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cochrane-simplification-train-600

cochrane-simplification-train-600

We identified three RCTs, all of which compared EVLA with surgery; one also compared UGFS with surgery. There were no trials comparing RFA with surgery. The EVLA versus surgery comparison included 311 participants: 185 received EVLA and 126 received surgery. In the UGFS comparison, each treatment group contained 21 people. For several outcomes in the EVLA comparison, only a single study provided relevant data; as a result, the current review is limited in its ability to demonstrate meaningful results for some planned outcomes. The quality of evidence according to GRADE was moderate to low for the outcome measures in the EVLA versus surgery comparison, but low for the UGFS versus surgery comparison. Reasons for downgrading in the EVLA versus surgery comparison were risk of bias (for some outcomes, the outcome assessors were not blinded; and in one study the EVLA-surgery allocation of 2:1 did not appear to be prespecified); imprecision (data were only available from a single small study and the CIs were relatively wide); indirectness (one trial reported results at six months rather than one year and was inadequately powered for SSV varices-only analysis). Reasons for downgrading in the UGFS versus surgery comparison were imprecision (only one trial offered UGFS and several participants were missing from the analysis) and a limitation in design (the study was inadequately powered for SSV participants alone). For the EVLA versus surgery comparison, recanalisation or persistence of reflux at six weeks occurred less frequently in the EVLA group than in the surgery group (OR 0.07, 95% CI 0.02 to 0.22; I2 = 51%; 289 participants, 3 studies, moderate-quality evidence). Recurrence of reflux at one year was also less frequent in the EVLA group than in the surgery group (OR 0.24, 95% CI 0.07 to 0.77; I2 = 0%; 119 participants, 2 studies, low-quality evidence). For the outcome clinical evidence of recurrence (i.e. presence of new visible varicose veins) at one year, there was no difference between the two treatment groups (OR 0.54, 95% CI 0.17 to 1.75; 99 participants, 1 study, low-quality evidence). Four participants each in the EVLA and surgery groups required reintervention due to technical failure (99 participants, 1 study, moderate-quality evidence). There was no difference between the two treatment groups for disease-specific quality of life (QoL) (Aberdeen Varicose Veins Questionnaire) either at six weeks (mean difference (MD) 0.15, 95% CI -1.65 to 1.95; I2 = 0%; 265 participants, 2 studies, moderate-quality evidence), or at one year (MD -1.08, 95% CI -3.39 to 1.23; 99 participants, 1 study, low-quality evidence). Main complications reported at six weeks were sural nerve injury, wound infection and deep venous thrombosis (DVT) (one DVT case in each treatment group; EVLA: 1/161, 0.6%; surgery 1/104, 1%; 265 participants, 2 studies, moderate-quality evidence). For the UGFS versus surgery comparison, there were insufficient data to detect clear differences between the two treatment groups for the two outcomes recanalisation or persistence of reflux at six weeks (OR 0.34, 95% CI 0.06 to 2.10; 33 participants, 1 study, low-quality evidence), and recurrence of reflux at one year (OR 1.19, 95% CI 0.29 to 4.92; 31 participants, 1 study, low-quality evidence). No other outcomes could be reported for this comparison because the study data were not stratified according to saphenous vein. Moderate- to low-quality evidence exists to suggest that recanalisation or persistence of reflux at six weeks and recurrence of reflux at one year are less frequent when EVLA is performed, compared with conventional surgery. For the UGFS versus conventional surgery comparison, the quality of evidence is assessed to be low; consequently, the effectiveness of UGFS compared with conventional surgery in the treatment of SSV varices is uncertain. Further RCTs for all comparisons are required with longer follow-up (at least five years). In addition, measurement of outcomes such as recurrence of reflux, time taken to return to work, duration of procedure, pain, etc., and choice of time points during follow-up should be standardised such that future trials evaluating newer technologies can be compared efficiently.

