We pooled the results of three trials (3012 participants) for the outcome of allergic contact dermatitis, however this comparison was underpowered, and it is unclear whether topical antibiotics affect the risk of allergic contact dermatitis (RR 3.94, 95% CI 0.46 to 34.00; very low-quality evidence, downgraded twice for risk of bias, once for imprecision). Topical antibiotic versus antiseptic We pooled the results of five trials (1299 participants) for the outcome of SSI. Topical antibiotics probably reduce the risk of SSI in people with surgical wounds healing by primary intention compared with using topical antiseptics (RR 0.49, 95% CI 0.30 to 0.80; moderate-quality evidence downgraded once for risk of bias). This equates to 43 fewer SSIs per 1000 patients treated with topical antibiotics instead of antiseptics (95% CI 17 to 59) and an NNTB of 24. We pooled the results of two trials (541 participants) for the outcome of allergic contact dermatitis; there was no clear difference in the risk of dermatitis between topical antibiotics and antiseptics, however this comparison was underpowered and a difference cannot be ruled out (RR 0.97, 95% CI 0.52 to 1.82; very low-quality evidence, downgraded twice for risk of bias and once for imprecision). Topical antibiotic versus topical antibiotic One study (99 participants) compared mupirocin ointment with a combination ointment of neomycin/polymyxin B/bacitracin zinc for the outcome of SSI. There was no clear difference in the risk of SSI, however this comparison was underpowered (very low-quality evidence downgraded twice for risk of bias, once for imprecision). A four-arm trial involved two antibiotic arms (neomycin sulfate/bacitracin zinc/polymyxin B sulphate combination ointment versus bacitracin zinc, 219 participants). There was no clear difference in risk of SSI between the combination ointment and the bacitracin zinc ointment. The quality of evidence for this outcome was low, downgraded once for risk of bias, and once for imprecision. Topical antibiotics applied to surgical wounds healing by primary intention probably reduce the risk of SSI relative to no antibiotic, and relative to topical antiseptics (moderate quality evidence). We are unable to draw conclusions regarding the effects of topical antibiotics on adverse outcomes such as allergic contact dermatitis due to lack of statistical power (small sample sizes). We are also unable to draw conclusions regarding the impact of increasing topical antibiotic use on antibiotic resistance. The relative effects of different topical antibiotics are unclear.

In May 2016 we searched for as many relevant studies as we could find that investigated the use of topical antibiotics on surgical wounds healing by primary intention. We managed to identify 14 studies which compared topical antibiotics with no treatment, or with antiseptics (i.e. other treatments applied to the skin to prevent bacterial infection), and with other topical antibiotics. Eight of these trials involved general surgery and six involved dermatological surgery (surgery involving only the skin). Many of the studies were small, and of low quality or at risk of bias. After examining them all, the authors concluded that the risk of having a surgical site infection was probably reduced by the use of topical antibiotics applied to wounds after surgery, whether the antibiotics were compared with an antiseptic, or to no treatment. As infection is a relatively rare event after surgery, the actual reduction in the rate of infection was 4.3% on average when the use of topical antibiotic was compared with antiseptic, and 2% when use of the topical antibiotic was compared with no treatment. It would require 24 patients on average to be treated with topical antibiotics instead of antiseptic, and 50 patients to be treated with topical antibiotic compared to no treatment in order to prevent one wound infection. Four studies reported on allergic contact dermatitis, but there was insufficient evidence to determine whether allergic contact dermatitis occurred any more frequently with topical antibiotics than with antiseptics or no treatment, and this should also be considered before deciding to use them. This plain language summary is up to date as of May 2016.

10.1002/14651858.CD011426.pub2

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Thirteen studies (1403 enrolled patients) were identified. Risks of bias attributes were frequently poorly performed. Low risk of bias was reported in six studies (50%) for sequence generation (selection bias) and in seven (58%) for allocation concealment (selection bias). Blinding of participants and personnel (performance bias) and of outcome assessment (detection bias) was at low risk of bias in three studies. Five studies reported complete outcome data (attrition bias) while eight studies reported expected outcomes so were at low risk of reporting bias. Eight studies evaluated therapy to prevent persistent kidney disease in HSP. There was no significant difference in the risk of persistent kidney disease any time after treatment (5 studies, 746 children: RR 0.74, 95% CI 0.42 to 1.32), or at one, three, six and 12 months in children given prednisone for 14 to 28 days at presentation of HSP compared with placebo or supportive treatment. There were no significant differences in the risk of persistent kidney disease with antiplatelet therapy in children with or without kidney disease at entry. Heparin significantly reduced the risk of persistent kidney disease by three months compared with placebo (1 study, 228 children: RR 0.27, 95% CI 0.14 to 0.55); no significant bleeding occurred. Four studies examined the treatment of severe HSP-associated kidney disease. Two studies (one involving 56 children and the other involving 54 adults) compared cyclophosphamide with placebo or supportive treatment and found no significant benefit of cyclophosphamide. There were no significant differences in adverse effects. In one study comparing cyclosporin with methylprednisolone (15 children) there was no significant difference in remission at final follow-up at a mean of 6.3 years (RR 1.37, 95% CI 0.74 to 2.54). In one study (17 children) comparing mycophenolate mofetil with azathioprine, there was no significant difference in the remission of proteinuria at one year (RR 1.32, 95% CI 0.86 to 2.03). No studies were identified which evaluated the efficacy of therapy on kidney disease in participants with recurrent episodes of HSP. There are no substantial changes in conclusions from this update compared with the initial review. From generally low quality evidence, we found no evidence of benefit from RCTs for the use of prednisone or antiplatelet agents to prevent persistent kidney disease in children with HSP. Though heparin appeared effective, this potentially dangerous therapy is not justified to prevent serious kidney disease when fewer than 2% of children with HSP develop severe kidney disease. No evidence of benefit has been found for cyclophosphamide treatment in children or adults with HSP and severe kidney disease. Because of small patient numbers and events leading to imprecision in results, it remains unclear whether cyclosporin and mycophenolate mofetil have any roles in the treatment of children with HSP and severe kidney disease.

This review identified 13 studies (1403 participants) investigating interventions for either preventing persistent HSP-associated kidney disease or treating severe kidney disease. Five studies (856 enrolled children) which compared prednisone tablets given for 14 to 28 days with placebo tablets or no specific treatment for the prevention of persistent kidney disease at 6 to 12 months after onset of HSP. No significant reduction in the frequency of persistent kidney disease was demonstrated. Two studies (129 children) showed no benefit of aspirin and dipyridamole (antiplatelet agents) to prevent persistent kidney disease. One study (228 children) suggested that heparin given by injection could reduce the risk for persistent kidney disease but this treatment has the potential side effect of severe bleeding so its administration is not justified when only one third of children develop any kidney disease and in most this is not serious and resolves completely. There appeared to be no serious side effects in these studies but information provided on side effects was limited. In patients with serious kidney disease, two studies (one in adults and one in children) showed that cyclophosphamide was no more effective than placebo or supportive treatment in preventing progressive kidney injury. Two small studies comparing cyclosporin with methylprednisolone/prednisone (15 children) and mycophenolate mofetil with azathioprine (17 children) found no significant benefits of cyclosporin or mycophenolate. However the numbers of children studied were too small to completely exclude a benefit so further studies are required. No serious side effects were reported. There are few data from randomised controlled studies examining interventions used to prevent or treat serious kidney disease in HSP except for short-term prednisone to prevent kidney disease. There was no evidence of benefit of short courses of prednisone in preventing serious kidney disease in HSP.

10.1002/14651858.CD005128.pub3

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The searches identified 22 trials (34 references). Four trials (200 participants) are included: one short-term single-center trial (n = 7) comparing insulin with oral repaglinide and no medication in people with cystic fibrosis-related diabetes and normal fasting glucose; one long-term multicenter trial (n = 100, 74 of whom had cystic fibrosis-related diabetes) comparing insulin with oral repaglinide and placebo; one long-term multicenter trial (n = 73) comparing insulin with oral repaglinide; and one 12-week single-center trial (n = 20) comparing the long-acting insulin glargine to short-term neutral protamine Hagedorn insulin. Two trials with data for the comparison of insulin to placebo did not report any significant differences between groups for the primary outcomes of blood glucose levels, lung function and nutritional status. This was also true for the single trial with data for the comparison of repaglinide to placebo. Two trials (one lasting one year and one lasting two years) contributed data for the comparison of insulin versus repaglinide. There were no significant differences for the primary outcomes at any time point, except at one year (in the two-year trial) when the insulin group had significant improvement in z score for body mass index compared to the repaglinide group. The single trial comparing glargine to neutral protamine Hagedorn insulin also did not report any significant differences in the review's primary outcomes. A few cases of hypoglycemia were seen in three out of the four trials (none in the longest trial), but these events resolved without further treatment. There was an unclear risk of bias from randomization and allocation concealment in two of the four included trials as the authors did not report any details; in the remaining two studies details for randomization led to a low risk of bias, but only one had sufficient details on allocation concealment to allow a low risk judgement, the second was unclear. There was a high risk from blinding for all trials (except for the comparison of oral repaglinide versus placebo) due to the nature of the interventions. Complete data for all outcomes were not available from any trial leading to a high risk of reporting bias. The amounts of insulin and repaglinide administered were not comparable and this may lead to bias in the results. None of the included trials were powered to show a significant improvement in lung function. This review has not found any significant conclusive evidence that long-acting insulins, short-acting insulins or oral hypoglycemic agents have a distinct advantage over one another in controlling hyperglycemia or clinical outcomes associated with cystic fibrosis-related diabetes. While some cystic fibrosis centers use oral medications to help control diabetes, the Cystic Fibrosis Foundation (USA) clinical practice guidelines support the use of insulin therapy and this remains the most widely-used treatment method. Randomized controlled trials specifically related to controlling diabetes with this impact on the course of pulmonary disease process in cystic fibrosis continue to be a high priority. There is no demonstrated advantage yet established for using oral hypoglycemic agents over insulin, and further trials need to be evaluated to establish whether there is clear benefit for using hypoglycemic agents. Agents that potentiate insulin action, especially agents with additional anti-inflammatory potential should be further investigated to see if there may be a clinical advantage to adding these medications to insulin as adjuvant therapy.

We included four randomized trials with a total of 200 participants. The trials' duration ranged from single doses to 24 months of treatment. Three trials compared insulin (given via a syringe) to repaglinide tablets and recruited 180 people between them. Trial participants had an average age of 25 years and mild to severe diabetes. One of these trials (73 people) compared the two treatment groups directly over a two-year period; the remaining two trials each had a third treatment arm - one (seven people) compared single doses of insulin to repaglinide and to no treatment and the other (100 people) compared insulin to repaglinide and to a placebo (a dummy tablet with no active medication) for 12 months. The fourth trial recruited 20 participants with an average age of 34 years and compared the long-acting insulin glargine to short-term neutral protamine Hagedorn insulin over a 12-week period. We were not able to show that any of the treatments were better than the others. Only a few cases of hypoglycemia (low blood sugar) were seen in three out of the four trials (none in the longest trial), but these events resolved without further treatment. Longer-term studies are still needed to see how controlling cystic fibrosis-related diabetes affects lung function. There also needs to be research into the use of agents used together with insulin to enhance its action, especially those agents with additional anti-inflammatory potential. The participants would have been mostly able to tell which treatment they were receiving (e.g. insulin via a syringe or repaglinide as a tablet), so we thought there was a high risk from blinding in all trials (except when comparing repaglinide tablets to placebo (dummy) tablets). In two trials we are satisfied that participants were put into the different treatment groups completely at random; however, the other two trial reports were not clear on how it was decided which group the participants were put into. In only one trial was it clear that no one knew in advance which group a participant would be put into, in the other three trials there were no details given. There could be some bias if it was known in advance which group the next participant would be in, e.g. healthier participants might be put into one group to show better results for that treatment. There were also many results which were not fully reported in the publications. Finally, there may be bias in the results as the amounts of insulin and repaglinide given were not comparable.

10.1002/14651858.CD004730.pub4

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Two effectiveness trials (9823 infants) and one safety trial (48 mothers) were included. The main outcomes were measured on infants born to a subset of those randomised women who became pregnant during the course of the studies. For our primary outcomes, there was no high-quality evidence according to GRADE assessments. One study (1182 infants) assessed the effectiveness of tetanus toxoid in comparison with influenza vaccine in preventing neonatal tetanus deaths. A single dose did not provide significant protection against neonatal tetanus deaths, (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.26 to 1.24; 494 infants; GRADE: low-quality evidence). However, a two- or three-dose course did provide protection against neonatal deaths, (RR 0.02, 95% CI 0.00 to 0.30; 688 infants; GRADE: moderate-quality evidence). Administration of a two- or three-dose course resulted in significant protection when all causes of death are considered as an outcome (RR 0.31, 95% CI 0.17 to 0.55; 688 infants; GRADE: moderate-quality evidence). No effect was detected on causes of death other than tetanus. Cases of neonatal tetanus after at least one dose of tetanus toxoid were reduced in the tetanus toxoid group, (RR 0.20, 95% CI 0.10 to 0.40; 1182 infants; GRADE: moderate-quality evidence). Another study, involving 8641 children, assessed the effectiveness of tetanus-diphtheria toxoid in comparison with cholera toxoid in preventing neonatal mortality after one or two doses. Neonatal mortality was reduced in the tetanus-diphtheria toxoid group (RR 0.68, 95% CI 0.56 to 0.82). In preventing deaths at four to 14 days, neonatal mortality was reduced again in the tetanus-diphtheria toxoid group (RR 0.38, 95% CI 0.27 to 0.55). The quality of evidence as assessed using GRADE was found to be low. The third small trial assessed that pain at injection site was reported more frequently among pregnant women who received tetanus diphtheria acellular pertussis than placebo (RR 5.68, 95% CI 1.54 to 20.94; GRADE: moderate-quality evidence). Available evidence supports the implementation of immunisation practices on women of reproductive age or pregnant women in communities with similar, or higher, levels of risk of neonatal tetanus, to the two study sites.

The evidence is current to January 2015, the review includes three trials. Two assessed the effectiveness of vaccinating women of reproductive age (9823 infants): one (1182 newborns) assessed the effects of tetanus toxoid against polyvalent influenza in preventing tetanus and deaths within the 30th day of life; the other (8641 newborns) assessed the effects of tetanus-diphtheria toxoid against cholera toxoid administered in women of reproductive age in preventing newborn deaths. The third trial (48 women and their newborns) assessed the safety of tetanus toxoid diphtheria acellular pertussis vaccine (Tdap) administration during pregnancy in comparison with placebo. A protective effect against deaths caused by tetanus was observed among the newborns from mothers who received at least two doses of the tetanus toxoid vaccine when compared with newborns from mothers who were immunised with influenza vaccine. A similar protective effect was seen with at least two doses of the tetanus vaccine against newborn deaths. Cases of tetanus were less frequent among newborns from women who received at least one dose of tetanus toxoid. This evidence was of moderate quality. In the second trial immunisation of women of reproductive age with tetanus diphtheria toxoid had a greater protective effect against newborn deaths than did cholera vaccine. The quality of the evidence was low for this outcome. In the third study no serious adverse events (during pregnancy or in babies) were related to the receiving of Tdap vaccine. The women experienced more pain with the vaccine injection than with the placebo. The available evidence supports the implementation of immunisation programs for women of reproductive age or pregnant women in communities with similar, or higher, levels of risk of tetanus in newborn babies as at the two study sites.

10.1002/14651858.CD002959.pub4

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We included six trials involving 418 patients for this review. The sample size in the trials varied from 30 to 131 patients. Only one trial involving 131 patients was of low risk of bias for mortality. This trial was at high risk of bias for other outcomes. Four trials excluded patients who underwent liver transplantation for acute liver failure. All the trials included livers obtained from cadaveric donors. The remaining five trials were of high risk of bias for all outcomes. Liver transplantation was performed by the conventional method (caval replacement) in two trials and piggy-back method (caval preservation) in one trial. The method of liver transplantation was not available in the remaining three trials. The comparisons performed included an initial hepatic artery flush versus initial portal vein flush; blood venting via inferior vena cava in addition to venting of storage fluid versus no blood venting; initial hepatic artery reperfusion versus initial portal vein reperfusion; simultaneous hepatic artery and portal vein reperfusion versus initial portal vein reperfusion; and retrograde inferior vena cava reperfusion versus simultaneous hepatic artery and portal vein reperfusion. Only one or two trials could be included under each comparison. There was no significant difference in mortality, graft survival, or severe morbidity rates in any of the comparisons. Quality of life was not reported in any of the trials. There is currently no evidence to support or refute the use of any specific technique of flushing or reperfusion during liver transplantation. Due to the paucity of data, absence of evidence should not be confused with evidence of absence of any differences. Further well designed trials with low risk of systematic error and low risk of random errors are necessary.

We included six trials involving 418 patients for this review. The number of patients included in the trials varied from 30 to 131. Most of the trials were at high risk of systematic errors (ie, there was a potential to arrive at wrong conclusions because of the way the trial was conducted) and random errors (there was a potential to arrive at the wrong conclusions because of the play of chance). The comparisons performed included initial hepatic artery flush versus initial portal vein flush; blood venting via the inferior vena cava in addition to venting of storage fluid versus no blood venting; initial hepatic artery reperfusion versus initial portal vein reperfusion; simultaneous hepatic artery and portal vein reperfusion versus initial portal vein reperfusion; and retrograde inferior vena cava reperfusion versus simultaneous hepatic artery and portal vein reperfusion. There were no significant differences in the risk of death or graft loss, or in the major complication rates, between the compared groups in any of the comparisons. Quality of life was not reported in any of the trials. There were no significant differences in the transfusion requirements, intensive therapy unit stay, or hospital stay between the compared groups in any of the comparisons. We are unable to advocate or refute any technique of flushing and reperfusion in patients undergoing liver transplantation. Further well designed trials with low risk of systematic error and low risk of random errors are necessary.

10.1002/14651858.CD007512.pub2

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A total of 2061 patients from seven RCTs were included for final analysis, with 1226 patients in the TOR group and 835 patients in the TAM group. The ORR for the TOR group was 25.8% (316/1226) whereas, the ORR for the TAM group was 26.9% (225/835). The pooled risk ratio (RR) suggested that the ORRs were not statistically different between the two groups (RR 1.02, 95% confidence interval (CI) 0.88 to 1.18, P = 0.83). The median TTP was 6.1 months for the TOR group and 5.8 months for the TAM group. The median OS was 27.8 months for the TOR group and 27.6 months for the TAM group. There were no significant differences in TTP and OS between the two therapeutic groups (for TTP: HR 1.08, 95% CI 0.94 to 1.24; for OS: HR 1.02, 95% CI 0.86 to 1.20). The frequencies of most adverse events were also similar in the two groups, while headache seemed to occur less in the TOR group than in the TAM group (RR 0.14, 95% CI 0.03 to 0.74, P = 0.02). There was no significant heterogeneity between studies in most of the above meta-analyses. Sensitivity analysis did not alter the results. TOR and TAM are equally effective and the safety profile of the former is at least not worse than the latter in the first-line treatment of patients with advanced breast cancer. Thus, TOR may serve as a reasonable alternative to TAM when anti-oestrogens are applicable but TAM is not the preferred choice for some reason.

Seven eligible studies were identified, all of which provided information on response to treatment (in 2061 patients), five on progression-free survival (in 1436 patients) and four on overall survival (in 1374 patients). The trials were generally old (conducted between late 1980s and early 1990s) and were of modest quality. Based on the data from these trials, 25.8% of the patients in the TOR group responded to the treatment, compared with 26.9% in the TAM group. The cancers of 50% of the patients in the TOR group had progressed after 6.1 months, compared with 5.8 months in the TAM group. Half of the patients in the TOR group survived longer than 27.8 months, compared with 27.6 months in the TAM group. The risk for progression and death in the TOR group was not significantly different from that in the TAM group. The frequencies of most adverse events were also similar in the two groups, except that the number of headaches occurring in the TOR group was only about one-seventh of that in the TAM group. However, considering the results of other large trials, we cannot exclude the possibility that this is purely a play of chance. Due to the lack of data, no conclusions can be made as to the long-term adverse effects achieved with either treatment. The evidence from this review suggests that TOR and TAM are equally effective and the safety profile of the former is at least not worse than the latter in the first-line treatment of patients with advanced breast cancer. Thus, TOR may serve as a reasonable alternative to TAM when anti-oestrogens are applicable but TAM is not the preferred choice for some reason.

10.1002/14651858.CD008926.pub2

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We found two trials with 132 participants that met our inclusion criteria. One of the included trials was a quasi-randomised trial. Adjunctive corticosteroids reduced the risk of death (typical RR 0.46, 95% confidence interval (CI) 0.24 to 0.88; typical RD -0.19, 95% CI -0.33 to -0.04; NNTB = 6; two studies, 132 participants, very low-quality evidence) but did not have a significant effect on the number of infants with sensorineural deafness at two years (RR 1.80, 95% CI 0.18 to 18.21; RD 0.04, 95% CI -0.12 to 0.21; one study, 38 participants, low-quality evidence). In one trial, dexamethasone reduced the likelihood of hearing loss at four to 10 weeks post discharge (RR 0.41, 95% CI 0.17 to 0.98; RD -0.25, 95% CI -0.48 to -0.01; one study, 59 participants, low-quality evidence). Data reported on the other outcomes of interest were insufficient. Very low-quality data from two randomised controlled trials suggest that some reduction in death and hearing loss may result from use of adjunctive steroids alongside standard antibiotic therapy for treatment of patients with neonatal meningitis. Benefit is not yet seen with regards to reduction in neurological sequelae. Researchers who wish to clarify these findings must conduct more robustly designed trials with greater numbers of participants, evaluating more relevant outcomes and providing adequate follow-up.

We identified two studies for inclusion. We found that giving steroids to babies affected with meningitis may reduce the number of children who would die or become deaf from the disease. However, most of this benefit was observed in only one trial. As of now, it appears as though steroids are not helpful with regard to preventing developmental delay. We are not able to make far reaching conclusions at this time, as the evidence that we found is limited and of low quality and could change if more results from larger and better designed studies become available.

10.1002/14651858.CD010435.pub2

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Nineteen longitudinal studies that followed up a total of over 29,000 baseline nonsmokers met inclusion criteria. The studies measured exposure or receptivity to advertising and promotion in a variety of ways, including having a favourite advertisement or an index of receptivity based on awareness of advertising and ownership of a promotional item. One study measured the number of tobacco advertisements in magazines read by participants. All studies assessed smoking behaviour change in participants who reported not smoking at baseline. In 18 of the 19 studies the nonsmoking adolescents who were more aware of tobacco advertising or receptive to it, were more likely to have experimented with cigarettes or become smokers at follow up. There was variation in the strength of association, and the degree to which potential confounders were controlled for. Longitudinal studies consistently suggest that exposure to tobacco advertising and promotion is associated with the likelihood that adolescents will start to smoke. Based on the strength and specificity of this association, evidence of a dose-response relationship, the consistency of findings across numerous observational studies, temporality of exposure and smoking behaviours observed, as well as the theoretical plausibility regarding the impact of advertising, we conclude that tobacco advertising and promotion increases the likelihood that adolescents will start to smoke.

There are no trials of the impact of tobacco advertising and promotional activities on people taking up smoking. However, there are studies following nonsmokers and their exposure to advertising (such as the number of tobacco advertisements in the magazines they read). The review found that in all these studies, nonsmoking adolescents who were more aware of or receptive to tobacco advertising were more likely to become smokers later.

10.1002/14651858.CD003439.pub2

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We included three new RCTs for this update, for a total of six included RCTs involving 559 children aged from 29 days to 12 years with pneumonia who were treated as inpatients. Pneumonia severity was described as moderate in one trial, severe in two trials, and was not stated in three trials. The studies assessed five different interventions: effects of conventional chest physiotherapy (3 studies, 211 children), positive expiratory pressure (1 study, 72 children), continuous positive airway pressure (CPAP) (1 study, 94 children), bubble CPAP (bCPAP) (1 study, 225 children), and assisted autogenic drainage (1 studies, 29 children). The included studies were conducted in Bangladesh, Brazil, China, Egypt, and South Africa. The studies were overall at low risk of bias. Blinding of participants was not possible in most studies, but we considered that the outcomes were unlikely to be influenced by the lack of blinding. One study of bCPAP reported that three deaths occurred in children in the physiotherapy group (N = 79), and 20 deaths in the control group (N = 146) (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.08 to 0.90; 225 children; low-quality evidence). One study of assisted autogenic drainage (N = 29), and one study of conventional chest physiotherapy (N = 72) reported no deaths occurred. It is uncertain whether chest physiotherapy techniques (bCPAP, assisted autogenic drainage, and conventional chest physiotherapy) reduced hospital stay duration (days) (mean difference (MD) 0.10, 95% CI -0.56 to 0.76; 4 studies; low-quality evidence). There was variation among clinical parameters used to define clinical resolution. Two small studies found no difference in resolution of fever between children in the physiotherapy (conventional chest physiotherapy and assisted autogenic drainage) and control groups. Of five studies that considered peripheral oxygen saturation levels, only two reported that use of chest physiotherapy (CPAP and conventional chest physiotherapy) showed a greater improvement in peripheral oxygen saturation levels. However, it was unclear whether respiratory rate (breaths/min) improved after conventional chest physiotherapy (MD -2.25, 95% CI -5.17 to 0.68; 2 studies, 122 children; low-quality evidence). Two studies assessed adverse events (number of events), but only one study reported any events (RR 1.28, 95% CI 0.98 to 1.67; 2 studies, 254 children; low-quality evidence). We could draw no reliable conclusions concerning the use of chest physiotherapy for children with pneumonia due to the small number of included trials with differing study characteristics and statistical presentation of data. Future studies should consider the following key points: appropriate sample size with adequate power to detect expected differences, standardisation of chest physiotherapy techniques, appropriate outcomes (such as duration of leukocytosis, and airway clearance), and adverse effects.

We included six studies involving 559 children with pneumonia aged from 29 days to 12 years. This is an update of a review published in 2013 and includes three new studies. Studies were conducted in hospitals in Bangladesh, Brazil, China, Egypt, and South Africa. Pneumonia was described as moderate to severe in three studies, but severity was not described in three studies. All studies included children who received physiotherapy and others who did not. All children also received standard medical treatment for pneumonia. The studies assessed deaths, length of hospital stay, time taken to attain normal test results (no signs of pneumonia), and adverse events. Four studies reported sources of funding (a child health agency, university, government research grants), and two did not report study funding sources. One study reported fewer deaths in children who received bubble continuous positive airway pressure (bCPAP). Physiotherapy techniques (bCPAP, assisted autogenic drainage, and conventional chest physiotherapy) were not associated with shorter hospital stays. Two studies reported improvements in blood oxygen levels after chest physiotherapy (CPAP and conventional chest physiotherapy). No clear improvement in respiratory rate was observed after conventional chest physiotherapy. Based on the available evidence, we could not confirm if chest physiotherapy is beneficial or not for children with pneumonia. We assessed the overall quality of the evidence as low due to inadequate study methods and design, differing results among studies, and few data.