We searched for all randomised controlled trials to March 2016 that compared at least one of the newer techniques with surgery, when treating short saphenous vein (SSVs; found in the lower leg) varices. We found three trials comparing EVLA with surgery; one trial compared UGFS with surgery, but none reported RFA. The main measures (outcomes) were recanalisation (blood flowing in the veins again) or persistence of reflux (due to failure of treatment) at six weeks; recurrence of reflux at one year; clinical evidence of recurrence (presence of new varicose veins) at one year; repeat treatment due to failure; quality of life (QoL) at six weeks and one year after the treatment; and complications after treatment. The EVLA versus surgery comparison included 311 participants: 185 received EVLA and 126 received surgery. In the UGFS comparison, each treatment group contained 21 people. For several outcomes in the EVLA comparison, only one study provided data; consequently, this review has limited ability to demonstrate meaningful results for some planned outcomes. EVLA versus surgery: there was less recanalisation or persistence of reflux at six weeks and less recurrence of reflux at one year in the EVLA group; however, there were insufficient data to report clear differences in clinical recurrence at one year. One trial reported four participants in each group required further treatment. There was no difference between treatments in QoL. Although some participants had postoperative complications (e.g., sural nerve injury (the sural nerve is in the calf), infection, deep venous thrombosis (DVT; blood clots in veins), inflammation of the wall of the vein), most complications improved without treatment and the two cases of DVT resolved after treatment with medicines. UGFS versus surgery: there were insufficient data to detect clear differences between treatment groups for recanalisation or persistence of reflux at six weeks and recurrence of reflux at one year. Data were not available for other outcomes. For the EVLA comparison, the quality of evidence was moderate for recanalisation or persistence of reflux, QoL and complications, all at six weeks, and retreatment due to technical failure, but low for recurrence of reflux, QoL and clinical evidence of recurrence after one year. The quality of evidence was downgraded due to imprecision (small number of trials with few participants) and bias (outcome assessors aware of treatment allocation in some studies and one study recruited insufficient participants with SSV). For the UGFS comparison, evidence was low quality because one study (with few participants with SSV) offered UGFS and several participants were missing from the analysis. The main difficulty with this review was lack of data: we found a small number of trials and two trials had substantial amounts of unavailable data. Further well-designed studies are needed.

10.1002/14651858.CD010878.pub2

cochrane-simplification-train-601

cochrane-simplification-train-601

Six randomised trials fulfilled the inclusion criteria. Two hundred and one randomised participants (male = 174) were included. The risk of bias in all the included trials was high. Five trials compared interferon alpha with no treatment in the control group. One of these trials had two treatment arms with a higher dose and lower dose of interferon alpha and a no-treatment control group. We analysed both treatment regimens as a single group in a primary analysis and as separate groups in the subgroup analysis of different interferon dosages. The sixth trial compared only a higher dose of interferon alpha with a lower dose. Meta-analysis of five trials comparing interferon alpha with no-treatment control group included 169 participants. There were seven drop-outs in the treatment group and nine in the control group. One patient out of 92 (1.1%) died in the interferon alpha group compared with zero out of 77 (0.0%) in the no-intervention control group (risk ratio (RR)) 3.00; 95% confidence interval (CI) 0.14 to 66.5). Interferon alpha led to failure of end of treatment virological response in 62/92 (67.4%) of the patients compared with 71/77 (92.2%) in the untreated controls (RR 0.76, 95% CI 0.66 to 0.87, P = 0.0001 by fixed-effect model and RR 0.71, 95% CI 0.43 to 1.16, P = 0.17 by random-effects model). Failure of normalisation of alanine aminotransferase (ALT) at the end of treatment was seen in 60/92 (65.2%) patients treated with interferon alpha versus 76/77 (98.7%) in the control group (RR 0.69, 95% CI 0.59 to 0.80, P < 0.00001). Sustained virological response was not achieved in 76/92 (82.6%) of patients on interferon compared with 73/77 (94.8%) of controls (RR 0.89, 95% CI 0.80 to 0.98, P = 0.02). Serum alanine aminotransferase was abnormal in 81/92 (88.0%) treated with interferon alpha patients at six months post-treatment follow-up compared with 76/77 (98.7%) in controls (RR 0.92, 95% CI 0.84 to 0.99, P = 0.04). There was no significant histological improvement in 67/92 (72.8%) patients treated with interferon alpha compared with 65/77 (84.4%) in controls (RR 0.86, 95% CI 0.74 to 1.00, P = 0.06). Two trials comparing a higher dose of interferon alpha with the lower dose showed no significant difference in sustained virological response (76.7% compared with 90.0%) (RR 0.85, 95% CI 0.68 to 1.07, P = 0.16). Adverse events such as flu-like symptoms, asthenia, weight loss, alopecia, thrombocytopenia, and leukopenia were reported in all these trials and the adverse events were related to interferon alpha. These were common and sometimes severe. One patient in the treatment group was reported to have died by suicide towards the end of the study period. Interferon alpha does not seem to cure hepatitis D in most patients. The agent seems effective in suppressing viral and liver disease activity in some patients, but this improvement is not sustained in the majority of patients. We cannot exclude overestimation of benefits and underestimation of harms due to high risk of bias (systematic errors) and high risk play of chance (random errors). Therefore, more randomised trials with large sample sizes and less risk of bias are needed before interferon can be recommended or refuted.