10.1002/14651858.CD010277.pub3

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Three trials met our predefined inclusion criteria and were included for analysis in the review (499 participants). All three trials compared a standard trigger (10 x 109/L) versus a higher trigger (20 x 109/L or 30 x 109/L). None of the trials compared a low trigger versus a standard trigger or an alternative platelet trigger. The trials were conducted between 1991 and 2001 and enrolled participants from fairly comparable patient populations. The original review contained four trials (658 participants); in the previous update of this review we excluded one trial (159 participants) because fewer than 80% of participants had a haematological disorder. We identified no new trials in this update of the review. Overall, the methodological quality of the studies was low across different outcomes according to GRADE methodology. None of the included studies were at low risk of bias in every domain, and all the included studies had some threats to validity. Three studies reported the number of participants with at least one clinically significant bleeding episode within 30 days from the start of the study. There was no evidence of a difference in the number of participants with a clinically significant bleeding episode between the standard and higher trigger groups (three studies; 499 participants; risk ratio (RR) 1.35, 95% confidence interval (CI) 0.95 to 1.90; low-quality evidence). One study reported the number of days with a clinically significant bleeding event (adjusted for repeated measures). There was no evidence of a difference in the number of days of bleeding per participant between the standard and higher trigger groups (one study; 255 participants; relative proportion of days with World Health Organization Grade 2 or worse bleeding (RR 1.71, 95% CI 0.84 to 3.48, P = 0.162; authors' own results; low-quality evidence). Two studies reported the number of participants with severe or life-threatening bleeding. There was no evidence of any difference in the number of participants with severe or life-threatening bleeding between a standard trigger level and a higher trigger level (two studies; 421 participants; RR 0.99, 95% CI 0.52 to 1.88; low-quality evidence). Only one study reported the time to first bleeding episode. There was no evidence of any difference in the time to the first bleeding episode between a standard trigger level and a higher trigger level (one study; 255 participants; hazard ratio 1.11, 95% CI 0.64 to 1.91; low-quality evidence). Only one study reported on all-cause mortality within 30 days from the start of the study. There was no evidence of any difference in all-cause mortality between standard and higher trigger groups (one study; 255 participants; RR 1.78, 95% CI 0.83 to 3.81; low-quality evidence). Three studies reported on the number of platelet transfusions per participant. Two studies reported on the mean number of platelet transfusions per participant. There was a significant reduction in the number of platelet transfusions per participant in the standard trigger group (two studies, mean difference -2.09, 95% CI -3.20 to -0.99; low-quality evidence). One study reported on the number of transfusion reactions. There was no evidence to demonstrate any difference in transfusion reactions between the standard and higher trigger groups (one study; 79 participants; RR 0.07, 95% CI 0.00 to 1.09). None of the studies reported on quality of life. In people with haematological disorders who are thrombocytopenic due to myelosuppressive chemotherapy or HSCT, we found low-quality evidence that a standard trigger level (10 x 109/L) is associated with no increase in the risk of bleeding when compared to a higher trigger level (20 x 109/L or 30 x 109/L). There was low-quality evidence that a standard trigger level is associated with a decreased number of transfusion episodes when compared to a higher trigger level (20 x 109/L or 30 x 109/L). Findings from this review were based on three studies and 499 participants. Without further evidence, it is reasonable to continue with the current practice of administering prophylactic platelet transfusions using the standard trigger level (10 x 109/L) in the absence of other risk factors for bleeding.

The evidence is current to July 2015. We found no new studies in this update of the review. This review identified three randomised controlled trials that compared giving platelet transfusions to prevent bleeding when the platelet count is 10 x 109/L (the current standard) or below versus giving platelet transfusions to prevent bleeding at higher platelet count levels (20 x 109/L or below or 30 x 109/L or below). None of the studies compared a lower trigger or alternative trigger to the current standard. These trials were conducted between 1991 and 2001 and included 499 participants. Two trials included adults with leukaemia who were receiving chemotherapy. One trial included children and adults receiving a stem cell transplant. Two of the three studies reported sources of funding. Neither of the studies that reported funding sources were industry sponsored. Giving platelet transfusions to people with low platelet counts due to blood cancers or their treatment to prevent bleeding when the platelet count was 10 x 109/L or below did not increase the risk of bleeding compared to giving a platelet transfusion at higher platelet counts (20 x 109/L or below or 30 x 109/L or below). Giving platelet transfusions to prevent bleeding only when the platelet count was 10 x 109/L or below resulted in a reduction in the number of platelets given. We found no evidence to demonstrate that giving a platelet transfusion when the platelet count was 10 x 109/L or below decreased the number of transfusion reactions compared to giving platelet transfusions at higher platelet counts (20 x 109/L or below or 30 x 109/L or below). None of the three studies reported any quality of life outcomes. Findings from this review were based on three studies and 499 participants. Without further evidence, it is reasonable to continue using platelet transfusions to prevent bleeding based on the current standard transfusion threshold (10 x 109/L). The evidence for most of the findings was of low quality. This was because participants and their doctors knew which study arm the participant had been allocated to, and also the estimate of the treatment effect was imprecise.

10.1002/14651858.CD010983.pub2

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Four trials (five articles) met the inclusion criteria of this review; three were RCTs and one was a quasi-RCT; and included a total of 280 participants treated in neonatal intensive care units in the UK. The trials were published between 1980 and 1990. The studies were sufficiently similar regarding the research question they asked and the interventions that we could combine the trials to assess the effect of the intervention. Meta-analysis showed that the intervention produced no significant difference when compared to conservative management for the outcomes of: placement of hydrocephalus shunt (typical risk ratio (RR) 0.96, 95% confidence interval (CI) 0.73 to 1.26; 3 trials, 233 infants; I² statistic = 0%; moderate quality evidence), death (RR 0.88, 95% CI 0.53 to 1.44; 4 trials, 280 infants; I² statistic = 0%; low quality evidence), major disability in survivors (RR 0.98, 95% CI 0.81 to 1.18; 2 trials, 141 infants; I² statistic = 11%; high quality evidence), multiple disability in survivors (RR 0.9, 95% CI 0.66 to 1.24; 2 trials, 141 infants; I² statistic = 0%; high quality evidence), death or disability (RR 0.99, 95% CI 0.86 to 1.14; 2 trials, 180 infants; I² statistic = 0%; high quality evidence), death or shunt (RR 0.91, 95% CI 0.75 to 1.11; 3 trials, 233 infants; I² statistic = 0%; moderate quality evidence), and infection of CSF presurgery (RR 1.73, 95% CI 0.53 to 5.67; 2 trials, 195 infants; low quality evidence). We assessed the quality of the evidence as high for the outcomes of major disability, multiple disability, and disability or death. We rated the evidence for the outcomes of shunt insertion, and death or shunt insertion as of moderate quality as one included trial used an alternation method of randomisation. For the outcomes of death and infection of CSF presurgery, the quality of the evidence was low as one trial used an alternation method, the number of participants was too low to assess the objectives with sufficient precision, and there was inconsistency regarding the findings in the included trials regarding the outcome of infection of CSF presurgery. There was no evidence that repeated removal of CSF via lumbar puncture, ventricular puncture or from a ventricular reservoir produces any benefit over conservative management in neonates with or at risk for developing PHH in terms of reduction of disability, death, or need for placement of a permanent shunt.

We searched for trials up to 24 March 2016 that compared removing CSF via lumbar or ventricular taps in all babies at risk of developing a build-up of fluid on the brain against a conservative approach where this was only done if there was evidence that the build-up of fluid was causing an excess of pressure in the brain. We included four trials that included a total of 280 preterm infants treated in neonatal intensive care units in the UK. The trials were published between 1980 and 1990. We found no evidence that removal of CSF by lumbar or ventricular taps reduces the need for a permanent shunt to be inserted. There was also no evidence that it reduced the risk of major disability, multiple disability, or death. There was insufficient evidence to determine if this approach can lead to an increased risk of developing an infection in the CSF. We assessed the outcomes of major disability, multiple disability, and disability or death as high quality evidence. We recorded the quality of the evidence for the outcomes of shunt insertion, and death or shunt insertion as low quality evidence, as there was an issue with the random allocation method in one included trial that reported on this outcome. For the outcomes of death and infection of CSF presurgery, the quality of the evidence was moderate due to the previously mentioned problem with allocation. In addition these studies did not have enough patients to sufficiently answer the question. In the case of the outcome infection of CSF presurgery, the results were inconsistent between the included trials.

10.1002/14651858.CD000216.pub2

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Three eligible trials involving 569 patients were identified. Due to methodological limitations in the included studies, there was considerable variation in the results of acute (risk range 38.67% to 96.51%) and chronic pain (risk range 7.83% to 40.47%) across the control groups. Therefore, meta-analysis was not performed but the results of the outcomes in the individual trials were compared. Two trials involving 322 patients reported less chronic pain after preperitoneal repair (relative risk (RR) 0.18, number needed to treat (NNT) 8; RR 0.51, NNT 5), whereas one trial, including 247 patients, described more chronic pain after this repair (RR 1.17, NNT 77). The same trials favoured the preperitoneal technique concerning acute pain (RR 0.17, NNT 3; RR 0.78, NNT 7), whereas in the third trial it was almost omnipresent and thus comparable in both intervention arms (RR 0.997, NNT 333). Early and late hernia recurrence rates were similar across the studies, whereas contrasting results were reported for other early outcomes as infection and hematoma. No late mesh infection occurred in the included trials. Both techniques are valid as they result in similar low recurrence rates. Evaluation of pain results in the individual trials shows some evidence that preperitoneal repair causes less or comparable acute and chronic pain compared to the Lichtenstein procedure. We emphasize the need for homogeneous high quality randomized trials comparing elective preperitoneal inguinal hernia techniques and Lichtenstein repair in terms of chronic pain.

The review authors identified three eligible controlled trials in which 569 patients were randomized to Lichtenstein or preperitoneal mesh repair. Due to methodological limitations in the included trials, the data were not pooled. Comparison of pain results in the individual trials showed that preperitoneal repair causes less chronic pain (relative risk (RR) 0.18, number needed to treat (NNT) 8; RR 0.51, NNT 5) compared to the Lichtenstein procedure in two trials involving 322 patients. One trial, including 247 patients, described more chronic pain after this repair (RR 1.17, NNT 77). The same trials favoured the preperitoneal technique concerning acute pain (RR 0.17, NNT 3; RR 0.78, NNT 7), whereas in the third trial it was almost omnipresent and thus comparable in both intervention arms (RR 0.997, NNT 333). This method also showed similar low recurrence rates after both types of repair. The results for other early complications were not consistent across the included trials. No mesh infections were reported. In conclusion, both techniques are valid causing few recurrences. Analysis of pain results in each trial shows some evidence that preperitoneal repair causes less or comparable acute and chronic pain compared to the Lichtenstein technique. As no robust conclusions concerning chronic pain after elective hernia surgery can be made, we highlight the need for homogeneous trials.

10.1002/14651858.CD008034.pub2

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We revisited decisions made in the earlier version of this review and excluded five studies that were previously included. We identified one new study for this update. This review includes six studies with 388 participants. We did not identify any studies in children. The included studies differed so much in their methods and comparisons that no synthesis of results was feasible. Only one study (103 participants) specifically reported the number of participants with a given level of pain relief, in this case a reduction of at least 20% - similar in both the methadone and morphine groups. Using an outcome of 'no worse than mild pain', methadone was similar to morphine in effectiveness, and most participants who could tolerate methadone achieved 'no worse than mild pain'. Adverse event withdrawals with methadone were uncommon (12/202) and similar in other groups. Deaths were uncommon except in one study where the majority of participants died, irrespective of treatment group. For specific adverse events, somnolence was more common with methadone than with morphine, while dry mouth was more common with morphine than with methadone. None of the studies reported effects on appetite. We judged the quality of evidence to be low, downgraded due to risk of bias and sparse data. For specific adverse events, we considered the quality of evidence to be very low, downgraded due to risk of bias, sparse data, and indirectness, as surrogates for appetite, thirst and somnolence were used. There were no data on the use of methadone in children. Based on low-quality evidence, methadone is a drug that has similar analgesic benefits to morphine and has a role in the management of cancer pain in adults. Other opioids such as morphine and fentanyl are easier to manage but may be more expensive than methadone in many economies.

In this updated review we set out to estimate how well methadone worked, how many people had side effects, and how severe those side effects were – for example, whether they were so severe that participants stopped taking their methadone. In May 2016, we found just six studies with 388 adult participants. The studies were often small, and compared different preparations. For pain relief there did not seem to be much difference between methadone and morphine. For most people pain was reduced from moderate or severe to mild or no pain with methadone. Methadone is associated with some unwanted effects, mainly sleepiness, constipation, and dry mouth. These can be severe enough to stop people taking methadone. No data were available about the use of methadone in children. We would like to see more consistency in study design, and especially in study reporting, which should include information on unwanted effects and the outcome of pain reduced to tolerable levels, that is, no worse than mild pain, so that people with cancer are not bothered by pain. We rated the quality of the evidence from 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 low or very low.

10.1002/14651858.CD003971.pub4

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For this update, eight additional studies were included making a total of 13 included studies with a combined total of 3081 randomised patients. Three studies compared UGFS with surgery, eight compared EVLT with surgery and five compared RFA with surgery (two studies had two or more comparisons with surgery). Study quality, evaluated through the six domains of risk of bias, was generally moderate for all included studies, however no study blinded participants, researchers and clinicians or outcome assessors. Also, nearly all included studies had other sources of bias. The overall quality of the evidence was moderate due to the variations in the reporting of results, which limited meaningful meta-analyses for the majority of proposed outcome measures. For the comparison UGFS versus surgery, the findings may have indicated no difference in the rate of recurrences in the surgical group when measured by clinicians, and no difference between the groups for symptomatic recurrence (odds ratio (OR) 1.74, 95% confidence interval (CI) 0.97 to 3.12; P = 0.06 and OR 1.28, 95% CI 0.66 to 2.49, respectively). Recanalisation and neovascularisation were only evaluated in a single study. Recanalisation at < 4 months had an OR of 0.66 (95% CI 0.20 to 2.12), recanalisation > 4 months an OR of 5.05 (95% CI 1.67 to 15.28) and for neovascularisation an OR of 0.05 (95% CI 0.00 to 0.94). There was no difference in the rate of technical failure between the two groups (OR 0.44, 95% CI 0.12 to 1.57). For EVLT versus surgery, there were no differences between the treatment groups for either clinician noted or symptomatic recurrence (OR 0.72, 95% CI 0.43 to 1.22; P = 0.22 and OR 0.87, 95% CI 0.47 to 1.62; P = 0.67, respectively). Both early and late recanalisation were no different between the two treatment groups (OR 1.05, 95% CI 0.09 to 12.77; P = 0.97 and OR 4.14, 95% CI 0.76 to 22.65; P = 0.10). Neovascularisation and technical failure were both statistically reduced in the laser treatment group (OR 0.05, 95% CI 0.01 to 0.22; P < 0.0001 and OR 0.29, 95% CI 0.14 to 0.60; P = 0.0009, respectively). Long-term (five-year) outcomes were evaluated in one study so no association could be derived,but it appeared that EVLT and surgery maintained similar findings. Comparing RFA versus surgery, there were no differences in clinician noted recurrence (OR 0.82, 95% CI 0.49 to 1.39; P = 0.47); symptomatic noted recurrence was only evaluated in a single study. There were also no differences between the treatment groups for recanalisation (early or late) (OR 0.68, 95% CI 0.01 to 81.18; P = 0.87 and OR 1.09, 95% CI 0.39 to 3.04; P = 0.87, respectively), neovascularisation (OR 0.31, 95% CI 0.06 to 1.65; P = 0.17) or technical failure (OR 0.82, 95% CI 0.07 to 10.10; P = 0.88). QoL scores, operative complications and pain were not amenable to meta-analysis, however quality of life generally increased similarly in all treatment groups and complications were generally low, especially major complications. Pain reporting varied greatly between the studies but in general pain was similar between the treatment groups. Currently available clinical trial evidence suggests that UGFS, EVLT and RFA are at least as effective as surgery in the treatment of great saphenous varicose veins. Due to large incompatibilities between trials and different time point measurements for outcomes, the evidence is lacking in robustness. Further randomised trials are needed, which should aim to report and analyse results in a congruent manner to facilitate future meta-analysis.

Our review brought together all available randomised controlled trials that compared the new techniques to surgery in the treatment of varicosities in the great saphenous vein. We found 13 trials, with a combined total of 3081 randomised patients, which met our inclusion criteria. Three trials compared foam sclerotherapy with surgery, eight trials compared endovenous laser therapy with surgery and five compared radiofrequency ablation with surgery (two studies had two or more comparisons with surgery). Overall the quality of the studies was acceptable, however none of the studies tried to conceal the treatment type from the participants, researchers and clinicians, or those who measured the outcomes. Most of the studies also had other biases. For foam compared with surgery, there was no difference between the treatment groups in the rate of recurrence as measured by a clinician and the rate of recurrence that was noted by patient symptoms. There was also no difference between the treatment groups for technical failure. Comparing laser therapy and surgery, there was no difference between the recurrence rates (either clinician noted or by symptoms) or for reopening of the treated vein (recanalisation). New vein growth (neovascularisation) and technical failure were both higher in the surgery group than in the laser group. For the comparison between radiofrequency ablation and surgery there were no differences between the treatment groups for recurrence, recanalisation, neovascularisation or technical failure. Outcomes that measure changes in patients' quality of life, operative complications and pain were not able to be compared directly, however quality of life generally increased similarly in all treatment groups and complications were generally low, especially major complications. Pain reporting varied greatly between the studies but in general pain was similar between the treatment groups. The limited evidence that is available supports that foam sclerotherapy, endovenous laser therapy and radiofrequency ablation are no worse than open surgery. However, it should be noted that there were large differences between the way the studies reported their outcomes, which included definitions and collection time points. These differences limited the findings of our review. We need more data from randomised controlled trials comparing these novel therapies to surgery before we really know their true potential.

10.1002/14651858.CD005624.pub3

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We included two unique studies with 446 randomised participants with clinically localised prostate cancer. The mean age, prostate volume, and prostate-specific antigen (PSA) of the participants were 61.3 years, 49.78 mL, and 7.09 ng/mL, respectively. Primary outcomes We found no study that addressed the outcome of prostate cancer-specific survival. Based on data from one trial, RARP likely results in little to no difference in urinary quality of life (MD -1.30, 95% CI -4.65 to 2.05) and sexual quality of life (MD 3.90, 95% CI -1.84 to 9.64). We rated the quality of evidence as moderate for both quality of life outcomes, downgrading for study limitations. Secondary outcomes We found no study that addressed the outcomes of biochemical recurrence-free survival or overall survival. Based on one trial, RARP may result in little to no difference in overall surgical complications (RR 0.41, 95% CI 0.16 to 1.04) or serious postoperative complications (RR 0.16, 95% CI 0.02 to 1.32). We rated the quality of evidence as low for both surgical complications, downgrading for study limitations and imprecision. Based on two studies, LRP or RARP may result in a small, possibly unimportant improvement in postoperative pain at one day (MD -1.05, 95% CI -1.42 to -0.68 ) and up to one week (MD -0.78, 95% CI -1.40 to -0.17). We rated the quality of evidence for both time-points as low, downgrading for study limitations and imprecision. Based on one study, RARP likely results in little to no difference in postoperative pain at 12 weeks (MD 0.01, 95% CI -0.32 to 0.34). We rated the quality of evidence as moderate, downgrading for study limitations. Based on one study, RARP likely reduces the length of hospital stay (MD -1.72, 95% CI -2.19 to -1.25). We rated the quality of evidence as moderate, downgrading for study limitations. Based on two study, LRP or RARP may reduce the frequency of blood transfusions (RR 0.24, 95% CI 0.12 to 0.46). Assuming a baseline risk for a blood transfusion to be 8.9%, LRP or RARP would result in 68 fewer blood transfusions per 1000 men (95% CI 78 fewer to 48 fewer). We rated the quality of evidence as low, downgrading for study limitations and indirectness. We were unable to perform any of the prespecified secondary analyses based on the available evidence. All available outcome data were short-term and we were unable to account for surgeon volume or experience. There is no high-quality evidence to inform the comparative effectiveness of LRP or RARP compared to ORP for oncological outcomes. Urinary and sexual quality of life-related outcomes appear similar. Overall and serious postoperative complication rates appear similar. The difference in postoperative pain may be minimal. Men undergoing LRP or RARP may have a shorter hospital stay and receive fewer blood transfusions. All available outcome data were short-term, and this study was unable to account for surgeon volume or experience.

This review identified two randomised controlled trials of 446 men with prostate cancer, with an average age of approximately 60 years, that compared LRP or RARP to ORP. We found no evidence as to how LRP or RARP compared to ORP in terms of reducing the risk of dying from prostate cancer, preventing the cancer from coming back or dying of any cause. Mens' quality of life was likely similar related to their urinary and sexual function. There appears to be no differences in postoperative surgical complications. LRP or RARP may have a small possibly unimportant effect on postoperative pain at one day and up to one week. However, no difference between RARP and ORP was found at 12 weeks postoperatively. Men having LRP or RARP likely have a shorter hospital stay and may need fewer blood transfusions. We found no trial evidence for any cancer outcome. The evidence for quality of life were moderate; that for overall and serious surgical complications were low quality. Postoperative pain were low (up to one week) and moderate (at 12 weeks) quality of evidence. The quality of evidence for hospital stay and blood transfusions were moderate and low, respectively. Collectively, the most outcomes were low to moderate quality of evidence. This means that our estimates are likely to be close to the truth but that there is a possibility that they may be different.

10.1002/14651858.CD009625.pub2

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We included 51 studies with 9052 participants. Of these, 45 trials assessed treatment outcomes at five weeks or less after commencement of treatment, and six trials assessed outcomes over a longer time frame. We believe that 24 trials had some form of conflict of interest, such as funding by pharmaceutical companies. Among the included studies were 12 ketoconazole trials (N = 3253), 11 ciclopirox trials (N = 3029), two lithium trials (N = 141), two bifonazole trials (N = 136) and one clotrimazole trial (N = 126) that compared the effectiveness of these treatments versus placebo or vehicle. Nine ketoconazole trials (N = 632) and one miconazole trial (N = 47) compared these treatments versus steroids. Fourteen studies (N = 1541) compared one antifungal versus another or compared different doses or schedules of administration of the same agent versus one another. Ketoconazole Topical ketoconazole 2% treatment showed a 31% lower risk of failed clearance of rashes compared with placebo (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.59 to 0.81, eight studies, low-quality evidence) at four weeks of follow-up, but the effect on side effects was uncertain because evidence was of very low quality (RR 0.97, 95% CI 0.58 to 1.64, six studies); heterogeneity between studies was substantial (I² = 74%). The median proportion of those who did not have clearance in the placebo groups was 69%. Ketoconazole treatment resulted in a remission rate similar to that of steroids (RR 1.17, 95% CI 0.95 to 1.44, six studies, low-quality evidence), but occurrence of side effects was 44% lower in the ketoconazole group than in the steroid group (RR 0.56, 95% CI 0.32 to 0.96, eight studies, moderate-quality evidence). Ketoconozale yielded a similar remission failure rate as ciclopirox (RR 1.09, 95% CI 0.95 to 1.26, three studies, low-quality evidence). Most comparisons between ketoconazole and other antifungals were based on single studies that showed comparability of treatment effects. Ciclopirox Ciclopirox 1% led to a lower failed remission rate than placebo at four weeks of follow-up (RR 0.79, 95% CI 0.67 to 0.94, eight studies, moderate-quality evidence) with similar rates of side effects (RR 0.9, 95% CI 0.72 to 1.11, four studies, moderate-quality evidence). Other antifungals Clotrimazole and miconazole efficacies were comparable with those of steroids on short-term assessment in single studies. Treatment effects on individual symptoms were less clear and were inconsistent, possibly because of difficulties encountered in measuring these symptoms. Evidence was insufficient to conclude that dose or mode of delivery influenced treatment outcome. Only one study reported on treatment compliance. No study assessed quality of life. One study assessed the maximum rash-free period but provided insufficient data for analysis. One small study in patients with HIV compared the effect of lithium versus placebo on seborrhoeic dermatitis of the face, but treatment outcomes were similar. Ketoconazole and ciclopirox are more effective than placebo, but limited evidence suggests that either of these agents is more effective than any other agent within the same class. Very few studies have assessed symptom clearance for longer periods than four weeks. Ketoconazole produced findings similar to those of steroids, but side effects were fewer. Treatment effect on overall quality of life remains unknown. Better outcome measures, studies of better quality and better reporting are all needed to improve the evidence base for antifungals for seborrhoeic dermatitis.

We included 51 studies with 9052 participants. Trials typically were four weeks long, and very few trials were longer. In all, 24 studies had some involvement of pharmaceutical companies such as funding or employment of the researchers. Particpants taking ketoconazole were 31% less likely than those given placebo to have symptoms that persisted at four weeks of follow-up. This was seen in eight studies with 2520 participants, but wide variation was noted between studies. Ketoconazole was as effective as steroids but had 44% fewer side effects. Without causing more side effects, ciclopirox was 21% more effective than placebo in achieving clinical clearance of rashes. Treatment effect on redness, itching or scaling symptoms of the skin was less clear. Evidence was insufficient to conclude that that one antifungal was superior to other antifungals, but this observation was based on few studies. Ketoconazole and ciclopirox are the most heavily investigated antifungals and are more effective than placebo. Other antifungals might have similar effects, but data are insufficient to underpin this. Common side effects were increased skin redness or itching, burning sensation and hair loss. No studies measured quality of life. Only one study reported on percentage of compliance in different treatment groups. Other studies used surrogates such as acceptability to represent compliance. We therefore could not assess the effect of compliance on treatment outcomes. One study on patients with HIV reported no clear effects of treatments. Evidence for the effects of ketoconazole compared with placebo or a steroid was assessed to be of low quality. Evidence derived from comparison of ciclopirox versus placebo was assessed to be of moderate quality. Better quality studies with longer follow-up and better reporting are needed to enlarge the evidence base for antifungals.