This meta analysis of six randomised clinical trials of interferon shows that even Interferon alpha is not an ideal drug for this infection. Among the 169 participants included in primary meta analysis, interferon alpha induced loss of virus, normalisation of liver tests, and improvement in the liver biopsy in more patients compared with those who were left untreated. Unfortunately, most of these patients did not have sustained response after stopping treatment. Additional analysis of two trials comparing a higher dose of interferon alpha with lower dose among randomly assigned participants showed no significant difference in outcome between the two groups. There were differences in dosage and duration of interferon alpha used among included trials as well as some other methodological weakness which places a high risk of bias in this meta analysis.

10.1002/14651858.CD006002.pub2

cochrane-simplification-train-602

cochrane-simplification-train-602

The latest search found four new trials and updated follow-up data on three trials included in the original review. Eighteen randomised control trials (19 trial arms; 56,934 participants) were included. Fourteen trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (OR 0.86, 95% CI 0.79 to 0.94); as was combined fatal and non-fatal CVD RR 0.75 (95% CI 0.70 to 0.81), combined fatal and non-fatal CHD events RR 0.73 (95% CI 0.67 to 0.80) and combined fatal and non-fatal stroke (RR 0.78, 95% CI 0.68 to 0.89). Reduction of revascularisation rates (RR 0.62, 95% CI 0.54 to 0.72) was also seen. Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no evidence of any serious harm caused by statin prescription. Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life. Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta-analysis indicate that these benefits are similar in people at lower (< 1% per year) risk of a major cardiovascular event. Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins.

Since the early statin randomised controlled trials were reported in the 1990s, several reviews of the effects of statins have been published highlighting their benefits particularly in people with a past history of CVD. Benefits include a reduction in CVD events. Statins have also been shown to reduce the risk of a first event in otherwise healthy individuals at high risk of CVD (primary prevention) but information on possible hazards has not been reported fully. The aim of this updated systematic review is to assess the effects, both in terms of benefits and harms of statins, for the primary prevention of CVD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE until 2011. We found 18 randomised controlled trials with 19 trial arms (56,934 patients) dating from 1994 to 2008. All were randomised control trials comparing statins with usual care or placebo. The mean age of the participants was 57 years (range 28 - 97 years), 60.3% were men, and of the eight trials that reported on ethnicity, 85.9 % were Caucasian. Duration of treatment was a minimum one year and with follow-up of a minimum of six months. All-cause mortality and fatal and non-fatal CVD events were reduced with the use of statins as was the need for revascularisation (the restoration of an adequate blood supply to the heart) by means of surgery (coronary artery bypass graft ) or by angioplasty (PTCA). Of 1000 people treated with a statin for five years, 18 would avoid a major CVD event which compares well with other treatments used for preventing cardiovascular disease. Taking statins did not increase the risk of serious adverse effects such as cancer. Statins are likely to be cost-effective in primary prevention.