10.1002/14651858.CD008138.pub3

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In three RCTs, 171 women over the age of 18 years were randomised to receive celecoxib 400 mg daily for 14 to 18 weeks versus placebo (one study, 130 participants), celecoxib 200 mg twice daily by mouth for six months versus placebo (one study, 25 participants), or rofecoxib 25 mg once daily by mouth for three months versus placebo (one study, 16 participants). The study with rofecoxib was discontinued when the medicine was withdrawn from the market in 2004. The trials ran from June 2005 to April 2012, June 2002 to October 2003, and May to October 2004, respectively. We have chosen to include the data from the rofecoxib study as outcomes may be similar when other such NSAIDs are utilised. Partial or complete regression of CIN 2 or CIN 3 occurred in 31 out of 70 (44%) in the treatment arms and 19 of 62 (31%) in the placebo arms (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.93 to 2.27; P value 0.10), three studies, 132 participants; moderate-certainty evidence). Complete regression of CIN 2 or CIN 3 occurred in 15 of 62 (24%) of those receiving celecoxib versus 10 of 54 (19%) of those receiving placebo (RR 1.31, 95% CI 0.65 to 2.67; P value 0.45, two studies, 116 participants; moderate-certainty evidence). Partial regression of CIN 2 or CIN 3 occurred in 14 of 62 (23%) of those receiving celecoxib versus 8 of 54 (15%) of those receiving placebo (RR 1.56, 95% CI 0.72 to 3.4; P value 0.26), two studies, 116 participants; moderate-certainty evidence). Progression to a higher grade of CIN, but not to invasive cancer, occurred in one of 12 (8%) of those receiving celecoxib and two of 13 (15%) receiving placebo (RR 0.54, 95% CI 0.05 to 5.24; P value 0.60, one study, 25 participants; very low-certainty evidence). Two studies reported no cases of progression to invasive cancer within the timeframe of the study. No toxicity was reported in the two original articles. The trial added in this update had one Grade 3 gastrointestinal adverse effect in the treatment arm, but otherwise had similar Grade 1 to 2 side effects between treatment and placebo groups. Although the studies were well-conducted and randomised, some risk of bias was detected in all studies. Furthermore, the duration of the studies was short, which may mask identifying progression to cancer. The addition of the trial in this update quadrupled the number of patients in the original review and was a well-designed multicentre trial thus, increasing the overall certainty of evidence from very low to moderate for this review. There are currently no convincing data to support a benefit for NSAIDs in the treatment of CIN. With the addition of this new, larger randomised trial we would rate this as overall moderate-certainty evidence by the GRADE criteria.

We identified three randomised studies up to August 2017, including 171 women over the age of 18 years, with moderate or severe CIN. The trials ran from June 2005 to April 2012, June 2002 to October 2003, and May to October 2004. One of them was discontinued before it was completed. The women were given either celecoxib or rofecoxib versus a placebo (sugar tablet) daily by mouth for a period of three to six months. With the addition of the third trial to this review, there is now a sufficient number of patients in the review to conclude that NSAIDs have minimal effect over placebo in causing regression of CIN. No patients progressed to invasive cervical cancer, and overall, the drug was well-tolerated compared to placebo. The studies appear to have been well-conducted. There are some questions related to the quality of evidence in relation to concealment and women dropping out of the study before completion of assigned medications. We therefore concluded that the certainty (quality) of the evidence was moderate. There was insufficient information to assess accuracy of the reporting of information. It is possible that there are other incomplete and unreported studies that have not been identified. The literature available at this time suggests that there are no convincing data to suggest NSAIDs as a treatment for CIN.

10.1002/14651858.CD004121.pub4

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We identified 14 randomised trials that involved over 13,000 premenopausal women with operable breast cancer, most of whom were ER+. The numbers of trials making the different comparisons were: (A) i. LHRH versus tamoxifen (three trials), ii. LHRH versus chemotherapy (four trials); (B) i. LHRH + tamoxifen versus tamoxifen (two trials), ii. LHRH + tamoxifen versus LHRH (three trials), iii. LHRH + tamoxifen versus chemotherapy (two trials), iv. LHRH + aromatase inhibitor versus LHRH + tamoxifen (one trial); (C) i. LHRH + chemotherapy versus LHRH (one trial), ii. LHRH + chemotherapy versus chemotherapy (five trials); (D) LHRH + tamoxifen + chemotherapy versus chemotherapy (three trials). The LHRH agonist in most of these trials was goserelin. For most of the treatment comparisons there are too few trials, too few randomised patients, or too little follow up to draw reliable estimates of the relative effects of different treatments. (A) LHRH monotherapy: results suggest that adjuvant LHRH agonist monotherapy is similar to older chemotherapy protocols (eg. CMF) in terms of recurrence-free and overall survival in ER+ patients. There are insufficient data to compare LHRH agonist monotherapy to tamoxifen alone, but available results suggest that these treatments are comparable in terms of recurrence-free survival. (B) LHRH + anti-oestrogen therapy: there are insufficient data to compare the combination of an LHRH agonist plus tamoxifen to tamoxifen alone. Results suggest that the LHRH agonist plus tamoxifen combination may be superior to an LHRH agonist alone or to chemotherapy alone, but the chemotherapy protocols tested are outdated. The data comparing LHRH agonists plus aromatase inhibitors to LHRH agonists plus tamoxifen are currently inconclusive. (C) LHRH + chemotherapy: there are insufficient data to compare the LHRH + chemotherapy combination to an LHRH agonist alone, although results from a single study suggest comparable efficacy in ER+ patients. There is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus chemotherapy combination in comparison to chemotherapy alone. (D) LHRH agonist + chemotherapy + tamoxifen: there is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus tamoxifen plus chemotherapy in comparison to chemotherapy alone. There are insufficient data to assess the effect of the addition of LHRH agonists to the current standard treatment of chemotherapy plus tamoxifen. Endocrine therapy with LHRH agonists appears to have fewer side-effects than the forms of chemotherapy assessed. The optimal duration of LHRH therapy in the adjuvant setting is unclear. Overall, the data from currently published clinical trials of LHRH agonists in the adjuvant setting for premenopausal women with endocrine-sensitive breast cancer are supportive of clinical benefit. Nonetheless, definitive comparisons against current clinical standards of care that include third generation chemotherapy regimens and tamoxifen are required before their place in the adjuvant setting can be properly defined. The authors conclude that the current data strongly support the continuation of current trials that definitively compare a variety of combinations of LHRH agonists and anti-oestrogenic strategies to the current standard of five years of tamoxifen.

We found seven trials comparing LHRH agonist therapy (alone) to other treatments. There is not enough evidence to compare LHRH agonists directly to tamoxifen. Four of the trials compared an LHRH agonist to a now superseded chemotherapy regimen. For ER+ women, these trials showed no significant differences between LHRH agonists and chemotherapy on recurrence and death, but LHRH agonists had fewer side effects. Six trials compared LHRH agonists in combination with tamoxifen to other treatments. There is currently insufficient information to reliably compare this combination with tamoxifen alone. The LHRH agonist plus tamoxifen combination may reduce the risk of breast cancer recurrence, but not death, when compared to an LHRH agonist alone or chemotherapy alone. There is insufficient evidence to know whether an LHRH agonist plus an aromatase inhibitor is better or worse than an LHRH agonist plus tamoxifen. Three trials compared combining an LHRH agonist plus chemotherapy plus tamoxifen to chemotherapy alone. There was a reduction in the risk of breast cancer recurrence, and possibly death, with the combination treatment. It is important to note that the current standard of care for premenopausal women with ER+ breast cancer is five years of tamoxifen, often with chemotherapy. We found no trials of LHRH agonist-containing regimens versus this standard. The women in the trials in this review need to continue to be followed up so that the longer-term effects can be investigated, to 10 and more years after diagnosis. More research is also needed to help choose between different types of LHRH agonist, and to find out if the length of time that the drug is used makes a difference. It is also unknown whether there are important differences between the effects of LHRH agonists and ovarian ablation by surgery or radiotherapy.

10.1002/14651858.CD004562.pub4

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Eight trials with 1753 patients were included. One trial with a 2 x 2 design was counted twice in the analysis. The analysis was performed including 11 comparisons based on 1975 patients. The median follow up was six years. The pooled hazard ratio of death was 0.82 (95% confidence interval (CI) 0.71 to 0.95; P = 0.006) corresponding to an absolute survival benefit of 6% at five years from chemotherapy (from 56% to 62%). The pooled hazard ratio of tumour failure or death was 0.76 (95% CI 0.67 to 0.86; P < 0.00001) corresponding to an absolute event-free survival benefit of 10% at five years from chemotherapy (from 42% to 52%). A significant interaction was observed between chemotherapy timings and overall survival (P = 0.005), explaining the heterogeneity observed in the treatment effect (P = 0.03) with the highest benefit from concomitant chemotherapy. Chemotherapy led to a small but significant benefit for overall survival and event-free survival. This benefit was essentially observed when chemotherapy was administered concomitantly with radiotherapy.

Eight trials (1753 patients) met the criteria for inclusion in this review. The addition of chemotherapy to standard radiotherapy provides a small but significant benefit in patients with nasopharyngeal cancer, especially when chemotherapy is administered at the same time as radiotherapy. The role of chemotherapy given before or after the radiotherapy is more questionable.

10.1002/14651858.CD004329.pub2

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Fourteen studies involving 29,319 people with diabetes were included and 11 studies involving 29,141 people were included in our meta-analyses. Treatment duration was 56.7 months on average (range 6 months to 10 years). Studies included people with a range of kidney function. Incomplete reporting of key methodological details resulted in uncertain risks of bias in many studies. Using GRADE assessment, we had moderate confidence in the effects of glucose lowering strategies on ESKD, all-cause mortality, myocardial infarction, and progressive protein leakage by kidney disease and low or very low confidence in effects of treatment on death related to cardiovascular complications and doubling of serum creatinine (SCr). For the primary outcomes, tight glycaemic control may make little or no difference to doubling of SCr compared with standard control (4 studies, 26,874 participants: RR 0.84, 95% CI 0.64 to 1.11; I2= 73%, low certainty evidence), development of ESKD (4 studies, 23,332 participants: RR 0.62, 95% CI 0.34 to 1.12; I2= 52%; low certainty evidence), all-cause mortality (9 studies, 29,094 participants: RR 0.99, 95% CI 0.86 to 1.13; I2= 50%; moderate certainty evidence), cardiovascular mortality (6 studies, 23,673 participants: RR 1.19, 95% CI 0.73 to 1.92; I2= 85%; low certainty evidence), or sudden death (4 studies, 5913 participants: RR 0.82, 95% CI 0.26 to 2.57; I2= 85%; very low certainty evidence). People who received treatment to achieve tighter glycaemic control probably experienced lower risks of non-fatal myocardial infarction (5 studies, 25,596 participants: RR 0.82, 95% CI 0.67 to 0.99; I2= 46%, moderate certainty evidence), onset of microalbuminuria (4 studies, 19,846 participants: RR 0.82, 95% CI 0.71 to 0.93; I2= 61%, moderate certainty evidence), and progression of microalbuminuria (5 studies, 13,266 participants: RR 0.59, 95% CI 0.38 to 0.93; I2= 75%, moderate certainty evidence). In absolute terms, tight versus standard glucose control treatment in 1,000 adults would lead to between zero and two people avoiding non-fatal myocardial infarction, while seven adults would avoid experiencing new-onset albuminuria and two would avoid worsening albuminuria. This review suggests that people who receive intensive glycaemic control for treatment of diabetes had comparable risks of kidney failure, death and major cardiovascular events as people who received less stringent blood glucose control, while experiencing small clinical benefits on the onset and progression of microalbuminuria and myocardial infarction. The adverse effects of glycaemic management are uncertain. Based on absolute treatment effects, the clinical impact of targeting an HbA1c < 7% or blood glucose < 6.6 mmol/L is unclear and the potential harms of this treatment approach are largely unmeasured.

Fourteen studies involving 29,319 people with at risk of diabetes complications were included and 11 studies involving 29,141 people were included in our analyses. Tighter blood glucose control generally didn't show any benefits for patients compared to less tight glucose control. There was no difference in the risks for patients on kidney failure, death, or heart disease complications. A very small number of patients (1 in every 1000 treated each year) might avoid a heart attack with more intense blood glucose management. Some patients would expect to have less protein leakage through kidney function although the clinical impact of this benefit is unclear in the long term. The potential problems with treatment, such as side effects and risks of very low blood glucose (hypoglycaemia) were not generally measured in the studies. The review concludes that people with diabetes receive uncertain benefits from tighter blood glucose control in the long-term and the immediate complications of this treatment approach are difficult to know accurately.

10.1002/14651858.CD010137.pub2

cochrane-simplification-train-353

cochrane-simplification-train-353

Seven trials involving 1558 participants were included in this review; 457 were involved in four trials of antibiotic medication, and 1101 were involved in three trials of beta-blocker medication. Five of the studies were rated at a high risk of bias. Individually, all of the included trials reported non-significant differences in AAA expansion rates between their intervention and control groups. The two major drug groups were then analysed separately. For AAA expansion it was only possible to combine two of the antibiotic trials in a meta-analysis. This demonstrated that roxithromycin had a small but significant protective effect (MD -0.86 mm; 95% confidence interval (CI) -1.57 to -0.14). When referral to AAA surgery was compared (including all four antibiotic trials in the meta-analysis), non-significantly fewer patients were referred in the intervention groups (OR 0.96; 95% CI 0.59 to 1.57) than the control groups. When only the trials reporting actual elective surgery were included in a subgroup analysis, the result remained statistically non-significant (OR 1.17; 95% CI 0.57 to 2.42). For the beta-blocker trials, when all were combined in a meta-analysis, there was a very small, non-significant protective effect for propranolol on AAA expansion (MD -0.08 mm; 95% CI -0.25 to 0.10), and non-significantly fewer patients were referred to AAA surgery in the propranolol group (OR 0.74; 95% CI 0.52 to 1.05). Bronchospasm and shortness of breath were the main adverse effects from the beta-blockers. In one trial the adverse effects were reportedly so severe that the trial was stopped early after two years. There is some limited evidence that antibiotic medication may have a slight protective effect in retarding the expansion rates of small AAAs. The quality of the evidence makes it unclear whether this translates into fewer referrals to AAA surgery, owing mainly to the small sample sizes of the studies. Antibiotics were generally well tolerated with minimal adverse effects. Propranolol was poorly tolerated by patients in all of the beta-blocker trials and demonstrated only minimal and non-significant protective effects. Further research on beta-blockers for AAA needs to consider the use of drugs other than propranolol. In general, there is surprisingly little high quality evidence on medical treatment for small AAAs, especially in relation to the use of newer beta-blockers, ACE inhibitors and statins.

We identified seven trials involving 1558 participants where the aneurysm diameters of patients randomised to receive medical treatment were compared to those participants given a control medication or surveillance imaging alone. Four trials studied the effects of antibiotics on slowing aneurysm growth, and showed a small protective effect. Three trials studied the effects of beta-blockers, and demonstrated a very small protective effect. Notably, the beta-blocker drugs were associated with a large number of adverse effects. It was unclear whether either drug type delayed referral to aneurysm surgery. The accuracy of the results was limited by the low number of participants (especially important when trying to detect small changes in aneurysm growth rates) and some potentially damaging biases.

10.1002/14651858.CD009536.pub2

cochrane-simplification-train-354

cochrane-simplification-train-354

Two RCTs involving 2024 patients (1502 adults and 522 children) were included in this review. Both RCTs excluded patients with suspected severe disease. It was not possible to pool the results due to incomplete data. Both included trials concluded that the use of chest radiographs did not result in a better clinical outcome (duration of illness and of symptoms) for patients with acute LRTIs. In the study involving children in South Africa, the median time to recovery was seven days (95% confidence interval (CI) six to eight days (radiograph group) and six to nine days (control group)), P value = 0.50, log-rank test) and the hazard ratio for recovery was 1.08 (95% CI 0.85 to 1.34). In the study with adult participants in the USA, the average duration of illness was 16.9 days versus 17.0 days (P value > 0.05) in the radiograph and no radiograph groups respectively. This result was not statistically significant and there were no significant differences in patient outcomes between the groups with or without chest radiograph. The study in adults also reports that chest radiographs did not affect the frequencies with which clinicians ordered return visits or antibiotics. However, there was a benefit of chest radiographs in a subgroup of the adult participants with an infiltrate on their radiograph, with a reduction in length of illness (16.2 days in the group allocated to chest radiographs and 22.6 in the non-chest radiograph group, P < 0.05), duration of cough (14.2 versus 21.3 days, P < 0.05) and duration of sputum production (8.5 versus 17.8 days, P < 0.05). The authors mention that this difference in outcome between the intervention and control group in this particular subgroup only was probably a result of "the higher proportion of patients treated with antibiotics when the radiograph was used in patient care". Hospitalisation rates were only reported in the study involving children and it was found that a higher proportion of patients in the radiograph group (4.7%) required hospitalisation compared to the control group (2.3%) with the result not being statistically significant (P = 0.14). None of the trials report the effect on mortality, complications of infection or adverse events from chest radiographs. Overall, the included studies had a low or unclear risk for blinding, attrition bias and reporting bias, but a high risk of selection bias. Both trials had strict exclusion criteria which is important but may limit the clinical practicability of the results as participants may not reflect those presenting in clinical practice. Data from two trials suggest that routine chest radiography does not affect the clinical outcomes in adults and children presenting to a hospital with signs and symptoms suggestive of a LRTI. This conclusion may be weakened by the risk of bias of the studies and the lack of complete data available.

Two trials with a total of 2024 participants were included in this review. The trial published in 1983 in the USA included only adults, while the trial in 1998 in South Africa included only children. Both trials were set in large metropolitan cities. We were unable to combine the results of the two studies due to incomplete data. However, both trials came to the same conclusion regarding the use of chest X-rays in chest infections, except in the subgroup of patients with evidence of infection (infiltrates) on their X-rays. In both adults and children, chest X-rays did not result in significant differences in recovery time. In summary, there were no differences in patient outcomes between the groups with or without chest X-ray. Although both studies suggest that chest X-rays do not improve patient outcomes, it is not clear if this finding can be applied to all populations and settings. Results may be different in resource poor countries. Our conclusions are limited due to the lack of complete data available and by the risk of bias of the studies. Adverse effects of chest X-rays were not assessed by either study. We assessed the quality of the evidence from both trials as being moderate. For the remainder of this review, X-rays will be referred to as radiographs. The evidence is current as of February 2013.

10.1002/14651858.CD009119.pub2

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cochrane-simplification-train-355

We included five studies involving 113 adults. Participants in four studies had mild to moderate asthma and the fifth study included participants independent of their asthma severity. There were substantial differences between the studies, including the training protocol, duration of training sessions (10 to 30 minutes) and duration of the intervention (3 to 25 weeks). Three clinical trials were produced by the same research group. Risk of bias in the included studies was difficult to ascertain accurately due to poor reporting of methods. The included studies showed a statistically significant increase in inspiratory muscle strength, measured by maximal inspiratory pressure (PImax) (mean difference (MD) 13.34 cmH2O, 95% CI 4.70 to 21.98, 4 studies, 84 participants, low quality evidence). Our other primary outcome, exacerbations requiring a course of oral or inhaled corticosteroids or emergency department visits, was not reported. For the secondary outcomes, results from one trial showed no statistically significant difference between the inspiratory muscle training group and the control group for maximal expiratory pressure, peak expiratory flow rate, forced expiratory volume in one second, forced vital capacity, sensation of dyspnoea and use of beta2-agonist. There were no studies describing inspiratory muscle endurance, hospital admissions or days off work or school. There is no conclusive evidence in this review to support or refute inspiratory muscle training for asthma. The evidence was limited by the small number of trials with few participants together with the risk of bias. More well conducted randomised controlled trials are needed. Future trials should investigate the following outcomes: lung function, exacerbation rate, asthma symptoms, hospital admissions, use of medications and days off work or school. Inspiratory muscle training should also be assessed in people with more severe asthma and conducted in children with asthma.

We found and included five studies in our review. Three studies were conducted by the same group of researchers in Israel (Weiner 2000; Weiner 2002; Weiner 2002a), one study (Sampaio 2002) was conducted in Brazil and one trial was conduced in the United Kingdom (McConnell 1998). A total of 113 adults with asthma (46 male and 67 female) were included. No study included children. The studies showed a significant improvement in inspiratory muscle strength (PImax). People with asthma who received IMT on average increased their inspiratory muscle strength, but it was not possible to state whether this improvement seen in inspiratory muscle strength translated into any clinical benefit. Results from one study showed no significant difference between the training group and the control group (no treatment or usual care) for expiratory muscle strength, lung function, sensation of dyspnoea (breathlessness) and use of reliever medication. There were no studies describing exacerbation events that required use of reliever medication or emergency department visits, inspiratory muscle endurance, hospital admissions and days off work or school. Given the insufficient evidence found in this review, we believe that there is a need for more well conducted studies in order to assess the efficacy of IMT in people with asthma, including children. There were substantial differences between the studies, including the training protocol, duration of training sessions (10 to 30 minutes) and duration of the intervention (over 3 to 25 weeks). The methodological quality of the studies included in this update was difficult to accurately ascertain. Study samples were small and the risk of bias was mostly unclear, due to inadequate reporting. Overall the quality of the evidence included in the review was very low. This summary was current to November 2012.

10.1002/14651858.CD003792.pub2

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cochrane-simplification-train-356

This review included eight studies (with a total of 590 participants). Seven studies investigated the effects of hearing aids, four combination hearing aids and three sound generators. Seven studies were parallel-group RCTs and one had a cross-over design. In general, risk of bias was unclear due to lack of detail about sequence generation and allocation concealment. There was also little or no use of blinding. No data for our outcomes were available for any of our three main comparisons (comparing hearing aids, sound generators and combination devices with a waiting list control group, placebo or education/information only). Data for our additional comparisons (comparing these devices with each other) were also few, with limited potential for data pooling. Hearing aid only versus sound generator device only One study compared patients fitted with sound generators versus those fitted with hearing aids and found no difference between them in their effects on our primary outcome, tinnitus symptom severity measured with the Tinnitus Handicap Inventory (THI) at 3, 6 or 12 months (low-quality evidence). The use of both types of device was associated with a clinically significant reduction in tinnitus symptom severity. Combination hearing aid versus hearing aid only Three studies compared combination hearing aids with hearing aids and measured tinnitus symptom severity using the THI or Tinnitus Functional Index. When we pooled the data we found no difference between them (standardised mean difference -0.15, 95% confidence interval -0.52 to 0.22; three studies; 114 participants) (low-quality evidence). The use of both types of device was again associated with a clinically significant reduction in tinnitus symptom severity. Adverse effects were not assessed in any of the included studies. None of the studies measured the secondary outcomes of depressive symptoms or depression, anxiety symptoms or generalised anxiety, or health-related quality of life as measured by a validated instrument, nor the newly developed core outcomes tinnitus intrusiveness, ability to ignore, concentration, quality of sleep and sense of control. There is no evidence to support the superiority of sound therapy for tinnitus over waiting list control, placebo or education/information with no device. There is insufficient evidence to support the superiority or inferiority of any of the sound therapy options (hearing aid, sound generator or combination hearing aid) over each other. The quality of evidence for the reported outcomes, assessed using GRADE, was low. Using a combination device, hearing aid or sound generator might result in little or no difference in tinnitus symptom severity. Future research into the effectiveness of sound therapy in patients with tinnitus should use rigorous methodology. Randomisation and blinding should be of the highest quality, given the subjective nature of tinnitus and the strong likelihood of a placebo response. The CONSORT statement should be used in the design and reporting of future studies. We also recommend the use of validated, patient-centred outcome measures for research in the field of tinnitus.

Our review identified eight randomised controlled trials with 590 participants in total. Seven studies looked at the effects of hearing aids, four combination hearing aids and three sound generators. Seven studies allocated participants into parallel groups and in one study participants tried each intervention in a random order. The outcomes that we looked for were severity of tinnitus symptoms, depression, anxiety, quality of life and side effects. In general, the risk of bias in the studies was unclear. There was also little or no use of blinding. We did not find any data for our outcomes for any of our three main comparisons (comparing hearing aids, sound generators and combination devices with a waiting list control group, placebo or education/information only). There were also few data for our additional comparisons (comparing these devices with each other) and it was difficult to pool (combine) the data. One study compared patients fitted with sound generators with those fitted with hearing aids and found no difference between them in their effects on our primary outcome, tinnitus symptom severity, at 3, 6 or 12 months. The use of both types of device was associated with a clinically significant reduction in tinnitus symptom severity. Three studies compared combination hearing aids/sound generators with hearing aids alone and measured tinnitus symptom severity. When we combined the data for tinnitus symptom severity we found no difference between them. The use of both types of device was again associated with a clinically significant reduction in tinnitus symptom severity. Adverse effects were not assessed in any of the included studies. None of the studies measured depressive symptoms or depression, anxiety symptoms or generalised anxiety, or other important outcomes of interest in this review. Where outcomes that we were interested in for this review were reported, we assessed the quality of the evidence available as low. Using a hearing aid, sound generator or combination device might result in little or no difference in tinnitus symptom severity.

10.1002/14651858.CD013094.pub2

cochrane-simplification-train-357

cochrane-simplification-train-357

Fourteen studies met the inclusion criteria, randomising 11,794 people with severe COPD. We looked at any LABA plus ICS inhaler (LABA/ICS) versus the same LABA component alone, and then we looked at the 10 studies which assessed fluticasone plus salmeterol (FPS) and the four studies assessing budesonide plus formoterol (BDF) separately. The studies were well-designed with low risk of bias for randomisation and blinding but they had high rates of attrition, which reduced our confidence in the results for outcomes other than mortality. Primary outcomes There was low quality evidence that exacerbation rates in people using LABA/ICS inhalers were lower in comparison to those with LABA alone, from nine studies which randomised 9921 participants (rate ratio 0.76; 95% CI 0.68 to 0.84). This corresponds to one exacerbation per person per year on LABA and 0.76 exacerbations per person per year on ICS/LABA. Our confidence in this effect was limited by statistical heterogeneity between the results of the studies (I2 = 68%) and a risk of bias from the high withdrawal rates across the studies. When analysed as the number of people experiencing one or more exacerbations over the course of the study, FPS lowered the odds of an exacerbation with an odds ratio (OR) of 0.83 (95% CI 0.70 to 0.98, 6 studies, 3357 participants). With a risk of an exacerbation of 47% in the LABA group over one year, 42% of people treated with LABA/ICS would be expected to experience an exacerbation. Concerns over the effect of reporting biases led us to downgrade the quality of evidence for this effect from high to moderate. There was no significant difference in the rate of hospitalisations (rate ratio 0.79; 95% CI 0.55 to 1.13, very low quality evidence due to risk of bias, statistical imprecision and inconsistency). There was no significant difference in mortality between people on combined inhalers and those on LABA, from 10 studies on 10,680 participants (OR 0.92; 95% CI 0.76 to 1.11, downgraded to moderate quality evidence due to statistical imprecision). Pneumonia occurred more commonly in people randomised to combined inhalers, from 12 studies with 11,076 participants (OR 1.55; 95% CI 1.20 to 2.01, moderate quality evidence due to risk of bias in relation to attrition) with an annual risk of around 3% on LABA alone compared to 4% on combination treatment. There were no significant differences between the results for either exacerbations or pneumonia from trials adding different doses or types of inhaled corticosteroid. Secondary outcomes ICS/LABA was more effective than LABA alone in improving health-related quality of life measured by the St George's Respiratory Questionnaire (1.58 units lower with FPS; 2.69 units lower with BDF), dyspnoea (0.09 units lower with FPS), symptoms (0.07 units lower with BDF), rescue medication (0.38 puffs per day fewer with FPS, 0.33 puffs per day fewer with BDF), and forced expiratory volume in one second (FEV1) (70 mL higher with FPS, 50 mL higher with BDF). Candidiasis (OR 3.75) and upper respiratory infection (OR 1.32) occurred more frequently with FPS than SAL. We did not combine adverse event data relating to candidiasis for BDF studies as the results were very inconsistent. Concerns over the analysis and availability of data from the studies bring into question the superiority of ICS/LABA over LABA alone in preventing exacerbations. The effects on hospitalisations were inconsistent and require further exploration. There was moderate quality evidence of an increased risk of pneumonia with ICS/LABA. There was moderate quality evidence that treatments had similar effects on mortality. Quality of life, symptoms score, rescue medication use and FEV1 improved more on ICS/LABA than on LABA, but the average differences were probably not clinically significant for these outcomes. To an individual patient the increased risk of pneumonia needs to be balanced against the possible reduction in exacerbations. More information would be useful on the relative benefits and adverse event rates with combination inhalers using different doses of inhaled corticosteroids. Evidence from head-to-head comparisons is needed to assess the comparative risks and benefits of the different combination inhalers.

We searched for randomised controlled trials (RCTs) that compared any combination inhaler versus the same LABA component inhaler used by people with COPD. The studies were well-designed with low risk of bias for randomisation and blinding but there were high numbers of people who dropped out of the trials, which affected our confidence in the results for the outcomes. Overall, we found 14 trials involving 11,794 people with COPD. The results of the studies showed that combined inhalers reduced the frequency of exacerbations compared with their LABA component alone, from, for example, an average of one exacerbation per year on a long-acting beta2-agonist to an average of 0.76 exacerbations per year on a combined inhaler. The risk of mortality was similar between the treatments, although the overall result was not precise enough to rule out an effect in favour of either treatment. There was evidence of an overall increased risk of pneumonia with combined inhalers, from around three per 100 people per year on LABA to four per 100 per year on combined inhalers. There was no significant difference between treatments in terms of hospitalisations although the results of the three studies were inconsistent so we cannot be certain what this means. Combined treatment was more effective than LABA in improving health-related quality of life, symptoms such as breathlessness and cough, some measures of lung function, and also reduced rescue medication use, but it is difficult to tell whether these differences would be meaningful for individual people with COPD. Fluticasone/salmeterol led to more candidiasis and chest infections compared with salmeterol. Future research is required to show whether combined therapy reduces hospitalisations, and to better estimate the increased risks of pneumonia. This will need more trials with different doses of inhaled corticosteroids and including direct comparisons of different combination inhalers. The conclusions of the review are current to November 2011.

10.1002/14651858.CD006829.pub2

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cochrane-simplification-train-358

No new trials were identified in this 2014 update. We included four trials (three RCTs and one quazi-RCT), with 759 children in the rapid viral testing group and 829 in the control group. Three out of the four studies were comparable in terms of young age of participants, with one study increasing the age of inclusion up to five years of age. All studies included either fever or respiratory symptoms as inclusion criteria (two required both, one required fever or respiratory symptoms, and one required only fever). All studies were comparable in terms of exclusion criteria, intervention, and outcome data. In terms of risk of bias, one study failed to utilize a random sequence generator, one study did not comment on completeness of outcome data, and only one of four studies included allocation concealment as part of the study design. None of the studies definitively blinded participants. Rapid viral testing resulted in a trend toward decreased antibiotic use in the ED, but this was not statistically significant. We found lower rates of chest radiography (RR 0.77, 95% CI 0.65 to 0.91) in the rapid viral testing group, but no effect on length of ED visits, or blood or urine testing in the ED. No study made mention of any adverse effects related to viral testing. There is insufficient evidence to support routine rapid viral testing to reduce antibiotic use in pediatric EDs. Rapid viral testing may or may not reduce rates of antibiotic use, and other investigations (urine and blood testing); these studies do not provide enough power to resolve this question. However, rapid viral testing does reduce the rate of chest X-rays in the ED. An adequately powered trial with antibiotic use as an outcome is needed.

We reviewed studies retrievable as of July 2014. We included four prospective controlled studies of previously healthy children under 18 years of age who attended an ED of an urgent care clinic because of fever and respiratory symptoms. Based on these four studies, involving 759 study participants, we found that in previously healthy children coming to the ED with fever and respiratory symptoms, a rapid viral test showed a trend towards fewer antibiotic prescriptions, but this finding was not statistically significant. However, we found that rapid viral testing reduces the use of chest X-rays. There are also blood and urine investigations that can be undertaken. The true impact of this intervention on the frequency of blood and urine testing, as well as the length of the ED visit, requires trials with larger numbers of children. None of the included studies reported harm or adverse events related to the intervention tested. The quality of the evidence was considered moderate with regard to risk of bias, indirectness, imprecision, publication bias and inconsistency. While none of the studies used blinding, the impact of the use of rapid viral testing is in its ability to provide diagnostic information. Blinding of this interventions to the clinician would be impossible and make the intervention useless.

10.1002/14651858.CD006452.pub4

cochrane-simplification-train-359

cochrane-simplification-train-359

Seven studies were included, they were all parallel-group studies, two studies were assessed as at low risk of bias and three at high risk of bias; two were considered to have unclear bias in their methodology. A total of 2241 participants were enrolled in these trials. Ibuprofen was found to be a superior analgesic to paracetamol at several doses with high quality evidence suggesting that ibuprofen 400 mg is superior to 1000 mg paracetamol based on pain relief (estimated from TOTPAR data) and the use of rescue medication meta-analyses. The risk ratio for at least 50% pain relief (based on TOTPAR) at six hours was 1.47 (95% confidence interval (CI) 1.28 to 1.69; five trials) favouring 400 mg ibuprofen over 1000 mg paracetamol, and the risk ratio for not using rescue medication (also favouring ibuprofen) was 1.50 (95% CI 1.25 to 1.79; four trials). The combined drug showed promising results, with a risk ratio for at least 50% of the maximum pain relief over six hours of 1.77 (95% CI 1.32 to 2.39) (paracetamol 1000 mg and ibuprofen 400 mg) (one trial; moderate quality evidence), and risk ratio not using rescue medication 1.60 (95% CI 1.36 to 1.88) (two trials; moderate quality evidence). The information available regarding adverse events from the studies (including nausea, vomiting, headaches and dizziness) indicated that they were comparable between the treatment groups. However, we could not formally analyse the data as it was not possible to work out how many adverse events there were in total. There is high quality evidence that ibuprofen is superior to paracetamol at doses of 200 mg to 512 mg and 600 mg to 1000 mg respectively based on pain relief and use of rescue medication data collected at six hours postoperatively. The majority of this evidence (five out of six trials) compared ibuprofen 400 mg with paracetamol 1000 mg, these are the most frequently prescribed doses in clinical practice. The novel combination drug is showing encouraging results based on the outcomes from two trials when compared to the single drugs.

The evidence on which this review is based was current as of 20 May 2013. Seven studies with a total of 2241 participants all involving a direct comparison of ibuprofen to paracetamol or the combination of both were included in this review. All participants had surgery to remove a lower wisdom tooth or teeth that required bone removal or at least caused moderate to severe pain. Painkillers were taken after surgery and different doses of the drugs were compared. The majority of the studies took place in the USA with one in Puerto Rico. Four of the trials took place in clinical research facilities, two in university dental hospitals and one in a private oral surgery clinic. The age of participants differed slightly between studies but was broadly similar, ranging from 15 to 65 years old. All studies included male and female participants. All the studies included in this review looked only at pain relief and intensity information after a single dose of the painkiller after surgery. It is known that pain does continue after this and the drugs evaluated in this review are normally taken every six to eight hours (maximum of four times per day). Ibuprofen is more effective than paracetamol at all doses studied in this review. On limited evidence, the combination of ibuprofen and paracetamol appeared to be no more effective than the single drugs when measured two hours after surgery. However, again on limited evidence, it was found to be more effective than the drugs taken singly when measured at six hours after surgery. Participants taking the combined drug also had a smaller chance of requiring rescue medication. The information available regarding adverse events from the studies (including nausea, vomiting, headaches and dizziness) indicated that they were comparable between the treatment groups. However, review authors could not formally analyse the data as it was not possible to work out how many adverse events there were in total. All of the results (outcomes) comparing ibuprofen to paracetamol are of high quality. This means that further research is very unlikely to change our confidence in the estimates of the effect. When comparing combined versus single drugs, the body of evidence for the proportion of patients with > 50% maximum pain relief (TOTPAR) over two and six hours, was assessed as of moderate quality due to imprecise estimates based on single studies. This means that further research is likely to have an important impact on our confidence in the estimate of the effect. The body of evidence for the use of rescue medication was assessed as being of high quality.

10.1002/14651858.CD004624.pub2

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cochrane-simplification-train-360

We found only one trial, which included 61 women, that met our inclusion criteria. This trial reported data on surgical versus clinical staging and an assessment of the two surgical staging techniques; laparoscopic (LAP) versus extraperitoneal (EXP) surgical staging. The clinical staging was either a contrast-enhanced computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the abdomen and pelvis to determine nodal status. In this trial, clinical staging appeared to significantly prolong overall and progression-free survival compared to surgical staging. There was no statistically significant difference in the number of women who experienced severe (grade 3 or 4) toxicity. There was no statistically significant difference in the risk of death, disease recurrence or progression, blood loss, severe toxicity and the duration of the operational procedure between LAP and EXP surgical staging techniques. The strength of the evidence is weak in this review as it is based on one small trial that was at moderate risk of bias. Since the last version of this review no new studies were found. From the one available RCT we found insufficient evidence that pre-treatment surgical para-aortic lymph node assessment for locally advanced cervical cancer is beneficial, and it may actually have an adverse effect on survival. However, this conclusion is based on analysis of a small single trial and therefore definitive guidance or recommendations for clinical practice cannot be made. Therefore, the decision to offer surgical pre-treatment assessment of para-aortic lymph nodes in locally advanced cervical cancer needs to be individualised. The uncertainty regarding any impact on survival from pre-treatment para-aortic lymph node assessment should be discussed openly with the women.

The purpose of this review was to assess the available literature on the effectiveness and safety of pre-treatment surgical para-aortic lymph node assessment for locally advanced cervical cancer. We found only one randomised controlled trial (RCT) that assessed non-surgical staging versus surgical staging. We found limited evidence that suggested that clinical staging may offer a survival benefit (in terms of overall and progression-free survival) compared with surgical staging, but the strength of the evidence from this small trial is weak and the trial was at moderate risk of bias. There was no statistically significant difference in any of the reported outcomes between two surgical staging techniques examined in the trial. Due to the small number of women with locally advanced cervical cancer in only one included trial there was insufficient evidence to conclude that any of the staging techniques are superior to each other. This review highlights the need for future good-quality, well-designed trials that report not only survival and severe adverse event outcomes but also examine quality of life (QoL) outcome data.

10.1002/14651858.CD008217.pub3

cochrane-simplification-train-361

cochrane-simplification-train-361

Fourteen randomised controlled trials (3576 patients) were included, with no new studies added in this update. There were important differences in the doses of radiotherapy investigated, the patient characteristics including disease stage and performance status and the outcome measures.The doses of RT investigated ranged from 10 Gy in 1 fraction (10Gy/1F) to 60 Gy/30F over six weeks, with a total of 19 different dose/ fractionation regimens. Potential biases were identified in some studies. Methods of randomisation, assessment of symptoms and statistical methods used were unclear in some papers. Withdrawal and drop-outs were accounted for in all but one study. All 13 studies that investigated symptoms reported that major thoracic symptoms improved following RT.There is no strong evidence that any regimen gives greater palliation. Higher dose regimens may give more acute toxicity and some regimens are associated with an increased risk of radiation myelitis. Variation in reporting of toxicities, in particular the absence of clear grading, means results of the meta-analysis should be treated with caution. Meta-analysis of overall survival broken down by performance status, a key variable, is included in this update. Further information was sought from all the original authors if stratified data was not included in the original publication. Three published studies contained sufficient data and seven authors were able to provide further information which represented 1992 patients (56% of all patients). The absence of data for nearly half of the patients has affected the quality of evidence. The meta-analysis showed no significant difference in 1-year overall survival between regimens with fewer radiotherapy fractions compared with regimens with more when patients were stratified by performance status. The results of the meta-analysis of 1-year overall survival for patients with good performance status (WHO performance status 0-1) showed moderately high heterogeneity and a summary result was not thought meaningful. The results of 1-year overall survival for patients with poor performance status was RR 0.96 (95% CI 0.91 to 1.02; moderate quality of evidence). Radiotherapy for patients with incurable non-small cell lung cancer can improve thoracic symptoms. Care should be taken with the dose to the spinal cord to reduce the risk of radiation myelopathy. The higher dose, more fractionated palliative radiotherapy regimens do not provide better or more durable palliation and their use to prolong survival is not supported by strong evidence. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients, need to be carried out.

Fourteen trials, including 3576 patients, were found that compared at least two different radiotherapy regimens. All involved patients with incurable lung cancer but the extent of the cancer and the fitness of the patients varied between the studies making direct comparisons difficult.The radiotherapy regimens in the trials varied from a single treatment to thirty treatments over six weeks.This update found no new trials and a meta-analysis (pooling the results of all trials) was carried out to see whether giving higher doses of radiation resulted in longer survival. All trials reported how long patients lived after their treatment and looked at the effect on symptoms as well as recording side-effects. However, the trials did not use the same methods for recording symptoms and side effects with some using the doctor's assessment and some using the patient's, making direct comparison difficult. This review shows that for most patients, a short course of radiotherapy with only one or two visits, improves common symptoms as effectively as longer courses, without more side effects. There is no strong evidence to support the view that a longer course of radiotherapy may give a better chance of living for one or two years, but it does result in more immediate side effects, especially sore swallowing. All the trials were randomised meaning patients involved in the study had an equal chance of getting either treatment. The use of a doctor's assessment of the patient's symptoms in some studies may have led to an under-estimation of the symptoms.

10.1002/14651858.CD002143.pub4

cochrane-simplification-train-362

cochrane-simplification-train-362

We identified two RCTs involving 978 women with cervical cancer stage IIB to IVA. As the trials were significantly different clinically, we did not perform meta-analyses. One industry-funded trial involving 515 women compared CCRT (cisplatin) versus CCRT (cisplatin and gemcitabine) plus ACT (two additional cycles). This trial reported significant improvement in progression-free survival (PFS) and overall survival (OS) in women who were given CCRT plus ACT compared with those treated with CCRT alone: Three-year PFS was 74.4% versus 65.0% (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.49 to 0.95, P value 0.027), and three-year OS was 80% versus 69% (HR 0.68, 95% CI 0.49 to 0.95, P value 0.022). However, as the CCRT chemotherapy differed between the two arms, we considered the findings to be at high risk of bias. The second trial was a four-arm study from which we extracted data on 463 women in two study arms receiving CCRT (intravenous mitomycin C and oral 5-fluorouracil (5-FU)) or CCRT plus ACT (oral 5-FU for three cycles). The HR for OS in women who received ACT after CCRT compared with the HR for OS in those who were given CCRT alone was 1.309 (95% CI 0.795 to 2.157), and the HR for disease-free survival (DFS) was 1.125 (95% CI 0.799 to 1.586). Haematological adverse events were more common in the ACT arms of both trials. Quality of life (QoL) was not reported in either trial. With limited data from only two trials, we found insufficient evidence to support the use of ACT after CCRT. Future large trials are required to demonstrate efficacy, toxicities and QoL.

The two studies were very different; therefore we could not pool their data. One trial conducted internationally between 2002 and 2004, involving 515 women, found that cancer took longer to return in women receiving ACT (cisplatin and gemcitabine), and more women in the ACT group were alive after three years than in the standard treatment group (80% versus 69%). We considered the findings to be at high risk of bias in this trial, as women were given different drugs during standard treatment, and so the overall effect of the study treatment could not be attributed to the ACT alone. The other trial, which was conducted in several hospitals in Thailand between 1988 and 1994, involved 463 women. ACT (5-fluorouracil) did not improve the length of survival or the time taken for cancer to return in women in this trial. A trend towards increased side effects was reported in the ACT arms of both studies. We found insufficient evidence to support giving additional anticancer drugs to women who have received standard treatment for locally advanced cervical cancer, as currently only limited data are available from two very different trials.

10.1002/14651858.CD010401.pub2

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cochrane-simplification-train-363

We selected 23 studies for inclusion (22 journal articles and one conference abstract). We evaluated the following scales: Cincinnati Prehospital Stroke Scale (CPSS; 11 studies), Recognition of Stroke in the Emergency Room (ROSIER; eight studies), Face Arm Speech Time (FAST; five studies), Los Angeles Prehospital Stroke Scale (LAPSS; five studies), Melbourne Ambulance Stroke Scale (MASS; three studies), Ontario Prehospital Stroke Screening Tool (OPSST; one study), Medic Prehospital Assessment for Code Stroke (MedPACS; one study) and PreHospital Ambulance Stroke Test (PreHAST; one study). Nine studies compared the accuracy of two or more scales. We considered 12 studies at high risk of bias and one with applicability concerns in the patient selection domain; 14 at unclear risk of bias and one with applicability concerns in the reference standard domain; and the risk of bias in the flow and timing domain was high in one study and unclear in another 16. We pooled the results from five studies evaluating ROSIER in the ER and five studies evaluating LAPSS in a prehospital setting. The studies included in the meta-analysis of ROSIER were of relatively good methodologic quality and produced a summary sensitivity of 0.88 (95% CI 0.84 to 0.91), with the prediction interval ranging from approximately 0.75 to 0.95. This means that the test will miss on average 12% of people with stroke/TIA which, depending on the circumstances, could range from 5% to 25%. We could not obtain a reliable summary estimate of specificity due to extreme heterogeneity in study-level results. The summary sensitivity of LAPSS was 0.83 (95% CI 0.75 to 0.89) and summary specificity 0.93 (95% CI 0.88 to 0.96). However, we were uncertain in the validity of these results as four of the studies were at high and one at uncertain risk of bias. We did not report summary estimates for the rest of the scales, as the number of studies per test per setting was small, the risk of bias was high or uncertain, the results were highly heterogenous, or a combination of these. Studies comparing two or more scales in the same participants reported that ROSIER and FAST had similar accuracy when used in the ER. In the field, CPSS was more sensitive than MedPACS and LAPSS, but had similar sensitivity to that of MASS; and MASS was more sensitive than LAPSS. In contrast, MASS, ROSIER and MedPACS were more specific than CPSS; and the difference in the specificities of MASS and LAPSS was not statistically significant. In the field, CPSS had consistently the highest sensitivity and, therefore, should be preferred to other scales. Further evidence is needed to determine its absolute accuracy and whether alternatives scales, such as MASS and ROSIER, which might have comparable sensitivity but higher specificity, should be used instead, to achieve better overall accuracy. In the ER, ROSIER should be the test of choice, as it was evaluated in more studies than FAST and showed consistently high sensitivity. In a cohort of 100 people of whom 62 have stroke/TIA, the test will miss on average seven people with stroke/TIA (ranging from three to 16). We were unable to obtain an estimate of its summary specificity. Because of the small number of studies per test per setting, high risk of bias, substantial differences in study characteristics and large between-study heterogeneity, these findings should be treated as provisional hypotheses that need further verification in better-designed studies.

The evidence is current to 30 January 2018. We included studies assessing the accuracy of stroke recognition scales when applied to adults suspected of stroke out of hospital. We included 23 studies evaluating the following scales: Cincinnati Prehospital Stroke Scale (CPSS; 11 studies), Recognition of Stroke in the Emergency Room (ROSIER; eight studies), Face Arm Speech Time (FAST; five studies), Los Angeles Prehospital Stroke Scale (LAPSS; five studies), Melbourne Ambulance Stroke Scale (MASS; three studies), Ontario Prehospital Stroke Screening Tool (OPSST; one study), Medic Prehospital Assessment for Code Stroke (MedPACS; one study) and PreHospital Ambulance Stroke Test (PreHAST; one study). Nine studies compared two or more scales in the same people. The results from five studies were combined to estimate the accuracy of ROSIER in the emergency room (ER) and five studies to estimate the accuracy of LAPSS when used by ambulance clinicians. Many of the studies were of poor or unclear quality and we could not be sure that their results were valid. Studies differed considerably in terms of included participants and other characteristics. As a consequence, studies evaluating the same scale reported variable results. We combined five studies evaluating ROSIER in the ER and obtained average sensitivity of 88% (88 out of 100 people with stroke/TIA will test positive on ROSIER). We were unable to obtain an estimate of specificity (how many people without stroke/TIA will test negative). We also combined the results for LAPSS, but the included studies were of poor quality and the results may not be valid. The rest of the scales were evaluated in a smaller number of studies or the results were too variable to be combined statistically. A small number of studies compared two or more scales when applied to the same participants. Such studies are more likely to produce valid results as the scales are used in the same circumstances. They reported that in the ER, ROSIER and FAST had similar accuracy, but ROSIER was evaluated in more studies. When used by ambulance staff, CPSS identified more people with stroke/TIA in all studies, but also more people without stroke/TIA tested positive. Current evidence suggests that CPSS should be used by ambulance clinicians in the field. Further research is needed to estimate the proportion of wrong results and whether alternatives scales, such as MASS and ROSIER, which might have comparable sensitivity but higher specificity, should be used instead to achieve better overall accuracy. In the ER, ROSIER should be the test of choice. In a group of 100 people of whom 62 have stroke/TIA, the test will miss on average seven people with stroke/TIA (ranging from three to 16). Because of the small number of studies evaluating the tests in a specific setting, poor quality, substantial differences in study characteristics and variability in results, these findings should be treated with caution and need further verification in better-designed studies.

10.1002/14651858.CD011427.pub2

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cochrane-simplification-train-364

Two studies tested gabapentin to treat fibromyalgia pain. One was identified in previous versions of the review and is included here. We identified another study as a conference abstract, with insufficient detail to determine eligibility for inclusion; it is awaiting assessment. The one included study of 150 participants was a 12-week, multi-centre, randomised, double-blind, placebo-controlled, parallel-group study using last-observation-carried-forward imputation for withdrawals. The maximum dose was 2400 mg daily. The overall risk of bias was low, except for attrition bias. At the end of the trial, the outcome of 50% reduction in pain over baseline was not reported. The outcome of 30% or greater reduction in pain over baseline was achieved by 38/75 participants (49%) with gabapentin compared with 23/75 (31%) with placebo (very low quality). A patient global impression of change any category of "better" was achieved by 68/75 (91%) with gabapentin and 35/75 (47%) with placebo (very low quality). Nineteen participants discontinued the study because of adverse events: 12 in the gabapentin group (16%) and 7 in the placebo group (9%) (very low quality). The number of serious adverse events were not reported, and no deaths were reported (very low quality). We have only very low quality evidence and are very uncertain about estimates of benefit and harm because of a small amount of data from a single trial. There is insufficient evidence to support or refute the suggestion that gabapentin reduces pain in fibromyalgia.

In May 2016 we searched for clinical trials where gabapentin was used to treat pain due to fibromyalgia in adults. We found one study that met the requirements for this review. The study tested 1200 to 2400 mg/day of gabapentin compared with a placebo over 12 weeks, in 150 people. The study did not report the number of people with pain reduced by half at the end of week 12. At that time 5 in 10 people taking gabapentin and 3 in 10 taking the placebo had their pain reduced by at least one third. A report of feeling better to any degree was reported by 9 in 10 taking gabapentin and 5 in 10 taking placebo. About 2 in 10 people taking gabapentin stopped taking the medicine because of side effects, compared with 1 in 10 taking the placebo. The study did not report the number of people with serious side effects, but did report that there were no deaths. We rated the quality of the evidence as very low because there was only a single small study with important study limitations. Several factors reduced our confidence in the result. Very low quality evidence means that we are very uncertain about the results.

10.1002/14651858.CD012188.pub2

cochrane-simplification-train-365

cochrane-simplification-train-365

We included five RCTs involving 201 carers assessing the effectiveness of MBSR. Controls used in included studies varied in structure and content. Mindfulness-based stress reduction programmes were compared with either active controls (those matched for time and attention with MBSR, i.e. education, social support, or progressive muscle relaxation), or inactive controls (those not matched for time and attention with MBSR, i.e. self help education or respite care). One trial used both active and inactive comparisons with MBSR. All studies were at high risk of bias in terms of blinding of outcome assessment. Most studies provided no information about selective reporting, incomplete outcome data, or allocation concealment. 1. Compared with active controls, MBSR may reduce depressive symptoms of carers at the end of the intervention (3 trials, 135 participants; standardised mean difference (SMD) -0.63, 95% confidence interval (CI) -0.98 to -0.28; P<0.001; low-quality evidence). We could not be certain of any effect on clinically significant depressive symptoms (very low-quality evidence). Mindfulness-based stress reduction compared with active control may decrease carer anxiety at the end of the intervention (1 trial, 78 participants; mean difference (MD) -7.50, 95% CI -13.11 to -1.89; P<0.001; low-quality evidence) and may slightly increase carer burden (3 trials, 135 participants; SMD 0.24, 95% CI -0.11 to 0.58; P=0.18; low-quality evidence), although both results were imprecise, and we could not exclude little or no effect. Due to the very low quality of the evidence, we could not be sure of any effect on carers' coping style, nor could we determine whether carers were more or less likely to drop out of treatment. 2. Compared with inactive controls, MBSR showed no clear evidence of any effect on depressive symptoms (2 trials, 50 participants; MD -1.97, 95% CI -6.89 to 2.95; P=0.43; low-quality evidence). We could not be certain of any effect on clinically significant depressive symptoms (very low-quality evidence). In this comparison, MBSR may also reduce carer anxiety at the end of the intervention (1 trial, 33 participants; MD -7.27, 95% CI -14.92 to 0.38; P=0.06; low-quality evidence), although we were unable to exclude little or no effect. Due to the very low quality of the evidence, we could not be certain of any effects of MBSR on carer burden, the use of positive coping strategies, or dropout rates. We found no studies that looked at quality of life of carers or care-recipients, or institutionalisation. Only one included study reported on adverse events, noting a single adverse event related to yoga practices at home After accounting for non-specific effects of the intervention (i.e. comparing it with an active control), low-quality evidence suggests that MBSR may reduce carers' depressive symptoms and anxiety, at least in the short term. There are significant limitations to the evidence base on MBSR in this population. Our GRADE assessment of the evidence was low to very low quality. We downgraded the quality of the evidence primarily because of high risk of detection or performance bias, and imprecision. In conclusion, MBSR has the potential to meet some important needs of the carer, but more high-quality studies in this field are needed to confirm its efficacy.