10.1002/14651858.CD004816.pub5

cochrane-simplification-train-603

cochrane-simplification-train-603

A total of 431 participants undergoing elective laparoscopic cholecystectomy were randomised to formal patient education (215 participants) versus standard care (216 participants) in four trials. The patient education included verbal education, multimedia DVD programme, computer-based multimedia programme, and PowerPoint presentation in the four trials. All the trials were of high risk of bias. One trial including 212 patients reported mortality. There was no mortality in either group in this trial. None of the trials reported surgery-related morbidity, quality of life, proportion of patients discharged as day-procedure laparoscopic cholecystectomy, the length of hospital stay, return to work, or the number of unplanned visits to the doctor. There were insufficient details to calculate the mean difference and 95% CI for the difference in pain scores at 9 to 24 hours (1 trial; 93 patients); and we did not identify clear evidence of an effect on patient knowledge (3 trials; 338 participants; SMD 0.19; 95% CI -0.02 to 0.41; very low quality evidence), patient satisfaction (2 trials; 305 patients; SMD 0.48; 95% CI -0.42 to 1.37; very low quality evidence), or patient anxiety (1 trial; 76 participants; SMD -0.37; 95% CI -0.82 to 0.09; very low quality evidence) between the two groups. A total of 173 participants undergoing elective laparoscopic cholecystectomy were randomised to electronic consent with repeat-back (patients repeating back the information provided) (92 participants) versus electronic consent without repeat-back (81 participants) in one trial of high risk of bias. The only outcome reported in this trial was patient knowledge. The effect on patient knowledge between the patient education with repeat-back versus patient education without repeat-back groups was imprecise and based on 1 trial of 173 participants; SMD 0.07; 95% CI -0.22 to 0.37; very low quality evidence). Due to the very low quality of the current evidence, the effects of formal patient education provided in addition to the standard information provided by doctors to patients compared with standard care remain uncertain. Further well-designed randomised clinical trials of low risk of bias are necessary.

We searched the medical literature in order to identify studies that provided information on the above question. The authors obtained information from randomised trials only since such types of trials provide the best information if conducted well. Two review authors independently identified the trials and collected the information. The information is current to March 2013. We found four trials including 431 patients undergoing elective laparoscopic cholecystectomy who received either formal patient education (215 participants) or standard care (216 participants). The choice of whether the patient received formal patient education or standard care was determined by a method similar to the toss of a coin in order to create comparable groups of patients. The patient education included providing information by just talking to the patient but in a more formal way or by using various method of presentation. All the trials were of high risk of bias (faults in study design that can result in erroneous conclusions). Only one trial including 212 participants reported deaths after surgery. There were no deaths in either group in this trial. There was no clear evidence of an effect on pain scores at 9 to 24 hours, patient knowledge, patient satisfaction, or patient anxiety associated with education. None of the trials reported surgical complications, quality of life, percentage of patients discharged as day-procedure laparoscopic cholecystectomy, length of hospital stay, return to work, or the number of unplanned visits to the doctor. A total of 173 participants undergoing elective laparoscopic cholecystectomy underwent patient education with repeat-back (patients repeating back the information provided) (92 participants) or patient education without repeat-back (81 participants) in one trial of high risk of bias. The only outcome reported in this trial was patient knowledge. The results we found for the effect onpatient knowledge between the patient education with repeat-back and patient education without repeat-back groups were uncertain and we could not exclude possible benefits of either education or control. Due to the very low quality of the current evidence, we are uncertain as to whether formal patient education provided in addition to the standard information provided by doctors has any benefit to patients. Further well-designed randomised clinical trials are necessary. The overall quality of the evidence was very low.