We searched for evidence up to September 2017 and found five randomised controlled trials (clinical trials where people are randomly assigned to one of two or more treatment groups) comparing MBSR to a variety of other interventions. We reported the effects of MBSR programmes compared with active controls (interventions in which participants received a similar amount of attention to those in the MBSR group, such as social support or progressive muscle relaxation) or inactive controls (interventions in which participants received less attention than those in the MBSR group, such as self help education). We were able to analyse study data from five randomised controlled trials involving a total of 201 carers. Findings from three studies (135 carers) showed that carers receiving MBSR may have a lower level of depressive symptoms at the end of treatment than those receiving an active control treatment. However, we found no clear evidence of any effect on depression when MBSR was compared with an inactive control treatment. Mindfulness-based stress reduction may also lead to a reduction in carers' anxiety symptoms at the end of treatment. Mindfulness-based stress reduction may slightly increase carers' feelings of burden. However, the results on anxiety and burden were very uncertain. We were unable to draw conclusions about carers' coping strategies and the risk of dropping out of treatment due to the very low quality of the evidence. None of the studies measured quality of life of carers or people with dementia, or the rate of admission of people with dementia to care homes or hospitals. Only one included study reported on adverse events, noting one minor adverse event (neck strain in one participant practising yoga at home) We considered the quality of the evidence to be low or very low, mainly because the studies were small and the way they were designed or conducted put them at risk of giving biased results. Consequently, we have limited confidence in the results. To summarise, the review provides preliminary evidence on the effect of MBSR in treating some stress-related problems of family carers of people with dementia. More good-quality studies are needed before we can confirm whether or not MBSR is beneficial for family carers of people with dementia.

10.1002/14651858.CD012791.pub2

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cochrane-simplification-train-366

The review includes 15 studies (N = 2428). Risk of selection bias is unclear in most of the studies, especially concerning allocation concealment. Other areas of risk such as missing data and selective reporting also caused some concern, although not affected on the direction of effect of our primary outcome, as demonstrated by sensitivity analysis. Many of the included trials have industry sponsorship of involvement. Nonetheless, generally people in the risperidone group are more likely to achieve a significant clinical improvement in mental state (6 RCTs, N = 864, RR 0.64, CI 0.52 to 0.78, very low-quality evidence). The effect withstood, even when three studies with >50% attrition rate were removed from the analysis (3 RCTs, N = 589, RR 0.77, CI 0.67 to 0.88). Participants receiving placebo were less likely to have a clinically significant improvement on Clinical Global Impression scale (CGI) than those receiving risperidone (4 RCTs, N = 594, RR 0.69, CI 0.57 to 0.83, very low-quality evidence). Overall, the risperidone group was 31% less likely to leave early compared to placebo group (12 RCTs, N = 2261, RR 0.69, 95% CI 0.62 to 0.78, low-quality evidence), but Incidence of significant extrapyramidal side effect was more likely to occur in the risperidone group (7 RCTs, N = 1511, RR 1.56, 95% CI 1.13 to 2.15, very low-quality evidence). When risperidone and placebo were augmented with clozapine, there is no significant differences between groups for clinical response as defined by a less than 20% reduction in PANSS/BPRS scores (2 RCTs, N = 98, RR 1.15, 95% CI 0.93 to 1.42, low-quality evidence) and attrition (leaving the study early for any reason) (3 RCTs, N = 167, RR 1.13, 95% CI 0.53 to 2.42, low quality evidence). One study measured clinically significant responses using the CGI, no effect was evident (1 RCT, N = 68, RR 1.12 95% CI 0.87 to 1.44, low quality evidence). No data were available for extrapyramidal adverse effects. Based on low quality evidence, risperidone appears to be benefitial in improving mental state compared with placebo, but it also causes more adverse events. Eight out of the 15 included trials were funded by pharmaceutical companies. The currently available evidence isvery low to low quality.

Searches for high-quality randomised trials were carried out in 2008, 2013 and 2015. The review now includes 15 studies with 2428 participants. The studies randomised participants (in- and outpatients) with schizophrenia or schizophrenia-like illnesses into treatment groups that received oral risperidone or placebo. Results from limited data suggest that risperidone is more effective than placebo for reducing the overall symptoms of schizophrenia, and participants receiving risperidone were more likely to comply with treatment. However, like the older typical antipsychotics, risperidone was also associated with serious side effects, such as parkinsonism. The evidence available was very low quality. Information and data were limited, poorly reported, and probably biased in favour of risperidone . Nearly half of the included trials were funded by drug companies. Firm conclusions are difficult to make based on the results of this review. Better conduct and reporting of trials could increase confidence in the results. Ben Gray, Senior Peer Researcher, McPin Foundation. http://mcpin.org/

10.1002/14651858.CD006918.pub3

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cochrane-simplification-train-367

Nineteen studies met the inclusion criteria (with 10,400 participants randomly assigned, lasting between 4 and 156 weeks, mean 42 weeks). Studies used three different combined preparations (fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol). The studies were generally at low risk of bias for blinding but at unclear or high risk for attrition bias because of participant dropouts. Compared with placebo, both fluticasone/salmeterol and budesonide/formoterol reduced the rate of exacerbations. Mometasone/formoterol reduced the number of participants experiencing one or more exacerbation. Pooled analysis of the combined therapies indicated that exacerbations were less frequent when compared with placebo (Rate Ratio 0.73; 95% CI 0.69 to 0.78, 7 studies, 7495 participants); the quality of this evidence when GRADE criteria were applied was rated as moderate. Participants included in these trials had on average one or two exacerbations per year, which means that treatment with combined therapy would lead to a reduction of one exacerbation every two to four years in these individuals. An overall reduction in mortality was seen, but this outcome was dominated by the results of one study (TORCH) of fluticasone/salmeterol. Generally, deaths in the smaller, shorter studies were too few to contribute to the overall estimate. Further longer studies on budesonide/formoterol and mometasone/formoterol are required to clarify whether this is seen more widely. When a baseline risk of death of 15.2% from the placebo arm of TORCH was used, the three-year number needed to treat for an additional beneficial outcome (NNTB) with fluticasone/salmeterol to prevent one extra death was 42 (95% CI 24 to 775). All three combined treatments led to statistically significant improvement in health status measurements, although the mean differences observed are relatively small in relation to the minimum clinically important difference. Furthermore, symptoms and lung function assessments favoured combined treatments. An increase in the risk of pneumonia was noted with combined inhalers compared with placebo treatment (OR 1.62, 95% CI 1.36 to 1.94), and the quality of this evidence was rated as moderate, but no dose effect was seen. The three-year NNTH for one extra case of pneumonia was 17, based on a 12.3% risk of pneumonia in the placebo arm of TORCH. Fewer participants withdrew from the combined treatment arms for adverse events or lack of efficacy. Combined inhaler therapy led to around a quarter fewer COPD exacerbations than were seen with placebo. A significant reduction in all-cause mortality was noted, but this outcome was dominated by one trial (TORCH), emphasising the need for further trials of longer duration. Furthermore, we note there has been some debate about the appropriateness of the analysis conducted in the TORCH trial (see Feeback). Increased risk of pneumonia is a concern; however, this did not translate into increased exacerbations, hospitalisations or deaths. Current evidence does not suggest any major differences between inhalers in terms of effects, but nor is the evidence strong enough to demonstrate that all are equivalent. Importantly, we cannot comment on the relative contribution of the individual components of combined therapy to the effects identified, as this review presents only the pair-wise comparison between combined therapy and placebo. To permit firmer conclusions about the effects of combined therapy, more data are needed, particularly in relation to the profile of adverse events and benefits in relation to different formulations and doses of inhaled ICS. Head-to-head comparisons are necessary to determine whether one combined inhaler is better than the others.

Nineteen studies involving 10,400 people were included in this review. The studies lasted between 4 and 156 weeks. All of the people included in the studies had COPD of different severity. Both men and women were included, and most of the studies included only adults aged 45 or older. All studies compared a combined inhaler with a placebo that was identical in appearance to the combined inhaler, so the people in the trials did not know whether they were taking the drug or the dummy inhaler. Some of the studies included two groups treated with the combined inhaler; one group was getting a higher dose and one group was getting a lower dose. The evidence presented here is current to June 2013. Most of the studies were sponsored by the pharmaceutical industry. We found that people receiving a combined inhaler were less likely to have a flare-up (‘exacerbation’) of their COPD. The chance of having an exacerbation was reduced by about one quarter. A small reduction in the risk of death was seen over three years, although most of the evidence about death comes from one large, long trial called TORCH. According to TORCH, approximately 42 people would need to be treated with a combined inhaler for three years to prevent one death. We also found that people receiving combined inhalers had small improvements in quality of life, symptoms related to COPD and their breathing tests. However, these improvements may not have been very noticeable to them. People treated with combined inhalers were more likely to have a lung infection called pneumonia. Again, most of the evidence about pneumonia comes from the TORCH trial. According to TORCH, when compared with placebo, for approximately every 17 people treated with combined inhaler, one extra person would get pneumonia. People treated with combined inhalers were no more or less likely to experience serious unwanted events, including side effects, during treatment. No consistent differences were found between the three different types of inhalers included in this review. However, it is important to note that we cannot tell from this review whether it is the combination that is important or whether one of the two drugs in the combined inhaler may have had the real impact. The evidence presented in this review is generally considered to be of moderate quality. Most of the studies did not clearly explain how they decided which people would receive the combined inhaler and which would receive placebo, and this is an important part of a well-conducted study. Also, more people receiving placebo dropped out of the trials than those receiving a combined inhaler. This often happened because of exacerbations of COPD. This means that by the end of the trial, the groups might have been unbalanced, and this could affect the accuracy of the results.

10.1002/14651858.CD003794.pub4

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cochrane-simplification-train-368

A statistically significant benefit was observed for auranofin when compared to placebo for tender joint scores, pain, patient and physician global assessments and ESR. The standardized weighted mean difference between treatment and placebo was -0.39 (95% CI -0.54, -0.25) for tender joint scores, -0.08 (95% CI -0.22, -0.07) for swollen joint scores, and the weighed mean difference was -4.68 (95% CI -6.59, -2.77) for pain scores. The WMD for ESR was -9.85mm (95% CI -16.46, -3.25). Withdrawals from adverse reactions were 1.5 times higher in the auranofin group OR = 1.52 (95% CI 0.94, 2.46) but this result was not statistically significant. Patients receiving placebo were four times more likely to discontinue treatment because of lack of efficacy than patients receiving auranofin OR=0.29 (95% CI: 0.19, 0.43). Auranofin appears to have a small clinically and statistically significant benefit on the disease activity of patients with RA. The beneficial effects appear to be modest compared to drugs such as methotrexate or parenteral gold. Its effects on long term health status and radiological progression are not clear at this time.

The objective of this review was to evaluate the short-term efficacy of auranofin for the treatment of rheumatoid arthritis when compared to placebo. Our results show that auranofin appears to be efficacious in the short-term treatment of patients with RA (6 months), and has a small but clinically and statistically significant benefit on the disease activity of these patients. Its effects on overall health status and radiological progression are not clear at this time, but would appear to be modest. Auranofin may be most appropriate for those patients with early and mild disease who are more likely to respond to less potent (and less toxic) therapies.

10.1002/14651858.CD002048

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cochrane-simplification-train-369

Eleven studies with a total of 3716 participants were included. A consistent and strong reduction in the risk of recurrent venous thromboembolic events was observed during prolonged treatment with VKA (risk ratio (RR) 0.20, 95% confidence interval (CI) 0.11 to 0.38) independent of the period elapsed since the index thrombotic event. A statistically significant "rebound" phenomenon (ie, an excess of recurrences shortly after cessation of prolonged treatment) was not found (RR 1.28, 95% CI 0.97 to 1.70). In addition, a substantial increase in bleeding complications was observed for patients receiving prolonged treatment during the entire period after randomization (RR 2.60, 95% CI 1.51 to 4.49). No reduction in mortality was noted during the entire study period (RR 0.89, 95% CI 0.66 to 1.21, P = 0.46). In conclusion, this review shows that treatment with VKA strongly reduces the risk of recurrent VTE for as long as they are used. However, the absolute risk of recurrent VTE declines over time, although the risk for major bleeding remains. Thus, the efficacy of VKA administration decreases over time since the index event.

The review authors searched the literature and were able to combine data from 11 randomized controlled clinical trials (3716 participants) comparing different durations of treatment with VKA in patients with a symptomatic VTE. Participants receiving prolonged treatment had around five times lower risk of recurrence of VTE. On the other hand, they had about three times higher risk of bleeding complications. Prolonged treatment did not reduce the risk of death. Prolonged use of VKA strongly reduced the risk of recurrent clots as long as they were used, but benefit decreased over time and the risk of major bleeding remained.

10.1002/14651858.CD001367.pub3

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cochrane-simplification-train-370

We identified two studies for inclusion. Both studies were randomised cross-over trials performed in single centres. Both studies used the Premature Infant Pain Profile (PIPP) score as a measure of pain response. Different methods of evaluating PIPP scores are presented including the absolute PIPP score, a PIPP score > 10 or > 12 and an increase in PIPP ≥ 4 from the baseline value. There is a nonsignificant reduction in pain scores at one minute and a nonsignificant increase at five minutes post insertion of the speculum. PIPP score > 12 at one minute resulted in a statistically significant reduction in the number of patients who experienced pain (typical risk ratio (RR) 0.56, 95% CI 0.36 to 0.89; typical risk difference (RD) -0.23, 95% CI -0.39 to -0.86; number needed to treat to benefit (NNTB) 4). When pain was defined as an increase in PIPP > 4 there was a statistically significant reduction in the absolute number of patients who experienced pain at one minute (typical RR 0.70, 95% CI 0.52 to 0.94; typical RD -0.19, 95% CI -0.34 to -0.04; NNTB 5.3). The administration of topical proparacaine 30 seconds prior to the ophthalmological evaluation was associated with a reduction in pain scores especially at the time of speculum insertion. However, despite treatment, screening remains a painful procedure and the role of nonpharmacological and pharmacological intervention including different local anaesthetic agents should be ascertained in future randomised trials.

This review highlights that retinopathy of prematurity is a painful examination and that instillation of local anaesthetic eyedrops immediately prior to examination of the eye is associated with a reduction in pain scores, as assessed by validated pain scores. Ongoing research is required to determine the optimum local anaesthetic eyedrop and other potentially important methods of reducing pain, including swaddling, and sucrose.

10.1002/14651858.CD007645.pub2

cochrane-simplification-train-371

cochrane-simplification-train-371

In this update we found four randomised controlled trials involving 317 participants in total. Three of them including 295 participants, 148 allocated to surgery and 147 to non-surgical treatment reported information on our primary outcome (improvement at three months of follow-up). The pooled estimate favoured surgery (RR 1.23, 95% CI 1.04 to 1.46). Two trials including 245 participants described outcome at six month follow-up, also favouring surgery (RR 1.19, 95% CI 1.02 to 1.39). Two trials reported clinical improvement at one year follow-up. They included 198 patients favouring surgery (RR 1.27, 95% CI 1.05 to 1.53). The only trial describing changes in neurophysiological parameters in both groups also favoured surgery (RR 1.44, 95% CI 1.05 to 1.97). Two trials described need for surgery during follow-up, including 198 patients. The pooled estimate for this outcome indicates that a significant proportion of people treated medically will require surgery while the risk of re-operation in surgically treated people is low (RR 0.04 favouring surgery, 95% CI 0.01 to 0.17). Complications of surgery and medical treatment were described by two trials with 226 participants. Although the incidence of complications was high in both groups, they were significantly more common in the surgical arm (RR 1.38, 95% CI 1.08 to 1.76). Surgical treatment of carpal tunnel syndrome relieves symptoms significantly better than splinting. Further research is needed to discover whether this conclusion applies to people with mild symptoms and whether surgical treatment is better than steroid injection.

This review aimed to compare surgical decompression with non-surgical treatments such as splinting or corticosteroid injections. Four trials were found and included, while three are awaiting assessment. The results suggest that surgical treatment is probably better than splinting but it is unclear whether it is better than steroid injection. Further research is needed for those with mild symptoms.

10.1002/14651858.CD001552.pub2

cochrane-simplification-train-372

cochrane-simplification-train-372

Four studies met the inclusion criteria. They were three cluster-randomised controlled trials and one with a stepped-wedge design. Changing task characteristics One study with 961 teachers in eight schools compared a task-based organisational change intervention along with stress management training to no intervention. It found a small reduction at 12 months in 10 out of 14 of the subscales in the Occupational Stress Inventory, with a mean difference (MD) varying from -3.84 to 0.13, and a small increase in the Work Ability Index (MD 2.27; 95% confidence interval (CI) 1.64 to 2.90; 708 participants, low-quality evidence). Changing organisational characteristics Two studies compared teacher training combined with school-wide coaching support to no intervention. One study with 59 teachers in 43 schools found no significant effects on job-related anxiety (MD -0.25 95% CI -0.61 to 0.11, very low-quality evidence) or depression (MD -0.26 95% CI -0.57 to 0.05, very low-quality evidence) after 24 months. The other study with 77 teachers in 18 schools found no significant effects on the Maslach Burnout Inventory subscales (e.g. emotional exhaustion subscale: MD -0.05 95% CI -0.52 to 0.42, low-quality evidence) or the Teacher Perceived Emotional Ability subscales (e.g. regulating emotions subscale: MD 0.11 95% CI -0.11 to 0.33, low-quality evidence) after six months. Multi-component intervention One study with 1102 teachers in 34 schools compared a multi-component intervention containing performance bonus, job promotion opportunities and mentoring support to a matched-comparison group consisting of 300 schools. It found moderately higher teacher retention rates (MD 11.50 95% CI 3.25 to 19.75 at 36 months follow-up, very low-quality evidence). However, the authors reported results only from one cohort out of four (eight schools), demonstrating a high risk of reporting bias. We found low-quality evidence that organisational interventions lead to improvements in teacher wellbeing and retention rates. We need further evaluation of the effects of organisational interventions for teacher wellbeing. These studies should follow a complex-interventions framework, use a cluster-randomised design and have large sample sizes.

We found four studies that included a total of 2199 teachers. They evaluated three types of work changes. One intervention consisted of changes in teachers' tasks such as redesigning work, establishing flexible work schedules and redesigning the work environment. Another intervention consisted of a school-wide coaching support network alongside individual training for teachers, in order to deliver a child development programme. The third intervention consisted of several components: performance bonus pay, job promotion opportunities and mentoring. Changes in tasks of teachers In one study with 961 teachers in eight schools, changes in tasks of teachers combined with stress management training resulted in a small reduction in work stress levels after one year follow-up compared to no intervention. There was also a small increase in work ability, meaning how well a worker is able to perform his or her work. However, the authors did not report how they changed teachers' tasks, limiting the results' usefulness elsewhere. Changing organisational features There were two studies of school-wide coaching support combined with teacher training. In one study with 43 schools and 59 participating teachers, there was no considerable effect on anxiety or depression after two years follow-up compared to no intervention. In the other study with 18 schools and 77 participating teachers, there was no considerable effect on burnout or emotional ability after six months follow-up compared to no intervention. Burnout is a state of prolonged severe stress. Emotional ability means understanding other people’s emotions, and understanding and controlling ones own emotions. Both studies had a small number of participants. Multicomponent programme In one study with 34 schools and 1102 teachers, the intervention included performance bonus pay, job promotion opportunities and mentoring. After three years follow-up and compared to 300 similar schools, there was a moderate reduction in resignation of teachers in the intervention schools. However, authors reported results only for eight schools. The quality of the evidence was low for all interventions because the authors did not report all the results and lost many participants for follow-up. All included studies also had interventions directed at individual teachers combined with changes at schools. Therefore, new and better quality studies directed at schools will probably change the conclusions of this review. Changing the way teachers' work is organised at schools may improve the teachers' wellbeing and may reduce teacher resignations. We need better-designed research in the development and testing of work changes in schools. In future studies, whether work at schools is changed or not should be determined according to chance. These studies should also have several hundred participants.

10.1002/14651858.CD010306.pub2

cochrane-simplification-train-373

cochrane-simplification-train-373

We included 25 studies of which 4 are awaiting assessment. The 21 studies that could be analysed were 1 RCT, 14 cRCTs and 6 CBAs with a total of at least 3479 employees in intervention and control groups. We judged 12 studies to have an unclear risk of bias and the remaining nine studies to have a high risk of bias. Sixteen studies focused on improving supervisor-employee interaction, whereas five studies aimed at improving the design of working environments by means of supervisor training. Training versus no intervention We found very low-quality evidence that supervisor training does not reduce employees' stress levels (6 studies) or absenteeism (1 study) when compared to no intervention, regardless of intervention type or follow-up. We found inconsistent, very low-quality evidence that supervisor training aimed at employee interaction may (2 studies) or may not (7 studies) improve employees' well-being when compared to no intervention. Effects from two studies were not estimable due to missing data. Training versus placebo We found moderate-quality evidence (2 studies) that supervisor training off the job aimed at employee interaction does not reduce employees' stress levels more than a placebo training at mid-term follow-up. We found low-quality evidence in one study that supervisor training on the job aimed at employee interaction does not reduce employees' absenteeism more than placebo training at long-term follow-up. Effects from one study were not estimable due to insufficient data. Training versus other training One study compared the effects of supervisor training off the job aimed at employee interaction on employees' stress levels to training off the job aimed at working conditions at long-term follow-up but due to insufficient data, effects were not estimable. Based on a small and heterogeneous sample of controlled intervention studies and in contrast to prevailing consensus that supervisor behaviour influences employees' health and well-being, we found inconsistent evidence that supervisor training may or may not improve employees' well-being when compared to no intervention. For all other types of interventions and outcomes, there was no evidence of a considerable effect. However, due to the very low- to moderate-quality of the evidence base, clear conclusions are currently unwarranted. Well-designed studies are needed to clarify effects of supervisor training on employees' stress, absenteeism, and well-being.

We included 25 studies of which 4 studies are awaiting assessment. The 21 studies that could be analysed included a total of 3479 employees. Sixteen studies trained supervisor-employee interaction, either off-the-job (9 studies) or on-the job (7 studies). Five studies trained the design of working environments, off-the-job in 2 studies and on-the job in 3 studies. The 21 studies compared 23 interventions with no training, sham training or other training at various times of follow-up. There is no considerable effect of supervisor training on employees' stress (6 studies) or absenteeism (1 study) when compared to no training. There is inconsistent evidence that supervisor training may (2 studies) or may not (7 studies) improve employees' well-being when compared to no training. Data were missing from two studies, so we could not calculate the effects of training on employee well-being. There is no effect of supervisor training on employees' stress (2 studies) or absenteeism (1 study) when compared to a placebo training. Data were missing from one study, so we could not calculate the effects of training on employee well-being. One study that evaluated supervisor training compared to another type of training to reduce employees' stress did not provide enough data to calculate its effects. The quality of the evidence was very low for most outcomes due to risk of bias in the studies, inconsistent results, and imprecise effects. Researchers should consider the shortcomings of studies included in this review in order to conduct well-designed studies in the future and report them appropriately. Overall, the data suggest that training of supervisors may not lead to reduced levels of stress and absenteeism, or improved levels of well-being in their employees. The discrepancy between the apparent scientific consensus and the empirical evidence might be attributed to weak study designs.High quality studies are needed to clarify if supervisor training affects employees' stress, absenteeism, and well-being.

10.1002/14651858.CD010905.pub2

cochrane-simplification-train-374

cochrane-simplification-train-374

We included nine randomised clinical trials (involving 861 women). The trials compared Chinese herbal medicines (various formulations) either alone (one trial), or in combination with other pharmaceuticals (seven trials) versus other pharmaceuticals alone. One study compared Chinese herbal medicines and other pharmaceuticals versus psychotherapy. We did not identify any trials comparing Chinese herbal medicines with placebo or no treatment, including bed rest. Various Chinese herbal medicines were used in the different trials (and some of the classical the formulations were modified in the trials). The Western pharmaceutical medicines included tocolytic drugs such as salbutamol and magnesium sulphate; hormonal supplementation with human chorionic gonadotrophin (HCG), progesterone or dydrogesterone; and supportive supplements such as vitamin E, vitamin K and folic acid. Overall, the methodological quality of the included studies was poor with unclear risk of bias for nearly all the 'Risk of bias' domains assessed. Chinese herbal medicines alone versus other pharmaceuticals alone - the live birth rate was no different between the two groups (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.67 to 1.65; one trial, 80 women). No data were available for the outcome of pregnancy rate (continuation of pregnancy after 20 weeks of gestation). In contrast, the continuing pregnancy rate (RR 1.27 95% CI 1.10 to 1.48, two trials, 189 women) and live birth rate (average RR 1.55; 95% CI 1.14 to 2.10; six trials, 601 women, Tau² = 0.10; I² = 73%) were higher among the group of women who received a combination of Chinese herbal medicines and other pharmaceuticals when compared with women who received other pharmaceuticals alone. For Chinese herbal medicines and psychotherapy versus psychotherapy alone (one study) - there was a higher live birth rate (RR 1.32; 95% CI 1.07 to 1.64; one trial, 90 women) in the group of women who received a combination of Chinese herbal medicines and psychotherapy compared to those women who received psychotherapy alone. No data were available on the continuing pregnancy rate for this comparison. Other primary outcomes (maternal adverse effect and toxicity rate and the perinatal adverse effect and toxicity rate) were not reported in most of the included studies. Two trials (341 women) reported that no maternal adverse effects were found (one trial compared (combined) medicines with other pharmaceuticals, and one trial compared combined Chinese herbal medicine alone versus other pharmaceuticals). One trial (Chinese herbal medicine alone versus other pharmaceuticals alone) reported that there were no abnormal fetuses (ultrasound) or after delivery. There were no data reported for any of this review's secondary outcomes. We found limited evidence (from nine studies with small sample sizes and unclear risk of bias) to assess the effectiveness of Chinese herbal medicines for treating unexplained recurrent miscarriage; no data were available to assess the safety of the intervention for the mother or her baby. There were no data relating to any of this review's secondary outcomes. From the limited data we found, a combination of Chinese herbal medicines and other pharmaceuticals (mainly Western medicines) may be more effective than Western medicines alone in terms of the rate of continuing pregnancy and the rate of live births. However, the methodological quality of the included studies was generally poor. A comparison of Chinese herbal medicines alone versus placebo or no treatment (including bed rest) was not possible as no relevant trials were identified. More high-quality studies are needed to further evaluate the effectiveness and safety of Chinese herbal medicines for unexplained recurrent miscarriage. In addition to assessing the effect of Chinese herbal medicines on pregnancy rate and the rate of live births, future studies should also consider safety issues (adverse effects and toxicity for the mother and her baby) as well as the secondary outcomes listed in this review. This review would provide more valuable information if the included studies could overcome the problems in their designs, such as lacking of qualified placebo-controlled trials, applying adequate randomisation methods and avoiding potential bias.

Different Chinese herbal medicine formulae (Shou Tai Pill, Yangxi Zaitai Decoction, Bushen Antai Decoction and some modified formulae) were used in the trials. The basic formula mostly contained some common Chinese herbal medicines (Chinese Dodder Seed, Chinese Taxillus Twig, Himalayan Teasel Root, Largehead Atractylodes Rhizome, Donkey-hide Glue, Eucommia Bark, Tangerine Peel, Szechwon Tangshen Root, White Paeony Root, Baical Skullcap Root, Mongolian Milkvetch Root, Chinese Angelica, etc). Western pharmaceutical medicines included tocolytic drugs such as salbutamol and magnesium sulphate, hormonal supplementation with human chorionic gonadotrophin, progesterone or dydrogesterone, and supportive supplements such as vitamin E, vitamin K and folic acid. We searched for evidence on 1 June 2015 and found nine trials (861 women) to assess the effectiveness of the interventions. All trials were methodologically poor and at an unclear risk of bias overall. No trial used placebo, no treatment or bed rest as a control intervention. One trial studied the effectiveness of psychotherapy compared with Chinese herbs. When Chinese herbal medicines were given in combination with other pharmaceuticals they were associated with higher rates of continuous pregnancy beyond 20 weeks (92.1% versus 72.0%, from two trials, involving 189 women) and live births (79.7% versus 44.2% from six trials, involving 601 women) compared to the other pharmaceuticals alone. Live birth rate was not different when comparing Chinese herbal medicines alone and other pharmaceuticals alone (in one trial, involving 80 women). A comparison of continuing pregnancy rate was not available in this trial. Compared with psychotherapy alone, the live birth rate was higher in the group of women who received a combination of Chinese herbal medicine and psychotherapy (91.1% versus 68.9%). The majority of studies did not report any information about adverse effects for the mothers or the babies. Only two trials (involving 341 women) reported that no maternal adverse effects were found (one trial comparing (combined) medicines with other pharmaceuticals and one trial comparing combined Chinese herbal medicine alone versus other pharmaceuticals alone). Only one trial (comparing Chinese herbal medicine alone versus other pharmaceuticals alone) reported that there were no abnormal babies either before or after delivery. No study recorded its limitations in the trial report. It is unclear which Chinese herbal medicines or their combinations are effective. According to the unique diagnosis and classification of Chinese medicine, the preparations (formulae) may differ according to the subtype of recurrent miscarriage. Most Chinese medicine practitioners modify the classical prescriptions depending on the individual clinical presentations. Some herbal medicines were modified from the classical formula for treatment. Therefore, the conclusion on effectiveness in our study could only represent the overall effects of Chinese herbal medicines on recurrent miscarriage in general. In conclusion, combined Chinese herbal medicines and other pharmaceuticals appear more beneficial than other pharmaceuticals alone for unexplained recurrent miscarriage, but the evidence on the effectiveness and safety of Chinese herbal medicines alone as treatment is unclear. We found no data to evaluate the safety and toxicity of this intervention for women and their babies and no data for all of our other maternal and infant outcomes. More high-quality studies are necessary to fully evaluate the utility of Chinese herbal medicines for unexplained recurrent miscarriage.

10.1002/14651858.CD010568.pub2

cochrane-simplification-train-375

cochrane-simplification-train-375

One study met our inclusion criteria (26 children with minimal change nephrotic syndrome) and 11 were excluded (nine cross-over studies, one where albumin was not used for nephrotic syndrome and one where authors did not state whether the children had oedema). Risk of bias for the included study was unclear for selection bias, high for performance and detection bias, low for attrition bias, and high for selective reporting. The included study compared albumin plus furosemide with an equal volume of dextrose. Of our prespecified outcomes, the authors reported clinical improvement as weight change, serum sodium and adverse outcomes (blood pressure). The authors reported a greater weight loss in the albumin treated group initially but no difference overall at 10 days. However, the data in the text and the figures were inconsistent so we could not confirm the authors statements (very low certainty evidence). It is uncertain whether albumin infusion improves serum sodium when compared with an equal volume of dextrose (MD 2.00 mEq/L, 95% CI -0.09 to 4.09), systolic blood pressure (MD 2.00 mmHg, 95% CI -3.52 to 7.52) or diastolic blood pressure (MD 2.00 mmHg, 95%CI -4.29 to 8.29). Death, quality of life, and kidney function were not reported. We identified only one small study that was relevant to our review, therefore we are unable to draw any conclusions regarding the use of human albumin with or without diuretics in nephrotic syndrome. More RCTs are needed.

The review found one small RCT (26 patients) comparing human albumin plus the diuretic furosemide with placebo suitable for inclusion. We found nine studies on people with nephrotic syndrome that tested these comparisons but these were 'cross-over' studies which we judged not suitable. To find out whether there was any improvement after albumin, the study measured weight loss and serum sodium. The adverse effect measured was blood pressure. Although the authors reported increased weight loss we were not able to confirm this due to inconsistency between the data reported in the table and the text. There was no change in serum sodium or blood pressure. We judged these outcomes all to be of very low certainty. Death, quality of life, and kidney function were not reported. Because there was only one small study found we cannot tell whether albumin is effective in people with nephrotic syndrome and we do not know from the studies we looked at whether it is safe. There is no evidence in adults. We judged the evidence to be very low certainty. Therefore RCTs are needed.

10.1002/14651858.CD009692.pub2

cochrane-simplification-train-376

cochrane-simplification-train-376

Seven trials involving 570 participants met the inclusion criteria. Two small trials compared DFO with placebo (plus standard antimalarial drugs in both groups). No evidence of benefit or harm was shown in relation to death, but the trials were small (435 participants). The risk of experiencing persistent seizures was lower with DFO compared with placebo (RR 0.80, 95% CI 0.67 to 0.95; 334 participants, 1 trial), but adverse effects were more common with DFO. One small trial involving 45 adults and children compared deferiprone with placebo (plus standard antimalarial drugs in both groups). Participants in the deferiprone group had significantly faster coma recovery (MD -27 h, 95% CI -34.20 to -19.80) and parasite clearance (MD -24 h, 95% CI -35.27 to -12.73). No adverse effects were reported for this trial. There are insufficient data to draw any conclusions for DFO and deferiprone. There are nonsignificant trends towards fewer seizures but overall harm (death) with DFO, and results from one small trial of deferiprone suggest shorter coma recovery and parasite clearance. 2008: We do not plan to update this review given the paucity of recent trials in this area and other priorities in malaria treatment research.

There are a number of different iron-chelating agents, such as desferrioxamine (DFO) and deferiprone, and all were considered in the review of trials, although DFO has to be given intravenously and so will be of little use in most malarious areas. The drugs may also display adverse effects like headaches, dizziness, muscle pain, and tiredness. The review found seven trials of DFO and deferiprone involving 570 participants. Although the drugs may have helped in part with parasite levels, there seemed to be adverse effects including concerns about possibility of an increase in death. There is insufficient evidence to support the use of iron-chelating agents as adjuncts in the treatment of malaria, and further trials are not expected.

10.1002/14651858.CD001474

cochrane-simplification-train-377

cochrane-simplification-train-377

One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with SCD. A total of 117 children with homozygous sickle cell (SS) disease aged six months to four years of age participated over a one-year period (analysis was restricted to 115 children). Serum folate measures, obtained after trial entry at six and 12 months, were available in 80 of 115 (70%) participants. There were significant differences between the folic acid and placebo groups with regards to serum folate values above 18 µg/L and values below 5 µg/L (low-quality evidence). In the folic acid group, values above 18 µg/L were observed in 33 of 41 (81%) compared to six of 39 (15%) participants in the placebo (calcium lactate) group. Additionally, there were no participants in the folic acid group with serum folate levels below 5 µg/L, whereas in the placebo group, 15 of 39 (39%) participants had levels below this threshold. Haematological indices were measured in 100 of 115 (87%) participants at baseline and at one year. After adjusting for sex and age group, the investigators reported no significant differences between the trial groups with regards to total haemoglobin concentrations, either at baseline or at one year (low-quality evidence). It is important to note that none of the raw data for the outcomes listed above were available for analysis. The proportions of participants who experienced certain clinical events were analysed in all 115 participants, for which raw data were available. There were no statistically significant differences noted; however, the trial was not powered to investigate differences between the folic acid and placebo groups with regards to: minor infections, risk ratio (RR) 0.99 (95% confidence interval (CI) 0.85 to 1.15) (low-quality evidence); major infections, RR 0.89 (95% CI 0.47 to 1.66) (low-quality evidence); dactylitis, RR 0.67 (95% CI 0.35 to 1.27) (low-quality evidence); acute splenic sequestration, RR 1.07 (95% CI 0.44 to 2.57) (low-quality evidence); or episodes of pain, RR 1.16 (95% CI 0.70 to 1.92) (low-quality evidence). However, the investigators reported a higher proportion of repeat dactylitis episodes in the placebo group, with two or more attacks occurring in 10 of 56 participants compared to two of 59 in the folic acid group (P < 0.05). Growth, determined by height-for-age and weight-for-age, as well as height and growth velocity, was measured in 103 of the 115 participants (90%), for which raw data were not available. The investigators reported no significant differences in growth between the two groups. The trial had a high risk of bias with regards to random sequence generation and incomplete outcome data. There was an unclear risk of bias in relation to allocation concealment, outcome assessment, and selective reporting. Finally, There was a low risk of bias with regards to blinding of participants and personnel. Overall the quality of the evidence in the review was low. There were no trials identified for other eligible comparisons, namely: folate supplementation (fortified foods and physical supplementation with tablets) versus placebo; folate supplementation (naturally occurring in diet) versus placebo; folate supplementation (fortified foods and physical supplementation with tablets) versus folate supplementation (naturally occurring in diet). One doubIe-blind, placebo-controlled triaI on folic acid supplementation in children with SCD was included in the review. Overall, the trial presented mixed evidence on the review's outcomes. No trials in adults were identified. With the limited evidence provided, we conclude that, while it is possible that folic acid supplementation may increase serum folate levels, the effect of supplementation on anaemia and any symptoms of anaemia remains unclear. If further trials were conducted, these may add evidence regarding the efficacy of folate supplementation. Future trials should assess clinical outcomes such as folate concentration, haemoglobin concentration, adverse effects and benefits of the intervention, especially with regards to SCD-related morbidity. Such trials should include people with SCD of all ages and both sexes, in any setting. To investigate the effects of folate supplementation, trials should recruit more participants and be of longer duration, with long-term follow-up, than the trial currently included in this review. However, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.

We included one trial with 117 children with SCD aged between six months and four years. This was a one-year doubIe-blind (both participants and doctors did not know which treatment group the participants were allocated to) controlled triaI comparing children taking folic acid supplements to those taking a placebo (a 'dummy' treatment). The trial investigators reported that folic acid supplementation led to higher levels of folic acid measured in the blood. However, there were no differences in haemoglobin concentrations at the end of one year. The trial also reported on clinical factors linked to treatment, including growth, major and minor infections, acute splenic sequestration, episodes of bone or abdominal pains. The investigators reported no differences in these outcomes from baseline to the end of the trial; however, the trial was not large enough to detect any possible differences reported between the folic acid group and the placebo group. In the included trial it was not clear how participants were allocated to receive folic acid or placebo. The method of making sure that participants and trial staff did not know what treatment each person was receiving (called allocation concealment) was also not described. These two factors mean that the trial had a high risk of biased results. The trial did not contain many participants. For many of its clinical endpoints, it was not designed to show differences between people taking folic acid and those taking a placebo. This means that the results from this trial are imprecise, and therefore hard to interpret. Finally, our review was meant to investigate folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in children and adults. Because we only identified one trial that investigated one form of supplementation in children, the results are not useful for other populations. Therefore, we judged the evidence from the included trial to be of low quality. Based on just one low quality study with evidence only to show that folate supplementation raises the blood levels of folic acid, we cannot state whether this treatment is effective or not. More trials with more people and longer treatment duration (and follow-up) of folate supplementation in people with SCD are needed to strengthen this review; however, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.

10.1002/14651858.CD011130.pub3

cochrane-simplification-train-378

cochrane-simplification-train-378

We included 34 studies, which includes one that was a follow-up study and 20 that were rated as being at high risk of bias. We conducted 14 meta-analyses assessing physical outcomes post-intervention. Nine meta-analyses showed significant findings favouring the intervention group for weight (MD -965.25 g; 95% CI -1360.52 to -569.98), length (MD -1.30 cm; 95% CI -1.60 to -1.00), head circumference (MD -0.81 cm; 95% CI -1.18 to -0.45), arm circumference (MD -0.47 cm; 95% CI -0.80 to -0.13), leg circumference (MD -0.31 cm; 95% CI -0.49 to -0.13), 24-hour sleep duration (MD -0.91 hr; 95% CI -1.51 to -0.30), time spent crying/fussing (MD -0.36; 95% CI -0.52 to -0.19), deceased levels of blood bilirubin (MD -38.11 mmol/L; 95% CI -50.61 to -25.61), and there were fewer cases of diarrhoea, RR 0.39; 95% CI 0.20 to 0.76). Non-significant results were obtained for cortisol levels, mean increase in duration of night sleep, mean increase in 24-hour sleep and for number of cases of upper respiratory tract disease and anaemia. Sensitivity analyses were conducted for weight, length and head circumference, and only the finding for length remained significant following removal of studies judged to be at high risk of bias. These three outcomes were the only ones that could also be meta-analysed at follow-up; although both weight and head circumference continued to be significant at 6-month follow-up, these findings were obtained from studies conducted in Eastern countries only. No sensitivity analyses were possible. We conducted 18 meta-analyses measuring aspects of mental health and development. A significant effect favouring the intervention group was found for gross motor skills (SMD -0.44; 95% CI -0.70 to -0.18), fine motor skills (SMD -0.61; 95% CI -0.87 to -0.35), personal and social behaviour (SMD -0.90; 95% CI -1.61 to -0.18) and psychomotor development (SMD -0.35; 95% CI -0.54 to -0.15); although the first three findings were obtained from only two studies, one of which was rated as being at high risk of bias, and the finding for psychomotor development was not maintained following following removal of studies judged to be at high risk of bias in a sensitivity analysis. No significant differences were found for a range of aspects of infant temperament, parent-infant interaction and mental development. Only parent-infant interaction could be meta-analysed at follow-up, and the result was again not significant. These findings do not currently support the use of infant massage with low-risk groups of parents and infants. Available evidence is of poor quality, and many studies do not address the biological plausibility of the outcomes being measured, or the mechanisms by which change might be achieved. Future research should focus on the impact of infant massage in higher-risk groups (for example, demographically and socially deprived parent-infant dyads), where there may be more potential for change.

This review aimed to assess the impact of infant massage on mental and physical outcomes for healthy mother-infant dyads in the first six months of life. A total of 34 randomised trials were included. Twenty of these had significant problems with their design and the way they were carried out. This means that the we are not as confident as we would otherwise be that the findings are valid. That is to say, the findings of these 20 included studies may over- or under-estimate the true effect of massage therapy. We combined the data for 14 outcomes measured physical health and 18 outcomes measured aspects of mental health or development. The results show limited statistically significant benefits for a number of aspects of physical health (for example, weight, length, head/arm/leg circumference, 24-hour sleep duration; time spent crying or fussing; blood bilirubin and number of episodes of illness) and mental health/development (for example, fine/gross motor skills personal and social behaviour and psychomotor development). However, all significant results were lost either at later follow-up points or when we removed the large number of studies regarded to be at high risk of bias. These findings do not currently support the use of infant massage with low-risk population groups of parents and infants. The results obtained from this review may be due to the poor quality of many of the included studies, the failure to address the mechanisms by which infant massage could have an impact on the outcomes being assessed, and the inclusion of inappropriate outcomes for population groups (such as weight gain). Future research should focus on the benefits of infant massage for higher-risk population groups (for example, socially deprived parent-infant dyads), the duration of massage programmes, and could address differences between babies being massaged by parents or healthcare professionals.

10.1002/14651858.CD005038.pub3

cochrane-simplification-train-379

cochrane-simplification-train-379

Four trials with high risk of bias were included in this review. Two trials evaluated oral nefopam (52 participants) and one trial each evaluated topical capsaicin (31 participants) and oromucosal cannabis (58 participants). The pooled analyses identified a significant reduction in pain levels favouring nefopam over placebo (weighted mean difference (WMD) -21.16, 95% CI -35.61 to -6.71; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5) after two weeks. There were insufficient data to assess withdrawals due to adverse events. Nefopam was associated with significantly more adverse events (RR 4.11, 95% CI 1.58 to 10.69; NNTH 9, 95% CI 2 to 367), which were predominantly nausea and sweating. In a mixed population trial, qualitative analysis of patients with RA showed a significantly greater reduction in pain favouring topical capsaicin over placebo at one and two weeks (MD -23.80, 95% CI -44.81 to -2.79; NNT 3, 95% CI 2 to 47; MD -34.40, 95% CI -54.66 to -14.14; NNT 2, 95% CI 1.4 to 6 respectively). No separate safety data were available for patients with RA, however 44% of patients developed burning at the site of application and 2% withdrew because of this. One small, low quality trial assessed oromucosal cannabis against placebo and found a small, significant difference favouring cannabis in the verbal rating score 'pain at present' (MD -0.72, 95% CI -1.31 to -0.13) after five weeks. Patients receiving cannabis were significantly more likely to suffer an adverse event (risk ratio (RR) 1.82, 95% CI 1.10 to 3.00; NNTH 3, 95% CI 3 to 13). These were most commonly dizziness (26%), dry mouth (13%) and light headedness (10%). There is currently weak evidence that oral nefopam, topical capsaicin and oromucosal cannabis are all superior to placebo in reducing pain in patients with RA. However, each agent is associated with a significant side effect profile. The confidence in our estimates is not strong given the difficulties with blinding, the small numbers of participants evaluated and the lack of adverse event data. In some patients, however, even a small degree of pain relief may be considered worthwhile. Until further research is available, given the relatively mild nature of the adverse events, capsaicin could be considered as an add-on therapy for patients with persistent local pain and inadequate response or intolerance to other treatments. Oral nefopam and oromucosal cannabis have more significant side effect profiles however and the potential harms seem to outweigh any modest benefit achieved.

We looked at all the published scientific literature and identified four drug trials that evaluated different neuromodulators. Two small studies with a total of 52 patients tested the drug nefopam (which is only available in some parts of the world). One trial each tested capsaicin cream (31 participants) and a cannabis based mouth spray (58 participants). Note: use of medicinal cannabis is illegal and therefore unavailable in most countries. When patients took nefopam they had a greater improvement in pain levels, on average 21 points on a 100 point scale, than those patients who were given a placebo (an inactive substance that has no treatment value). However, patients on nefopam also developed side effects, which mainly consisted of nausea and sweating. Many patients stopped taking the drug because the symptoms were so bad. These studies were performed in the 1980s when treatment for RA was very different to what it is now. Until further, larger studies are carried out to better assess nefopam, with many other effective pain relieving medications on the market, the risks of harm seem to outweigh the benefit arguing against its routine use. In the one small study testing capsaicin cream (0.025%) in patients with persistent knee pain, patients also had better pain relief with capsaicin cream than for those given a placebo cream. On average, patients receiving the active treatment improved by 34 more points (out of 100) than the control group. The most common side effect was a local burning sensation at the site that the cream was applied. This was usually mild but was moderate to severe in a few patients. About 50% of patients who use capsaicin cream on their skin will develop this local burning but only 2 in 100 will stop treatment because of this. The one small study of the cannabis based mouth spray Setivax also showed reduced pain levels in patients, to a small extent. Pain was measured on a 0 to 5 point scale and there was an improvement in patients receiving Setivax of 0.74 points. About one in every three patients taking this medication developed a side effect, which was commonly dizziness (26%), dry mouth (13%) or light headedness (10%). Although this is only one study, weighing up these side effects and the minimal benefit on pain levels, until further trials are carried out we cannot recommend the use of this medication.

10.1002/14651858.CD008921.pub2

cochrane-simplification-train-380

cochrane-simplification-train-380

Twenty studies met our inclusion criteria. Five investigated performance-based reward, where groups of smokers competed against each other to win a prize (N = 915). The remaining 15 used performance-based eligibility, where cessation resulted in entry into a prize draw (N = 10,580). Five of these used Quit & Win contests (N = 4282), of which three were population-level interventions. Fourteen studies were RCTs, and the remainder quasi-randomized or controlled trials. Six had suitable abstinence data for a meta-analysis, which did not show evidence of effectiveness of performance-based eligibility interventions (risk ratio (RR) 1.16, 95% confidence interval (CI) 0.77 to 1.74, N = 3201, I2 = 57%). No trials that used performance-based rewards found a beneficial effect of the intervention on long-term quit rates. The three population-level Quit & Win studies found higher smoking cessation rates in the intervention group (4% to 16.9%) than the control group at long-term follow-up, but none were RCTs and all had important between-group differences in baseline characteristics. These studies suggested that fewer than one in 500 smokers would quit because of the contest. Reported unintended consequences in all sets of studies generally related to discrepancies between self-reported smoking status and biochemically-verified smoking status. More serious adverse events were not attributed to the competition intervention. Using the GRADE system we rated the overall quality of the evidence for smoking cessation as ‘very low', because of the high and unclear risk of bias associated with the included studies, substantial clinical and methodological heterogeneity, and the limited population investigated. At present, it is impossible to draw any firm conclusions about the effectiveness, or a lack of it, of smoking cessation competitions. This is due to a lack of well-designed comparative studies. Smoking cessation competitions have not been shown to enhance long-term cessation rates. The limited evidence suggesting that population-based Quit & Win contests at local and regional level might deliver quit rates above baseline community rates has not been tested adequately using rigorous study designs. It is also unclear whether the value or frequency of possible cash reward schedules influence the success of competitions. Future studies should be designed to compensate for the substantial biases in the current evidence base.

This review has merged studies from two previous reviews. One of the reviews was of competitions and incentives for quitting smoking. The studies that investigated incentives are now in a separate review. Here we include the studies which investigated competitions, alongside the studies originally included in our review of Quit & Win contests. We also searched for more recent relevant studies that were published up to June 2018. We include 20 studies of more than 11,000 participants that investigated competitions to encourage people to quit smoking. In five of these studies, groups of smokers recruited from workplaces competed directly against each other. In the other 15 studies, successful quitters were entered into prize draws. None of the studies in which groups of smokers competed against each other directly found that more people quit than in similar groups of smokers who were not entered into a competition. Combining the results of randomized controlled trials of lottery-type competitions, which provide the best evidence, did not show evidence that competitions increase rates of quitting smoking. Three Quit & Win contests did find that people who were in the contest had higher quit rates than people in a comparison community, who did not take part. However, these studies were of low quality and appeared to have very little effect on the overall smoking rates in the community, as fewer than one in 500 smokers appeared to quit because of the Quit & Win contest. Fourteen of the 20 studies included were randomized controlled trials, but many of these did not describe their methods well enough for us to decide whether they were of high quality. Overall, we judged the quality of the evidence included in this review to be very low, so we can draw no strong conclusions from the findings. It is important that any future research in this area is designed to be of high quality and is reported in detail, so that we can increase the confidence we have in our findings.

10.1002/14651858.CD013272

cochrane-simplification-train-381

cochrane-simplification-train-381

Two studies met the inclusion criteria, involving a total of 22,106 participants. One study tested low height beds and the other tested bed exit alarms. Both studies used standard care for their control group and both studies were conducted in hospitals. No study investigating bed rails met the inclusion criteria. Due to the clinical heterogeneity of the interventions in the included studies pooling of data and meta-analysis was inappropriate, and so the results of the studies are described. A single cluster randomised trial of low height beds in 18 hospital wards, including 22,036 participants, found no significant reduction in the frequency of patient injuries due to their beds (there were no injuries in either group), patient falls in the bedroom (rate ratio 0.69, 95% CI 0.35 to 1.34), all falls (rate ratio 1.26, 95% CI 0.83 to 1.90) or patient injuries due to all falls (rate ratio 1.35, 95% CI 0.68 to 2.68). One randomised controlled trial of bed exit alarms in one hospital geriatric ward, involving 70 participants, found no significant reduction in the frequency of patient injuries due to their beds (there were no injuries in either group), patient falls out of bed (rate ratio 0.25, 95% CI 0.03 to 2.24), all falls (rate ratio 0.42, 95% CI 0.15 to 1.18) or patient injuries due to all falls (no injuries in either group). The effectiveness of interventions designed to prevent patient injuries from their beds (including bed rails, low height beds and bed exit alarms) remains uncertain. The available evidence shows no significant increase or decrease in the rate of injuries with the use of low height beds and bed exit alarms. Limitations of the two included studies include lack of blinding and insufficient power. No randomised controlled trials of bed rails were identified. Future reports should fully describe the standard care received by the control group.

Two randomised studies are included in this review. Both studies targeted patients most likely to fall. One trial was of low height beds (22,036 patients) and the other investigated bed exit alarms (70 patients). The results of each study showed there is no significant increase or decrease in the rate of injuries or falls from bed. Although one study was large, fewer than half of the patients received a low height bed and so this group of patients may have been too small to detect a statistically significant benefit or harm in the analysis. No randomised controlled trials of bed rails were found. The researchers suggest that future reports should fully describe what standard care was received by the control group.