10.1002/14651858.CD009933.pub2

cochrane-simplification-train-604

cochrane-simplification-train-604

Over 900 children were recruited for the secretin trials. Twenty-five established standardised outcome measures were reported to assess core features of ASD, communication, behaviour, visuospatial skills, affect and adverse events. One standardised measure of global impression was also used. No more than four studies used any one outcome measure similarly. When duration from the start of the intervention to outcome assessment was known, outcomes were reported at between three and six weeks. Meta-analysis of data was not possible but there is now consistency of findings, with RCTs of the efficacy of secretin in autism not showing improvements for core features of ASD. There is no evidence that single or multiple dose intravenous secretin is effective and as such currently it should not be recommended or administered as a treatment for ASD. Further experimental assessment of secretin's effectiveness for ASD can only be justified if there is new high-quality and replicated scientific evidence that either finds that secretin has a role in neurotransmission in a way that could benefit all children with ASD or identifies important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing.

This review included 16 randomised trials with a placebo control group, with over 900 children involved. The review found no evidence that single or multiple dose intravenous secretin is effective in improving the main problems seen in ASD, namely a lack of social interaction and communication and restrictive, repetitive behaviours and routines. As such, currently it should not be recommended or administered as a treatment for ASD. Further experimental assessment of secretin's effectiveness for ASD can only be justified if there is convincing new evidence that finds that secretin can influence brain function in a way that could benefit children with ASD or a link is proven between secretin and the known cause of ASD for some or all children.

10.1002/14651858.CD003495.pub3

cochrane-simplification-train-605

cochrane-simplification-train-605

Forty-four trials were included. The antibiotics assessed were cefepime, ceftazidime, piperacillin-tazobactam, imipenem and meropenem. Adequate allocation concealment and generation were reported in about half of the trials and only two trials were double-blinded. The risk for all-cause mortality was significantly higher with cefepime compared to other beta-lactams (RR 1.39, 95% CI 1.04 to 1.86, 21 trials, 3471 participants), without heterogeneity and with higher RRs in trials at low risk for bias. There were no differences in secondary outcomes but for a non-significantly higher rate of bacterial superinfections with cefepime. Mortality was significantly lower with piperacillin-tazobactam compared to other antibiotics (RR 0.56, 95% CI 0.34 to 0.92, 8 trials, 1314 participants), without heterogeneity. Carbapenems resulted in similar all-cause mortality and a lower rate of clinical failure and antibiotic modifications as compared to other antibiotics, but a higher rate of diarrhea caused by Clostridium difficile. Current evidence supports the use of piperacillin-tazobactam in locations where antibiotic resistance profiles do not mandate empirical use of carbapenems. Carbapenems result in a higher rate of antibiotic-associated and Clostridium difficile-associated diarrhea. There is a high level of evidence that all-cause mortality is higher with cefepime compared to other beta-lactams and it should not be used as monotherapy for patients with febrile neutropenia.

We identified 44 studies comparing different antibiotics. Cefepime resulted in significantly higher mortality compared to all other antibiotics combined, at the end of patients' hospital stay or 30 days after entry into the study. The risk was 39% higher with cefepime, ranging from 4 to 86% increased risk. We did not find an explanation for this when looking into other outcomes reported in the primary studies. Piperacillin-tazobactam resulted in lower mortality than other antibiotics. The other antibiotics (ceftazidime, imipenem and meropenem) showed comparable efficacy, with a lower rate of antibiotic changes for imipenem or meropenem and a higher rate of severe diarrhea with these two antibiotics. We conclude that piperacillin-tazobactam might be the preferred antibiotic for the treatment of cancer patients with fever and neutropenia and that cefepime should not be used. Antibiotic selection (other than cefepime) depends on the individual patient and the type of bacteria prevalent in the specific hospital.

10.1002/14651858.CD005197.pub3

cochrane-simplification-train-606

cochrane-simplification-train-606

The review authors discovered no new trials in the new searches in June 2009, November 2011, or January 2016. Six trials with 587 participants provided data for the primary outcome. According to moderate quality evidence, the disability grade change after four weeks in the corticosteroid groups was not significantly different from that in the control groups, mean difference (MD) 0.36 less improvement (95% confidence intervals (CI) 0.16 more to 0.88 less improvement). In four trials of oral corticosteroids with 120 participants in total, there was very low quality evidence of less improvement after four weeks with corticosteroids than without corticosteroids, MD 0.82 disability grades less improvement (95% CI 0.17 to 1.47 grades less). In two trials with a combined total of 467 participants, there was moderate quality evidence of no significant difference of a disability grade more improvement after four weeks with intravenous corticosteroids (MD 0.17, 95% CI -0.06 to 0.39). According to moderate quality evidence, there was also no significant difference between the corticosteroid treated and control groups for improvement by one or more grades after four weeks (risk ratio (RR) 1.08, 95% CI 0.93 to 1.24) or for death or disability after one year (RR 1.51, 95% CI 0.91 to 2.5). We found high quality evidence that the occurrence of diabetes was more common (RR 2.21, 95% CI 1.19 to 4.12) and hypertension less common (RR 0.15, 95% CI 0.05 to 0.41) in the corticosteroid-treated participants. According to moderate quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome. According to very low quality evidence, oral corticosteroids delay recovery. Diabetes requiring insulin was more common and hypertension less common with corticosteroids based on high quality evidence.

There were eight clinical trials with altogether 653 participants. Only six trials with altogether 587 participants gave information about the primary outcome measure for this review, which was change in a seven-point disability scale. Financial support came from Baxter Bioscience for one trial, research councils for two trials, the National Institutes of Health for one trial, and unstated sources for the others. According to moderate quality evidence, when we pooled the results of the six trials with the necessary information there was no significant difference in change in disability grade after four weeks. Also according to moderate quality evidence, there was no difference in the percentage of participants who died or were left disabled after one year. We considered the evidence about disability unreliable because of marked variations between the trials. In four small trials of oral corticosteroids, with 120 participants, there was significantly less improvement after four weeks with corticosteroids than without corticosteroids but we considered the evidence quality very low. By contrast, according to moderate quality evidence, in two large trials of intravenous (injected into a vein) corticosteroids with a combined total of 467 participants, there was a slight improvement in disability after four weeks, but the results allowed for the possibility of no effect. Corticosteroids were not associated with a significant increase in harm except that diabetes was significantly more common than with placebo or supportive treatment alone. Although high blood pressure is a known harmful effect of corticosteroids, high blood pressure was unexpectedly much less common in the corticosteroid-treated participants. The lack of benefit from corticosteroids is not understood but might be because the drugs have a harmful effect on muscles which counteracts the benefit from reducing inflammation in nerves. The review is assessed as up to date to January 2016.