10.1002/14651858.CD008931.pub3

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cochrane-simplification-train-382

Studies enrolled 37724 North American youth; participants were ethnically diverse. Programs took place in schools (10), community facilities (24), both schools and community facilities (2), healthcare facilities (2), and family homes (1). Median final follow-up occurred 12 months after baseline. Results showed no evidence that abstinence-plus programs can affect self-reported sexually transmitted infection (STI) incidence, and limited evidence that programs can reduce self-reported pregnancy incidence. Results for behavioral outcomes were promising; 23 of 39 evaluations found a significantly protective intervention effect for at least one behavioral outcome. Consistently favorable program effects were found for HIV knowledge. No adverse effects were observed. Several evaluations found that one version of an abstinence-plus program was more effective than another, suggesting that more research into intervention mechanisms is warranted. Methodological strengths included large samples and statistical controls for baseline values. Weaknesses included under-utilization of relevant outcomes, self-report bias, and analyses neglecting attrition and clustered randomization. Many abstinence-plus programs appear to reduce short-term and long-term HIV risk behavior among youth in high-income countries. Evidence for program effects on biological measures is limited. Evaluations consistently show no adverse program effects for any outcomes, including the incidence and frequency of sexual activity. Trials comparing abstinence-only, abstinence-plus, and safer-sex interventions are needed.

This review included 39 randomized and quasi-randomized controlled trials comparing abstinence-plus programs to various control groups (eg "usual care," no intervention). Although we conducted an extensive international search for trials, all included studies were conducted among youth in the US, Canada, and the Bahamas (total baseline enrolment=37724 participants). The included programs took place in schools, community centers, and healthcare facilities. We did not conduct a meta-analysis because of missing data and variation in program designs. Using various control groups, 24 of 39 evaluations showed a significantly protective intervention effect on at least one biological or behavioral outcome at short-term, medium-term, or long-term follow-up. Eight trials found no evidence that abstinence-plus programs affect self-reported sexually transmitted infection (STI) incidence and limited evidence that programs have a protective effect on self-reported pregnancy incidence. Results for behavioral outcomes were inconsistent across studies. Findings in almost every trial assessing HIV-related knowledge favored the intervention group over controls. No harms were observed for any outcome, including incidence and frequency of sexual activity. Limitations for this review include underreporting of relevant outcomes, reliance on program participants to report their behaviors accurately, and methodological weaknesses in the trials.

10.1002/14651858.CD007006

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cochrane-simplification-train-383

Four studies (606 patients) were included. All of the studies were rated as having a low risk of bias. Pooled analyses revealed that vedolizumab was significantly superior to placebo for induction of remission, clinical response, and endoscopic remission and prevention of relapse. After 4 to 6 weeks of therapy 77% (293/382) of vedolizumab patients failed to enter clinical remission compared to 92% (205/224) of placebo patients (RR 0.86, 95% CI 0.80 to 0.91; 4 studies 606 patients). After 6 weeks of therapy 48% of vedolizumab patients failed to have a clinical response compared to 72% of placebo patients (RR 0.68, 95% CI 0.59 to 0.78; 3 studies 601 patients). After 4 to 6 weeks of therapy 68% of vedolizumab patients failed to enter endoscopic remission compared to 81% of placebo patients (RR 0.82, 95% CI 0.75 to 0.91; 3 studies, b583 patients). After 52 weeks of therapy, 54% of vedolizumab patients had a clinical relapse compared to 84% of placebo patients (RR 0.67, 95% CI 0.59 to 0.77; 1 study, 373 patients). One small study (28 patients) found no statistically significant difference in endoscopic response (RR 1.00, 95% CI 0.62 to 1.61). GRADE analyses indicated that the overall quality of the evidence for the primary outcomes was high for induction of remission and moderate for relapse (due to sparse data 246 events). There was no statistically significant difference between vedolizumab and placebo in terms of the risk of any adverse event (RR 0.99, 95% CI 0.93 to 1.07), or serious adverse events (RR 1.01, 95% CI 0.72 to 1.42). There was a statistically significant difference in withdrawals due to adverse events. Six per cent of vedolizumab patients withdrew due to an adverse event compared to 11% of placebo patients (RR 0.55, 95% CI 0.35 to 0.87; 2 studies, 941 patients). Adverse events commonly reported across the studies included: worsening ulcerative colitis, headache, nasopharyngitis, upper respiratory tract infection, nausea, and abdominal pain. Moderate to high quality data from four studies shows that vedolizumab is superior to placebo for induction of clinical remission and response and endoscopic remission in patients with moderate to severely active ulcerative colitis and prevention of relapse in patients with quiescent ulcerative colitis. Moderate quality data from one study suggests that vedolizumab is superior to placebo for prevention of relapse in patients with quiescent ulcerative colitis. Adverse events appear to be similar to placebo. Future trials are needed to define the optimal dose, frequency of administration and long-term efficacy and safety of vedolizumab used for induction and maintenance therapy of ulcerative colitis. Vedolizumab should be compared to other currently approved therapies for ulcerative colitis in these trials.

Four studies including 606 patients were included in this review. Pooled analysis of these trials revealed vedolizumab is significantly more effective than placebo (sham infusion) for inducing clinical remission and response (improvement of symptoms), as well as endoscopic remission (healing of inflamed mucosa in the colon) in patients with moderate to severely active ulcerative colitis. Evidence from one study suggests that vedolizumab is superior to placebo for preventing relapse (recurrence of active disease) in patients with ulcerative colitis in remission. Patients receiving vedolizumab were no more likely than placebo patients to experience side effects or serious side effects. Commonly reported side effects included: worsening ulcerative colitis, headache, nasopharyngitis (inflammation of nose and throat), upper respiratory tract infection, nausea, and abdominal pain. Further research is needed in order to define the optimal dose, frequency of drug administration and the long-term effectiveness and safety of vedolizumab used for induction and maintenance of remission in ulcerative colitis. Vedolizumab should be compared to other currently approved therapies of ulcerative colitis in these studies.

10.1002/14651858.CD007571.pub2

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cochrane-simplification-train-384

Thirty-seven studies met the inclusion criteria and included a total of 5080 participants (range 50 to 1732). Enteric fever prevalence rates in the study populations ranged from 1% to 75% (median prevalence 24%, interquartile range (IQR) 11% to 46%). The included studies evaluated 16 different RDTs, and 16 studies compared two or more different RDTs. Only three studies used the Grade 1 reference standard, and only 11 studies recruited unselected febrile patients. Most included studies were from Asia, with five studies from sub-Saharan Africa. All of the RDTs were designed to detect S.Typhi infection only. Most studies evaluated three RDTs and their variants: TUBEX in 14 studies; Typhidot (Typhidot, Typhidot-M, and TyphiRapid-Tr02) in 22 studies; and the Test-It Typhoid immunochromatographic lateral flow assay, and its earlier prototypes (dipstick, latex agglutination) developed by the Royal Tropical Institute, Amsterdam (KIT) in nine studies. Meta-analyses showed an average sensitivity of 78% (95% confidence interval (CI) 71% to 85%) and specificity of 87% (95% CI 82% to 91%) for TUBEX; and an average sensitivity of 69% (95% CI 59% to 78%) and specificity of 90% (95% CI 78% to 93%) for all Test-It Typhoid and prototype tests (KIT). Across all forms of the Typhidot test, the average sensitivity was 84% (95% CI 73% to 91%) and specificity was 79% (95% CI 70% to 87%). When we based the analysis on the 13 studies of the Typhidot test that either reported indeterminate test results or where the test format means there are no indeterminate results, the average sensitivity was 78% (95% CI 65% to 87%) and specificity was 77% (95% CI 66% to 86%). We did not identify any difference in either sensitivity or specificity between TUBEX, Typhidot, and Test-it Typhoid tests when based on comparison to the 13 Typhidot studies where indeterminate results are either reported or not applicable. If TUBEX and Test-it Typhoid are compared to all Typhidot studies, the sensitivity of Typhidot was higher than Test-it Typhoid (15% (95% CI 2% to 28%), but other comparisons did not show a difference at the 95% level of CIs. In a hypothetical cohort of 1000 patients presenting with fever where 30% (300 patients) have enteric fever, on average Typhidot tests reporting indeterminate results or where tests do not produce indeterminate results will miss the diagnosis in 66 patients with enteric fever, TUBEX will miss 66, and Test-It Typhoid and prototype (KIT) tests will miss 93. In the 700 people without enteric fever, the number of people incorrectly diagnosed with enteric fever would be 161 with Typhidot tests, 91 with TUBEX, and 70 with Test-It Typhoid and prototype (KIT) tests. The CIs around these estimates were wide, with no difference in false positive results shown between tests. The quality of the data for each study was evaluated using a standardized checklist called QUADAS-2. Overall, the certainty of the evidence in the studies that evaluated enteric fever RDTs was low. In 37 studies that evaluated the diagnostic accuracy of RDTs for enteric fever, few studies were at a low risk of bias. The three main RDT tests and variants had moderate diagnostic accuracy. There was no evidence of a difference between the average sensitivity and specificity of the three main RDT tests. More robust evaluations of alternative RDTs for enteric fever are needed.

Cochrane researchers searched the available literature up to 4 March 2016 and included 37 studies. Most studies recruited participants from South Asia. Most participants were adults, with 22 studies including children. All of the RDTs evaluated detected Salmonella Typhi (typhoid fever) only. Quality of the evidence The Cochrane researchers evaluated the quality of the data for each study using a standardized checklist called QUADAS-2. High quality studies that compared different types of RDT in the same patients were few in number. Two-thirds of the included studies did not evaluate the RDTs in the context of patients who are typically tested for the disease. Many studies utilized a particular study design (a case control study) which risks overestimating RDT accuracy. In the studies evaluating the Typhidot RDT, it was often unclear how many test results were indeterminate, when the test cannot distinguish a current episode of infection from a previous disease episode. Overall, the certainty of the evidence in the studies that evaluated enteric fever RDTs was low. Key results Sensitivity indicates the percentage of patients with a positive test result who are correctly diagnosed with disease. Specificity indicates the percentage of patients who are correctly identified as not having disease. TUBEX showed an average sensitivity of 78% and specificity of 87%. Typhidot studies, grouped together to include Typhidot, Typhidot-M, and TyphiRapid-Tr02, showed an average sensitivity of 84% and specificity of 79%. When Typhidot studies with clear reporting of indeterminate results are considered, the average sensitivity and specificity of Typhidot was 78% and 77% respectively. Test-It Typhoid and prototypes (KIT) showed an average sensitivity of 69% and specificity of 90%. Based on these results, in 1000 patients with fever where 30% (300 patients) have enteric fever, we would expect Typhidot tests reporting indeterminate results or where tests do not produce indeterminate results to, on average, miss the diagnosis (give a false negative result) in 66 patients with enteric fever, TUBEX to miss 66, and Test-It Typhoid and prototypes (KIT) to miss 93. In the 700 people without enteric fever, the number of people incorrectly given a diagnosis of enteric fever (a false positive result) would be on average 161 with these Typhidot tests, 91 with TUBEX, and 70 with the Test-It Typhoid and prototypes (KIT). These differences in the number of false negative and false positive results in patients from the different tests are not statistically important. The RDTs evaluated are not sufficiently accurate to replace blood culture as a diagnostic test for enteric fever.

10.1002/14651858.CD008892.pub2

cochrane-simplification-train-385

cochrane-simplification-train-385

Two studies (154 participants) were included. There is low quality evidence from one randomised controlled study that exercises as an adjunctive to other conservative treatments increase the efficacy of these treatments (thoracic curve reduced: mean difference (MD) 9.00, (95% confidence interval (CI) 5.47 to 12.53); lumbar curve reduced:MD 8.00, (95% CI 5.08 to 10.92)). There is very low quality evidence from a prospective controlled cohort study that scoliosis-specific exercises structured within an exercise programme can reduce brace prescription (risk ratio (RR) 0.24, (95% CI 0.06 to1.04) as compared to usual physiotherapy (many different kinds of general exercises according to the preferences of the single therapists within different facilities). There is a lack of high quality evidence to recommend the use of SSE for AIS. One very low quality study suggested that these exercises may be more effective than electrostimulation, traction and postural training to avoid scoliosis progression, but better quality research needs to be conducted before the use of SSE can be recommended in clinical practice.

The purpose of this review was to evaluate the effectiveness of SSEs in reducing curve progression and postponing or avoiding invasive treatment such as surgery in adolescents with AIS. Two studies involving 154 patients total were included. The review found no evidences for or against SSE. The two included studies yielded very low quality evidence that SSEs added to other treatments are more effective than electrical stimulation, traction and posture training for avoiding curve progression, and that SSEs as a standalone treatment yield almost the same results as general physiotherapy. Possible limitations of this review included the small number of studies that met the inclusion criteria and a high risk of bias, particularly selection bias. More randomised controlled trials are needed in this area, along with a deeper understanding of the types of SSEs useful for the adolescent with AIS.

10.1002/14651858.CD007837.pub2

cochrane-simplification-train-386

cochrane-simplification-train-386

We included six trials, four of which took place in the USA. Four trials employed randomised controlled trial (RCT) designs. Trials were conducted in workplaces from the manufacturing, industrial and services-based sectors. The sample sizes of workplaces ranged from 12 to 114. Workplace policies and practices targeted included: healthy catering policies; point-of-purchase nutrition labelling; environmental supports for healthy eating and physical activity; tobacco control policies; weight management programmes; and adherence to guidelines for staff health promotion. All implementation interventions utilised multiple implementation strategies, the most common of which were educational meetings, tailored interventions and local consensus processes. Four trials compared an implementation strategy intervention with a no intervention control, one trial compared different implementation interventions, and one three-arm trial compared two implementation strategies with each other and a control. Four trials reported a single implementation outcome, whilst the other two reported multiple outcomes. Investigators assessed outcomes using surveys, audits and environmental observations. We judged most trials to be at high risk of performance and detection bias and at unclear risk of reporting and attrition bias. Of the five trials comparing implementation strategies with a no intervention control, pooled analysis was possible for three RCTs reporting continuous score-based measures of implementation outcomes. The meta-analysis found no difference in standardised effects (standardised mean difference (SMD) −0.01, 95% CI −0.32 to 0.30; 164 participants; 3 studies; low certainty evidence), suggesting no benefit of implementation support in improving policy or practice implementation, relative to control. Findings for other continuous or dichotomous implementation outcomes reported across these five trials were mixed. For the two non-randomised trials examining comparative effectiveness, both reported improvements in implementation, favouring the more intensive implementation group (very low certainty evidence). Three trials examined the impact of implementation strategies on employee health behaviours, reporting mixed effects for diet and weight status (very low certainty evidence) and no effect for physical activity (very low certainty evidence) or tobacco use (low certainty evidence). One trial reported an increase in absolute workplace costs for health promotion in the implementation group (low certainty evidence). None of the included trials assessed adverse consequences. Limitations of the review included the small number of trials identified and the lack of consistent terminology applied in the implementation science field, which may have resulted in us overlooking potentially relevant trials in the search. Available evidence regarding the effectiveness of implementation strategies for improving implementation of health-promoting policies and practices in the workplace setting is sparse and inconsistent. Low certainty evidence suggests that such strategies may make little or no difference on measures of implementation fidelity or different employee health behaviour outcomes. It is also unclear if such strategies are cost-effective or have potential unintended adverse consequences. The limited number of trials identified suggests implementation research in the workplace setting is in its infancy, warranting further research to guide evidence translation in this setting.

We looked for studies that compared strategies to support the implementation of health-promoting policies and practices in workplaces versus either no implementation strategy or different implementation strategies. Implementation strategies could include quality improvement initiatives, education, and training, among others. They could target policies or practices directly instituted in the workplace (e.g. workplace healthy catering policy), as well as workplace-led efforts to encourage the use of external health promotion services (e.g. employee gym membership subsidies). We found six eligible studies that investigated these strategies. Most took place in the USA, and workplaces were in the manufacturing, industrial and services-based sectors. The number of workplaces examined in the studies ranged from 12 to 114. Implementation strategies in the six studies targeted different workplace policies and practices: healthy catering; point-of-purchase nutrition labelling; environmental prompts and supports for healthy eating and physical activity; tobacco control policies; sponsorship of employee weight management programmes; and adherence to national guidelines for staff health promotion. All studies used multiple strategies to improve the implementation of these policies and practices, including: educational meetings, interventions tailored to the specific needs of the workplace, and workplace consensus processes to implement a policy or practice. Four studies compared implementation strategies versus no intervention, one study compared different implementation strategies, and one study compared two implementation strategies with each other and a control. Researchers used surveys, audits and observations in workplaces to evaluate the effect of the strategies on the implementation of workplace policies and practices. The evidence is current to 31 August 2017. When we combined findings from three studies, we did not find any difference in the level of implementation of health-promoting policies or practices between workplaces that received implementation strategy support versus those that did not, indicating that these strategies may make little to no difference. In the two trials comparing different implementation strategies, both reported improvements in implementation, favouring the more intensive implementation support group. Findings for effects on employee health behaviours were inconsistent and based on very low to low certainty evidence, so it is unclear whether the implementation strategies improved these outcomes. One of the included studies reported on cost, and none on the unintended adverse consequences of implementation strategies. There were few included studies, and they used inconsistent terminology to describe implementation strategies, limiting the strength of the evidence. We rated the certainty of the evidence as low for the effect of implementation strategies on policy and practice implementation, based on four randomised studies (where groups are randomly assigned to different study groups), and very low based on two non-randomised studies. We also graded evidence on employee health behaviours and cost outcomes as low and very low. The findings of the review do not provide clear evidence regarding the impact of implementation strategies on workplace health-promoting policy and practice implementation or on employee health behaviours. Further research is needed.

10.1002/14651858.CD012439.pub2

cochrane-simplification-train-387

cochrane-simplification-train-387

Nine randomized controlled trials involving the prophylactic use of antibiotics in patients having urodynamic studies were identified and these included 973 patients in total; one study was an abstract. Two further trials were excluded from the review. The methods of the included trials were poorly described. The primary outcome in all trials was the rate of developing significant bacteriuria, defined as the presence of more than 100,000 bacteria per millilitre of a mid-stream urine sample on culture and sensitivity testing. The other outcomes included pyrexia, haematuria, dysuria and adverse reactions to antibiotics. The administration of prophylactic antibiotics when compared to a placebo reduced the risk of significant bacteriuria (4% with antibiotics versus 12% without, risk ratio (RR) 0.35, 95% CI 0.22 to 0.56) in both men and women. The administration of prophylactic antibiotics also reduced the risk of haematuria (RR 0.46, 95% CI 0.23 to 0.91). However, there was no statistically significant difference in the primary outcome, risk of symptomatic urinary tract infection (40/201, 20% versus 59/214, 28%; RR 0.73, 95% CI 0.52 to 1.03); or in the risk of fever (RR 5.16, 95% CI 0.94 to 28.16) or dysuria (RR 0.83, 95% CI 0.5 to 1.36). Only two of 135 people had an adverse reaction to the antibiotics. The number of patients needed to treat with antibiotics to prevent bacteriuria was 12.3. Amongst women, the number needed to treat to prevent bacteriuria was 13.4; while amongst men it was 9.1 (number needed to treat = 1/ absolute risk reduction). Prophylactic antibiotics did reduce the risk of bacteriuria after urodynamic studies but there was not enough evidence to suggest that this effect reduced symptomatic urinary tract infections. There was no statistically significant difference in the risk of fever, dysuria or adverse reactions. Potential benefits have to be weighed against clinical and financial implications, and the risk of adverse effects.

We identified nine trials including 973 people. We found that people were less likely to have bacteria in their urine after urodynamic studies if they had antibiotics (4% versus 12%). While they did have fewer urinary tract infections (20% compared with 28% with no antibiotics), this did not reach statistical significance. There were too few adverse effects, such as fever, pain when passing urine or a reaction to the antibiotics, for the findings to be reliable. However, people were less likely to have blood in their urine with antibiotics. There was no information about other treatments which might help reduce infections, nor about different doses or types of antibiotics.

10.1002/14651858.CD008224.pub2

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This review included 16 studies with a total of 1024 participants aged between five and 18 years, all of whom were recruited from paediatric outpatient clinics. Studies were conducted in seven countries: seven in the USA, four in Iran, and one each in the UK, Switzerland, Turkey, Sri Lanka, and India. Follow-up ranged from two weeks to four months. The studies examined the following interventions to treat RAP: tricyclic antidepressants, antibiotics, 5-HT4 receptor agonists, antispasmodics, antihistamines, H2 receptor antagonists, serotonin antagonists, selective serotonin re-uptake inhibitors, a dopamine receptor antagonist, and a hormone. Although some single studies reported that treatments were effective, all of these studies were either small or had key methodological weaknesses with a substantial risk of bias. None of these 'positive' results have been reproduced in subsequent studies. We judged the evidence of effectiveness to be of low quality. No adverse effects were reported in these studies. There is currently no convincing evidence to support the use of drugs to treat RAP in children. Well-conducted clinical trials are needed to evaluate any possible benefits and risks of pharmacological interventions. In practice, if a clinician chooses to use a drug as a 'therapeutic trial', they and the patient need to be aware that RAP is a fluctuating condition and any 'response' may reflect the natural history of the condition or a placebo effect, rather than drug efficacy.

We searched the scientific literature worldwide up to June 2016 for research studies of drug treatments for children with RAP. We found 16 studies that met our criteria, examining antidepressants, antibiotics, antihistamines, antispasmodics, a dopamine receptor antagonist, and a hormone treatment. Fourteen studies compared drug treatments to a placebo, and two to usual medical care. The trials were carried out in seven countries: seven in the USA, four in Iran, one in the UK, one in Switzerland, one in Turkey, one in Sri Lanka, and one in India. The studies included a total of 1024 children aged between five and 18 years. All children were recruited from outpatient clinics. Follow-up lasted between two weeks and four months. This review suggests there is no evidence for the use of medications to improve symptoms or the child's quality of life. Consequently, if medications are prescribed, this should be done within a well-conducted clinical trial. If a medication is prescribed to a child with RAP, it must be remembered that RAP varies with time, and therefore any improvement or worsening may due to the natural history of the condition rather than a medication response. Many of the studies had some weaknesses in their design and how they were reported, therefore the overall quality of the evidence for medications in RAP is low. The studies with better methods included few children and have not been reproduced by other researchers since.

10.1002/14651858.CD010973.pub2

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Six studies (involving 2105 women) are included. Overall, the included studies were not of high quality, and only two had both adequate randomisation sequence generation and allocation concealment. All studies that were able to be included enrolled only women at increased risk of complications. Comparison of traditional CTG versus no CTG showed no significant difference identified in perinatal mortality (risk ratio (RR) 2.05, 95% confidence interval (CI) 0.95 to 4.42, 2.3% versus 1.1%, four studies, N = 1627, low quality evidence) or potentially preventable deaths (RR 2.46, 95% CI 0.96 to 6.30, four studies, N = 1627), though the meta-analysis was underpowered to assess this outcome. Similarly, there was no significant difference identified in caesarean sections (RR 1.06, 95% CI 0.88 to 1.28, 19.7% versus 18.5%, three trials, N = 1279, low quality evidence). There was also no significant difference identified for secondary outcomes related to Apgar scores less than seven at five minutes (RR 0.83, 95% CI 0.37 to 1.88, one trial, N = 396, very low quality evidence); or admission to neonatal special care units or neonatal intensive care units (RR 1.08, 95% CI 0.84 to 1.39, two trials, N = 883, low quality evidence), nor in the other secondary outcomes that were assessed. There were no eligible studies that compared computerised CTG with no CTG. Comparison of computerised CTG versus traditional CTG showed a significant reduction in perinatal mortality with computerised CTG (RR 0.20, 95% CI 0.04 to 0.88, two studies, 0.9% versus 4.2%, 469 women, moderate quality evidence). However, there was no significant difference identified in potentially preventable deaths (RR 0.23, 95% CI 0.04 to 1.29, two studies, N = 469), though the meta-analysis was underpowered to assess this outcome. There was no significant difference identified in caesarean sections (RR 0.87, 95% CI 0.61 to 1.24, 63% versus 72%, one study, N = 59, low quality evidence), Apgar scores less than seven at five minutes (RR 1.31, 95% CI 0.30 to 5.74, two studies, N = 469, very low quality evidence) or in secondary outcomes. There is no clear evidence that antenatal CTG improves perinatal outcome, but further studies focusing on the use of computerised CTG in specific populations of women with increased risk of complications are warranted.

The review looked to see if using CTG during pregnancy might improve outcomes for babies by identifying those with complications. It looked for studies that included women at both increased risk, and at low risk, of complications. The review included six studies with all of the women at increased risk of complications. Four of the studies were undertaken in the 1980s and two in the late 1990s. The included studies were not of high quality. There were no differences in outcomes identified (low/very low quality evidence), although when computerised interpretation of the CTG trace was used, the findings looked promising. However, CTG monitors, associated technologies and the way midwives and obstetricians care for women with different complications in pregnancy have changed over the years. This means that more studies are needed now to see if outcomes for babies at increased risk of complications can be improved with antenatal CTG, particularly computerised CTG.

10.1002/14651858.CD007863.pub4

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Seventeen studies with a total of 3898 participants were analysed. One studied fibrin sealant, and the other 16 studied HA. No evidence was found of a treatment effect of fibrin sealant as an adherence compound. For HA, evidence of a positive treatment effect was identified in the six trials that reported live birth rates (odds ratio (OR) 1.41, 95% confidence interval (CI) 1.17 to 1.69; six RCTs, N = 1950, I2 = 0%, moderate-quality evidence). Furthermore, the 14 trials reporting clinical pregnancy rates showed evidence of treatment benefit when embryos were transferred in media containing functional concentrations of HA (OR 1.39, 95% CI 1.21 to 1.60; 14 RCTs, N = 3452, I2 = 46%, moderate-quality evidence) as compared with low or no use of HA. The multiple pregnancy rate (OR 1.86, 95% CI 1.49 to 2.31; five RCTs, N = 1951, I2 = 0%, moderate-quality evidence) was significantly increased in the high HA group, but no significant differences in adverse event rates were found (OR 0.74, 95% CI 0.49 to 1.12; four RCTs, N = 1525, I2 = 0%, moderate-quality evidence). Evidence suggests improved clinical pregnancy and live birth rates with the use of functional concentrations of HA as an adherence compound in ART cycles. However, the evidence obtained is of moderate quality. The increase in multiple pregnancy rate may be the result of use of a combination of an adherence compound and a policy of transferring more than one embryo. Further studies of adherence compounds with single embryo transfer need to be undertaken.

Seventeen randomised controlled trials (3898 participants) were included in the review. One studied fibrin sealant, and the other 16 studied HA. Investigators compared embryo transfer in a medium containing high versus low or no hyaluronic acid and in a medium containing fibrin sealant versus transfer in a medium with no fibrin sealant. Outcomes reported included live birth rates, clinical pregnancy rates, implantation rates, multiple pregnancy rates and other adverse events. The mean age of the women ranged from 27.5 to 35.7 years. The evidence gathered is current to November 2013. Analysis of the 16 studies that were identified using functional concentrations of HA showed an increase in the chances of pregnancy and live birth (450 vs 367 per 1000) but also an increase in the chance of the more risky outcome of multiple pregnancy (282 vs 175 per 1000). This increase in multiple pregnancy rate may be the result of improved pregnancy outcomes due to the addition of the adherence compound and the policy of transferring more than one embryo back into the uterus. Evidence obtained for these comparisons was of moderate quality. It is important to note that evidence of a higher delivery rate was not found in all analyses; however, it was found in the overall meta-analysis. Based on the single identified study that used fibrin sealant, no evidence indicates that the addition of this compound to an embryo transfer medium improved pregnancy outcomes.

10.1002/14651858.CD007421.pub3

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We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing. We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups. We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in patients with MS remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MS patients with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed.

We searched medical databases for randomised controlled trials (where participants were randomly allocated to one of two or more treatment groups) of adults with MS. Neither patients nor researchers were told which treatment was given. Doctors had diagnosed MS and memory impairment using standard methods. Key results and quality of evidence Up to July 2013, we found only seven studies with 625 participants that met our requirements although the quality of the included studies was overall low. We did not find convincing evidence to support the use of these drugs as effective symptomatic treatments for memory disorder in people with MS. There was moderate-quality evidence that donepezil 10 mg daily was ineffective in improving memory in MS patients with mild memory problems, but it was well tolerated. Side effects such as nausea, diarrhoea and abnormal dreams, although not frequent, were reported for donepezil, while ginkgo biloba, memantine and rivastigmine were well tolerated and no serious side effects were reported. There is one ongoing study that may ultimately provide valuable evidence in the future updates.

10.1002/14651858.CD008876.pub3

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Fourteen clinical trials, involving 721 participants, met the criteria for inclusion in the review. Thirteen studies compared a pharmaceutical treatment with placebo (or a low dose of the intervention), in heterogenous groups of degenerative cerebellar ataxias. Three compounds were studied in two trials each: a levorotatory form of 5-hydroxytryptophan (L-5HT), idebenone and thyrotropin-releasing hormone tartrate (TRH-T); each of the other compounds (riluzole, varenicline, buspirone, betamethasone, coenzyme Q10 with vitamin E, α-tocopheryl quinone and erythropoietin) were studied in one trial. The 14th trial, involving a mixed group of participants with spinocerebellar ataxia, compared the effectiveness of nonspecific physiotherapy and occupational therapy within an inpatient hospital setting to no treatment. No studies utilised traditional speech therapies. We defined the primary outcome measure in this review as the percentage change (improvement) in overall speech production immediately following completion of the intervention or later, measured by any validated speech assessment tool. None of the trials included speech as a primary outcome or examined speech using any validated speech assessment tool. Eleven studies reported speech outcomes derived from a subscale embedded within disease rating scales. The remaining three studies used alternative assessments to measure speech, including mean time to produce a standard sentence, a subjective rating of speech on a 14-point analogue scale, patient-reported assessment of the impact of dysarthria on activities of daily living and acoustic measures of syllable length. One study measured speech both subjectively as part of a disease rating scale and with further measures of speech timing. Three studies utilised the Short Form-36 Health Survey (SF-36) and one used the Child Health Questionnaire as measures of general quality of life. A further study utilised the Functional Independence Measure to assess functional health. Five studies reported statistically significant improvement on an overall disease rating scale in which a speech subscale was included. Only three of those studies provided specific data on speech performance; all were comparisons with placebo. Improvements in overall disease severity were observed with α-tocopheryl quinone; however, no significant changes were found on the speech subscale in a group of individuals with Friedreich ataxia. A statistically significant improvement in speech according to a speech disorders subscale was observed with betamethasone. Riluzole was found to have a statistically significant effect on speech in a group of participants with mixed hereditary, sporadic and unknown origin ataxias. No significant differences were observed between treatment and placebo in any other pharmaceutical study. A statistically significant improvement in functional independence occurred at the end of the treatment period in the rehabilitation study compared to the delayed treatment group but these effects were not present 12 to 24 weeks after treatment. Of the four studies that assessed quality of life, none found a significant effect. A variety of minor adverse events were reported for the 13 pharmaceutical therapies, including gastrointestinal side effects and nausea. Serious adverse effects were reported in two participants in one of the L-5HT trials (participants discontinued due to gastrointestinal effects), and in four participants (three taking idebenone, one taking placebo) in the idebenone studies. Serious adverse events with idebenone were gastrointestinal side effects and, in people with a previous history of these events, chest pain and idiopathic thrombocytopenic purpura. The rehabilitation study did not report any adverse events. We considered six studies to be at high risk of bias in some respect. We suspected inadequate blinding of participants or assessors in four studies and poor randomisation in a further two studies. There was a high risk of reporting bias in two studies and attrition bias in four studies. Only one study had a low risk of bias across all criteria. Taken together with other limitations of the studies relating to the validity of the measurement scales used, we downgraded the quality of the evidence for many of the outcomes to low or very low. There is insufficient and low or very low quality evidence from either RCTs or observational studies to determine the effectiveness of any treatment for speech disorder in any of the hereditary ataxia syndromes.

We searched widely for clinical trials and found 14 trials of treatments for speech problems in hereditary ataxias. The trials involved 721 participants. The duration of treatment was between two weeks and two years. Thirteen trials compared a medicine to a placebo and the 14th compared a mixed physiotherapy and occupational therapy treatment to no treatment. Ten different medicines were tested: L-hydroxytryptophan (L-5HT) (two studies), thyrotropin-releasing hormone (TRH) (two studies), varenicline, riluzole, idebenone (two studies), betamethasone, coenzyme Q10 with vitamin E, buspirone, ɑ-tocopheryl quinone and erythropoietin. We did not find any studies of traditional speech therapies. There were three ongoing trials. When planning the review, we decided to use the percentage change in speech production after treatment as our primary measure of whether treatments were effective. None of the studies measured speech in a way that allowed us to report this. Five studies reported improvement in overall disease severity but only two studies, of riluzole in various ataxias and betamethasone in ataxia telangiectasia, demonstrated improvement of speech production. It is difficult to say whether these improvements in speech might make a meaningful difference to patients. A variety of minor adverse events occurred with the medicines, including effects on the stomach and intestines, such as feeling sick. This kind of effect caused two people taking L-5HT to stop treatment. Another person experienced this effect while taking idebenone. Two more people taking idebenone experienced heart or autoimmune problems; however, they each had experienced those problems earlier in their life. None of the other studies found differences in speech performance on active treatment. All trials had some problems in conduct or design that could potentially affect the findings. Most of the included studies were small and looked at a mixed group of people with different forms of ataxia. The current evidence base is of low or very low quality and does not allow us to decide whether treatments for speech problems in the hereditary ataxia syndromes are effective. The evidence is up to date to October 2013.

10.1002/14651858.CD008953.pub2

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We found only one study that met our inclusion criteria. This was a randomised double blind, placebo-controlled multicentre study conducted to evaluate the effectiveness of a single dose of intravenous tranexamic acid (15 mg/kg body weight) versus placebo, given immediately before surgery for reducing blood loss and the need for red blood cell transfusion. The mean total estimated blood loss was 668.34 mL and 916.93 mL for participants assigned to tranexamic acid and placebo groups, respectively. The mean difference (MD) of total estimated blood loss between the groups did not show a clinically important effect (MD − 248.59 mL; 95% confidence interval (CI) − 550.9 to 53.79; one study, 100 participants; moderate quality evidence). The mean number of transfused units of blood components was not different between the two groups (low quality evidence). There were no noted differences in the incidence of reoperation, readmission or thromboembolic events (very low quality evidence). We considered the methodology of the included study to be at low risk of selection, detection, and reporting biases. However, we were concerned about an imbalance of some baseline characteristics between the groups, and as there was no protocol for blood transfusion, the rate of blood transfusion may vary depending on the practice of each participating hospital. Currently, there is insufficient evidence to recommend the routine use of tranexamic acid for reducing blood loss in women undergoing cytoreductive surgery for advanced EOC, as only limited data are available from a single, low quality RCT at low overall risk of bias.

Although tranexamic acid did numerically reduce blood loss, there was no clinical benefit, as the difference in blood loss was minimal, and there was no difference in need for blood transfusion, suggesting that this level of blood loss did not make a difference to the patient's well-being. Additionally, there was incomplete and limited evidence regarding tranexamic acid-related adverse events, so we can say little about whether tranexamic acid is safe for women with advanced ovarian cancer. The evidence we found from a single study was therefore insufficient to support routinely giving prophylactic tranexamic acid for cytoreductive surgery. This review indicates the need for future good quality, well-designed randomised controlled trials to provide more evidence on the effectiveness, safety and appropriate administration of tranexamic acid. The quality of the evidence was variable; therefore the overall the strength of the evidence reported in this review is low, as it is based on only one small randomised controlled study.

10.1002/14651858.CD011732.pub2

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No trials comparing different systolic BP targets were found. Seven trials (22,089 subjects) comparing different diastolic BP targets were included. Despite a -4/-3 mmHg greater achieved reduction in systolic/diastolic BP, p< 0.001, attempting to achieve "lower targets" instead of "standard targets" did not change total mortality (RR 0.92, 95% CI 0.86-1.15), myocardial infarction (RR 0.90, 95% CI 0.74-1.09), stroke (RR 0.99, 95% CI 0.79-1.25) , congestive heart failure (RR 0.88, 95% CI 0.59-1.32), major cardiovascular events (RR 0.94, 95% CI 0.83-1.07), or end-stage renal disease (RR 1.01, 95% CI 0.81-1.27). The net health effect of lower targets cannot be fully assessed due to lack of information regarding all total serious adverse events and withdrawals due to adverse effects in 6 of 7 trials. A sensitivity analysis in diabetic patients and in patients with chronic renal disease also did not show a reduction in any of the mortality and morbidity outcomes with lower targets as compared to standard targets. Treating patients to lower than standard BP targets, ≤140-160/90-100 mmHg, does not reduce mortality or morbidity. Because guidelines are recommending even lower targets for diabetes mellitus and chronic renal disease, we are currently conducting systematic reviews in those groups of patients.

This review was performed to find and assess all trials designed to answer whether lower blood pressure targets are better than standard blood pressure targets. Data from 7 trials in over 22,000 people were analysed. Using more drugs in the lower target groups did achieve modestly lower blood pressures. However, this strategy did not prolong survival or reduce stroke, heart attack, heart failure or kidney failure. More trials are needed, but at present there is no evidence to support aiming for a blood pressure target lower than 140/90 mmHg in any hypertensive patient.

10.1002/14651858.CD004349.pub2

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We found 10 trials (23 reports) of education and support for breastfeeding that included women with twins or higher order multiples. The quality of evidence was mixed, and the risk of bias was mostly high or unclear. It is difficult to blind women or staff to group allocation for this intervention, so in all studies there was high risk of performance and high or unclear risk of detection bias. Trials recruited 5787 women (this included 512 women interviewed as part of a cluster randomised trial); of these, data were available from two studies for 42 women with twins or higher order multiples. None of the interventions were specifically designed for women with more than one infant, and the outcomes for multiples were not reported separately for each infant. Due to the scarcity of evidence and the format in which data were reported, a narrative description of the data is presented, no analyses are presented in this review, and we were unable to GRADE the evidence. The two trials with data for women with multiple births compared home nurse visits versus usual care (15 women), and telephone peer counselling versus usual care (27 women). The number of women who initiated breastfeeding was reported (all 15 women in one study, 25 out of 27 women in one study). Stopping any breastfeeding before four to six weeks postpartum, stopping exclusive breastfeeding before four to six weeks postpartum, stopping any breastfeeding before six months postpartum andstopping exclusive breastfeeding before six months postpartum were not explicitly reported, and there were insufficient data to draw any meaningful conclusions from survival data. Stopping breast milk expression before four to six weeks postpartum, andstopping breast milk expression before six months postpartum were not reported. Measures ofmaternal satisfaction were reported in one study of 15 women, but there were insufficient data to draw any conclusions; no other secondary outcomes were reported for women with multiple births in either study. No adverse events were reported. We found no evidence from randomised controlled trials about the effectiveness of breastfeeding education and support for women with twins or higher order multiples, or the most effective way to provide education and support . There was no evidence about the best way to deliver the intervention, the timing of care, or the best person to deliver the care. There is a need for well-designed, adequately powered studies of interventions designed for women with twins or higher order multiples to find out what types of education and support are effective in helping these mothers to breastfeed their babies.

We searched for randomised controlled trials on 30 June 2016 and 1 July 2016 and found 10 studies (23 reports) to include in our review. All the studies were of education and support for all mothers, not just those giving birth to more than one baby, which introduced methodological issues for looking specifically at multiple births. Trials recruited 5787 women (this included 512 women interviewed as part of a cluster randomised trial). The number of babies from multiple pregnancies was small and none of the studies had sufficient numbers to provide information about how interventions worked for mothers of multiples. There were several problems with how the studies had been done, including women knowing if they were in the group getting support. The authors of two of the studies sent us their findings for women with multiple births (42 women in total). The trials compared home nurse visits versus usual care (15 women), and telephone peer counselling versus usual care (27 women). They looked at the number of women stopping any or exclusive breastfeeding before four weeks after giving birth and before six months, without any clear improvements provided by the intervention. All 15 women in one study and 25 out of 27 women in the other had started breastfeeding. There was no information on breast milk expression. Other outcome measures were reported, including a measure of maternal satisfaction in one study of 15 women, but there were not sufficient numbers to allow us to draw any conclusions. No adverse events were reported. We could not draw conclusions from the evidence available from randomised controlled trials about whether education and support helps mothers of multiples to breastfeed. None of the studies were designed to offer tailored support or education to women who give birth to more than one baby. More research is needed to find out what types of education and support could help mothers of multiples to breastfeed their babies. Data from these studies should be presented and analysed in an appropriate way for multiple babies.

10.1002/14651858.CD012003.pub2

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We included 23 studies in this review, involving a total of 1372 participants (an addition of 10 studies, 724 participants from the original review); 227 full texts were screened in the update and 377 full texts were screened in the original review leaving 35 publications from a total of 23 unique studies included in the review. We planned to include all cancers, but only studies involving breast, prostate, colorectal and lung cancer met the inclusion criteria. Thirteen studies incorporated a target level of exercise that could meet current recommendations for moderate-intensity aerobic exercise (i.e.150 minutes per week); or resistance exercise (i.e. strength training exercises at least two days per week). Adherence to exercise interventions, which is crucial for understanding treatment dose, is still reported inconsistently. Eight studies reported intervention adherence of 75% or greater to an exercise prescription that met current guidelines. These studies all included a component of supervision: in our analysis of BCTs we designated these studies as 'Tier 1 trials'. Six studies reported intervention adherence of 75% or greater to an aerobic exercise goal that was less than the current guideline recommendations: in our analysis of BCTs we designated these studies as 'Tier 2 trials.' A hierarchy of BCTs was developed for Tier 1 and Tier 2 trials, with programme goal setting, setting of graded tasks and instruction of how to perform behaviour being amongst the most frequent BCTs. Despite the uncertainty surrounding adherence in some of the included studies, interventions resulted in improvements in aerobic exercise tolerance at eight to 12 weeks (SMD 0.54, 95% CI 0.37 to 0.70; 604 participants, 10 studies; low-quality evidence) versus usual care. At six months, aerobic exercise tolerance was also improved (SMD 0.56, 95% CI 0.39 to 0.72; 591 participants; 7 studies; low-quality evidence). Since the last version of this review, none of the new relevant studies have provided additional information to change the conclusions. We have found some improved understanding of how to encourage previously inactive cancer survivors to achieve international physical activity guidelines. Goal setting, setting of graded tasks and instruction of how to perform behaviour, feature in interventions that meet recommendations targets and report adherence of 75% or more. However, long-term follow-up data are still limited, and the majority of studies are in white women with breast cancer. There are still a considerable number of published studies with numerous and varied issues related to high risk of bias and poor reporting standards. Additionally, the meta-analyses were often graded as consisting of low- to very low-certainty evidence. A very small number of serious adverse effects were reported amongst the studies, providing reassurance exercise is safe for this population.

We included only studies that compared an exercise intervention with a usual care comparison or 'waiting list' control. Only studies that included sedentary people over the age of 18 with the same cancer diagnosis were eligible. Participants must have been allocated to exercise or usual care at random. We searched for evidence from research databases from 1946 to May 2018. We included 23 studies involving 1372 participants in total. Evidence suggests that exercise studies that incorporate an element of supervision can help cancer survivors. However, we still have a poor understanding of how to promote exercise long term (over six months). There is some concern that research is not being reported as clearly as it should be. We found that setting goals, graded physical activity tasks and providing instructions on how to perform the exercises could help people to do beneficial amounts of exercise. In addition, we found some evidence that in people who do meet recommended exercise levels, get fitter for up to six months. The main problems that we found regarding the quality of studies in this review included: not knowing how study investigators conducted randomisation for the trials and not knowing whether investigators who were doing trial assessments knew to which group the person they were assessing had been randomly assigned. The quality of the evidence from these studies was found to be low due to the majority of the trials often containing a low number of participants. The main conclusions from this review are that exercise is generally safe for cancer survivors. We have a better understanding of how to encourage cancer survivors to meet current exercise recommendations. However, there is still a lack of evidence of how to encourage exercise in cancer survivors over six months.

10.1002/14651858.CD010192.pub3

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We included nine studies reporting on 10 psychological interventions and one combined intervention. The studies included 1546 participants. No RCTs were found of pharmacological interventions, exercise programmes or employee assistance programmes. We assessed seven studies as having low risk of bias and the studies that were pooled together were comparable. For those who received no treatment, compared with CBT, the assumed time to partial and full RTW was 88 and 252 days respectively. Based on two studies with a total of 159 participants, moderate-quality evidence showed that CBT had similar results for time (measured in days) until partial RTW compared to no treatment at one-year follow-up (mean difference (MD) -8.78, 95% confidence interval (CI) -23.26 to 5.71). We found low-quality evidence of similar results for CBT and no treatment on the reduction of days until full RTW at one-year follow-up (MD -35.73, 95% CI -113.15 to 41.69) (one study with 105 participants included in the analysis). Based on moderate-quality evidence, problem solving therapy (PST) significantly reduced time until partial RTW at one-year follow-up compared to non-guideline based care (MD -17.00, 95% CI -26.48 to -7.52) (one study with 192 participants clustered among 33 treatment providers included in the analysis), but we found moderate-quality evidence of no significant effect on reducing days until full RTW at one-year follow-up (MD -17.73, 95% CI -37.35 to 1.90) (two studies with 342 participants included in the analysis). We found moderate-quality evidence that CBT did not significantly reduce time until partial RTW and low-quality evidence that it did not significantly reduce time to full RTW compared with no treatment. Moderate-quality evidence showed that PST significantly enhanced partial RTW at one-year follow-up compared to non-guideline based care but did not significantly enhance time to full RTW at one-year follow-up. An important limitation was the small number of studies included in the meta-analyses and the small number of participants, which lowered the power of the analyses.

Our study assessed how effective these treatments are at enabling the sick-listed worker to return to partial or full-time work. We searched databases containing articles from different scientific journals and looked for studies that tested whether a certain type of treatment helped the worker to return to work when on sick leave because of an adjustment disorder. We found nine relevant studies. In total, 10 psychological treatments were evaluated and one combined treatment consisting of a psychological treatment and relaxation techniques. We found no studies on pharmacological interventions, exercise programmes or employee assistance programmes. The nine studies included in this review reported in total on 1546 participants. Of the 10 psychological treatments, five consisted of cognitive behavioural therapy and five of problem solving therapy, which are commonly used types of treatment for patients with mental health problems. Our results showed that workers on sick leave because of an adjustment disorder can be helped with making their first step back to work (i.e. partial return to work) by treating them with problem solving therapy. On average, workers who are offered problem solving therapy start 17 days earlier with partial return to work compared to workers who receive no treatment or the usual treatment from their occupational physician or general practitioner. However, we also found that cognitive behavioural therapy or problem solving therapy does not help the worker return to work with full-time hours any quicker than workers who receive no treatment or the usual treatment from their occupational physicians or general practitioners. These results are based on moderate-quality evidence, which implies that further research is likely to have an important impact on our confidence in the results and may change the results.

10.1002/14651858.CD006389.pub2

cochrane-simplification-train-398

cochrane-simplification-train-398

The review currently includes nine studies with an average 60 participants per study. All of these studies are now over 60 years old, conducted between 1955 and 1962. When chlorpromazine was compared with reserpine for people with schizophrenia, improvement in global state was better at short term for those receiving chlorpromazine (n = 781, 6 RCTs, RR 'not improved' 0.75 95% CI 0.62 to 0.92, low-quality evidence). Short-term improvement in paranoid distortion was measured using the Multidimensional Scale for Rating Psychiatric Patients (MSRPP). Data showed no clear difference between treatment groups (n = 19, 1 RCT, RR 1.33 95% CI 0.62 to 2.89, very low-quality evidence). There was no difference in functioning: occupational adjustment, medium term (n = 40, 1 RCT, RR 0.83 95% CI 0.47 to 1.47, moderate-quality evidence) and general behaviour (n = 98, 1 RCT, RR 0.79 CI 0.41 to 1.53, moderate-quality evidence). Adverse events were poorly reported. For 'toxic reaction' there was, again, no obvious difference between the two compounds (n = 210, 3 RCTs, RR 1.68 95% CI 0.43 to 6.54, moderate-quality evidence), and this also applied to leaving the study early (n = 229, 4 RCTs, RR 1.16 95% CI 0.94 to 1.42, moderate-quality evidence). Judged by standards of today, the evidence is largely of limited quality. However, some of these 1950s studies are remarkable in their foresight and clarity. Reserpine did have some effect on global state - but chlorpromazine did seem to perform better. Important issues regarding adverse effects were not really addressed by these trials. Chlorpromazine remains on the WHO list of essential drugs. Reserpine is now almost obsolete, although, probably as a result of evidence other than that reported in the pioneering trials used in this review.

The review currently includes nine studies with around 60 participants per study. All of these studies are now over 60 years old, conducted between 1955 and 1962 and include people with the most severe illnesses. Key results Chlorpromazine does better than reserpine for 'improvement in global state' with most trials reporting on this outcome. There was no clear difference between the drugs for 'occupational adjustment', 'general behaviour', and, rather surprisingly, adverse events and finally, leaving the study early. Quality of the evidence Judged by standards of today, the evidence is largely of limited quality. However, some of these 1950s studies are remarkable in their foresight and clarity.

10.1002/14651858.CD012122.pub2

cochrane-simplification-train-399

cochrane-simplification-train-399

Only one study, funded by Pfizer, met the inclusion criteria for the review. A total of 64 participants (with chronic pain due to chronic pancreatitis) were randomly assigned to receive escalating doses of pregabalin (150 mg per day to 600 mg per day; 34 participants) or matching placebo (30 participants). Participants received pregabalin or placebo for three weeks on an outpatient basis; the outcomes were measured at the end of the treatment (i.e. three weeks from commencement of treatment). Potential participants taking concomitant analgesic medication and expected to stay on a stable regime during the trial were allowed to enter the study. This trial was at low risk of bias. The overall quality of evidence was low or moderate. Only the short-term outcomes were available in this trial. The medium and long-term outcomes, number of work days lost, and length of hospital stay due to admissions for pain control were not available. This trial found that the changes in opiate use (MD -26.00 mg; 95% CI -47.36 to -4.64; participants = 64; moderate-quality evidence), and pain score percentage changes from baseline (MD -12.00; 95% CI -21.82 to -2.18; participants = 64; moderate-quality evidence) were better in participants taking pregabalin compared to those taking placebo. This trial also found that there were more adverse events in participants taking pregabalin compared to those taking placebo (RR 1.71; 95% CI 1.20 to 2.43; participants = 64). The differences between pregabalin and placebo were imprecise for short-term health-related quality of life measured with the EORTC CLQ-30 questionnaire (MD 11.40; 95% CI -3.28 to 26.08; participants = 64; moderate-quality evidence), proportion of people with serious adverse events (RR 1.76; 95% CI 0.35 to 8.96; participants = 64; low-quality evidence), and proportion of people requiring hospital admissions (RR 0.44; 95% CI 0.04 to 4.62; participants = 64; low quality evidence). Based on low- to moderate-quality evidence, short-term use of pregabalin decreases short-term opiate use, and short-term pain scores, but increases the adverse events compared to placebo, in people with chronic pain due to chronic pancreatitis. The clinical implication of the decreases in short-term opiate use and short-term pain scores is not known. Future trials assessing the role of pregabalin in decreasing chronic pain in chronic pancreatitis should assess the medium- or long-term effects of pregabalin and should include outcomes such as, quality of life, treatment-related adverse events, number of work days lost, number of hospital admissions, and the length of hospital stay, in addition to pain scores, to assess the clinical and socioeconomic impact.

We only found one study funded by Pfizer that met our inclusion criteria. A total of 64 participants with chronic pain due to chronic pancreatitis received either increasing doses of pregabalin (150 mg per day to 600 mg per day; 34 participants) or matching placebo (sham treatment; 30 participants) on an outpatient basis. The decision about whether a participant received pregabalin or placebo was made using methods similar to toss of a coin, to ensure that the participants in the two groups were similar. Participants received pregabalin or placebo for three weeks, then the outcomes were measured. Potential participants taking other pain-killers were allowed to take part in the study. Thus, this trial evaluates the role of pregabalin in addition to other analgesics for decreasing chronic abdominal pain due to chronic pancreatitis. Only the short-term outcomes were available in this trial. This trial found that the changes in opiate use (drugs similar to morphine), and pain scores from baseline were better in participants taking pregabalin compared to those taking placebo. It was not clear whether these changes had a significant impact on the life of the participants.This trial also found that there were more side-effects in participants taking pregabalin compared to those taking placebo. The differences between pregabalin and placebo were imprecise for short-term health-related quality of life, percentage of people with serious side-effects, and percentage of people requiring hospital admissions. Medium- and long-term outcomes, number of work days lost, and length of hospital stay were not available in this trial. The quality of evidence was low or moderate. As a result, further studies are required on this topic.

10.1002/14651858.CD011522.pub2