10.1002/14651858.CD001446.pub5

cochrane-simplification-train-607

cochrane-simplification-train-607

Ten randomised controlled trials were included. Limitations in the design, conduct and reporting of these trials resulted in unclear or high risk of bias assessments relating to allocation concealment, assessor blinding, incomplete and selective outcome reporting. Only limited pooling of the data was possible. Neuromuscular training was the basis of conservative treatment evaluated in four trials. Neuromuscular training compared with no training resulted in better ankle function scores at the end of four weeks training (Ankle Joint Functional Assessment Tool (AJFAT): mean difference (MD) 3.00, 95% CI 0.3 to 5.70; 1 trial, 19 participants; Foot and Ankle Disability Index (FADI) data: MD 8.83, 95% CI 4.46 to 13.20; 2 trials, 56 participants). The fourth trial (19 participants) found no significant difference in the functional outcome after six weeks training programme on a cyclo-ergometer with a bi-directional compared with a traditional uni-directional pedal. Longer-term follow-up data were not available for these four trials. Four studies compared surgical procedures for chronic ankle instability. One trial (40 participants) found more nerve injuries after tenodesis than anatomical reconstruction (risk ratio (RR) 5.50, 95% CI 1.39 to 21.71). One trial (99 participants) comparing dynamic versus static tenodesis excluded 17 patients allocated dynamic tenodesis because their tendons were too thin. The same trial found that dynamic tenodesis resulted in higher numbers of people with unsatisfactory function (RR 8.62, 95% CI 1.97 to 37.77, 82 participants). One trial comparing techniques of lateral ankle ligament reconstruction (60 participants) found that operating time was shorter using the reinsertion technique than the imbrication method (MD -9.00 minutes, 95% CI -13.48 to -4.52). Two trials (70 participants) compared functional mobilisation with immobilisation after surgery. These found early mobilisation led to earlier return to work (MD -2.00 weeks, 95% CI -3.06 to -0.94; 1 trial) and to sports (MD -3.00 weeks, 95% CI -4.49 to -1.51; 1 trial). Neuromuscular training alone appears effective in the short term but whether this advantage would persist on longer-term follow-up is not known. While there is insufficient evidence to support any one surgical intervention over another surgical intervention for chronic ankle instability, it is likely that there are limitations to the use of dynamic tenodesis. After surgical reconstruction, early functional rehabilitation appears to be superior to six weeks immobilisation in restoring early function.

This review includes 10 small and flawed trials that recruited a total of 388 people with chronic ankle instability. Limitations in the design, conduct and reporting of these trials meant that it was difficult to be certain that their results were valid. Three trials compared neuromuscular training with no training. These found a programme of neuromuscular training appears to provide short term improvement in functional stability. One trial testing the use of a special cycle pedal found that it did not make an important difference to function. However, none of these four trials followed-up patients after the end of treatment. Four trials compared different types of surgical intervention. There was insufficient evidence to strongly support any specific surgical procedure for treating chronic ankle instability. Two trials found that, after surgical reconstruction, early functional rehabilitation enabled patients to return to work and sports quicker than six weeks immobilisation.

10.1002/14651858.CD004124.pub3

cochrane-simplification-train-608

cochrane-simplification-train-608

Six randomised clinical trials with 581 participants with chronic hepatitis C were included. All trials had high risk of bias. The included trials compared amantadine versus other antiviral drugs: ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. Standard antiviral therapy (interferon-alpha, interferon-alpha plus ribavirin, or peg interferon alpha) was administered equally to the intervention and the control groups in five trials, depending on when the trial was conducted. Four trials compared amantadine versus ribavirin. There were no deaths or liver-related morbidity in the two intervention groups (0/216 (0%) versus 0/211 (0%); 4 trials; very low quality of the evidence). The lower estimated risk for (serious) adverse events leading to treatment discontinuation with amantadine was imprecise (RR 0.56, 95% CI 0.27 to 1.16; based on 10/216 (5%) versus 18/211 (9%) participants in 4 trials; very low quality of the evidence). There were more participants with failure of sustained virological response in the amantadine group than in the ribavirin group (206/216 (96%) versus 176/211 (84%); RR 1.14, 95% CI 1.07 to 1.22, 4 trials; low quality of the evidence). Amantadine versus ribavirin more often failed to achieve end-of follow-up biochemical response (41/46 (89%) versus 31/46 (67%); RR 1.31, 95% CI 1.05 to 1.63; 2 trials; very low quality of the evidence). One trial compared amantadine versus mycophenolate mofetil. There were no significant differences between the two treatment groups, except that amantadine was inferior to mycophenolate mofetil regarding the outcome failure to achieve end-of treatment virological response (low quality of evidence). One trial each compared amantadine versus interferon-alpha or interferon-gamma. Both comparisons showed no significant differences in the treatment outcomes (very low quality of the evidence). The observed effects could be due to real effects, systematic errors (bias), or random errors (play of chance). This possible influence on the observed effect by play of chance is due to the fact that trial sequential analyses could not confirm our findings. We were not able to perform meta-analyses on failure of histological improvement and quality of life due to lack of valid data in all trial comparisons. This systematic review has identified evidence of very low quality for the key outcomes of all-cause mortality or liver-related morbidity and adverse events in people with chronic hepatitis C when treated with amantadine compared with ribavirin, mycophenolate, interferon-alpha, or interferon-gamma. The timeframe for measuring the composite outcome was insufficient in the included trials. There was low quality evidence that amantadine led to more participants who failed to achieve sustained virological response compared with ribavirin. This observation may be real or caused by systematic errors (bias), but it does not seem to be caused by random error (play of chance). Due to the low quality of the evidence, we are unable to determine definitively whether amantadine is less effective than other antivirals in patients with chronic hepatitis C. As it appears less likely that future trials assessing amantadine or potentially other aminoadamantanes for patients with chronic hepatitis C would show strong benefits, it is probably better to focus on the assessments of other direct acting antiviral drugs. We found no evidence assessing other aminoadamantanes in randomised clinical trials in order to recommend or refute their use.

Only amantadine has been tested in randomised clinical trials including participants with chronic hepatitis C. The main goal of these trials was to investigate whether amantadine as a single therapy or amantadine in combination with other antiviral therapies, compared with placebo or no intervention (with or without antiviral therapy), could increase the proportion of patients with virus eradication from the blood. This review evaluates whether amantadine versus other antiviral drugs has any beneficial or harmful effect in patients with chronic hepatitis C. The trials compared amantadine with ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. The primary outcomes were the composite of all-cause mortality or liver-related morbidity and adverse events. This review includes six randomised clinical trials with a total of 581 patients. All the included trials were with high risk of bias. This review did not demonstrate any benefits or harms of amantadine on all-cause mortality or liver-related morbidity and on adverse events, but data were sparse. Compared with ribavirin, amantadine seemed to lead to more participants who fail to achieve sustained virological response (that is, undetectable hepatitis C virus RNA in serum by sensitivity testing six months after the end of treatment). This may be real or due to bias (systematic errors), but it does not seem to be due to play of chance (random errors), as trial sequential analysis confirmed the result. Compared with mycophenolate mofetil, amantadine seemed less effective in achieving end-of-treatment virological response. Compared with interferon-alpha or interferon-gamma, amantadine did not seem to offer benefits. Accordingly, the evidence from this review does not support the routine clinical use of amantadine. Therefore, it is probably better to examine the effects of other direct acting antivirals in the hepatitis C field than to conduct more randomised clinical trials on amantadine. We found no randomised clinical trials assessing other aminoadamantanes, for example rimantadine.

10.1002/14651858.CD011132.pub2

cochrane-simplification-train-609

cochrane-simplification-train-609

We added six studies to this update. Overall, we included 23 studies (2669 participants). For the majority of outcomes (two-thirds), we could not perform a meta-analysis since outcomes were not measured, or data were provided by one trial only. No study reported data on the number of participants with pain intensity reduction of at least 50% from baseline. Only one study reported data on the number of participants below 30/100 mm on the Visual Analogue Scale (VAS) in pain intensity (very low-quality evidence). Psychological interventions did not reduce pain intensity in the short-term interval (g 0.39, 95% CI -0.18 to 0.96, 2 studies, 104 participants, low-quality evidence), medium-term interval (g -0.02, 95% CI -0.24 to 0.20, 4 studies, 413 participants, moderate-quality evidence) or in the long-term interval (g 0.05, 95% CI -0.20 to 0.30, 2 studies, 200 participants, moderate-quality evidence). No study reported data on median time to re-medication or on number of participants re-medicated. Only two studies provided data on postoperative analgesic use in the short-term interval, showing that psychological interventions did not reduce the use of analgesic medication (g 1.18, 95% CI -2.03 to 4.39, 2 studies, 104 participants, low-quality evidence). Studies revealed that psychological interventions reduced mental distress in the medium-term (g 0.37, 95% CI 0.13 to 0.60, 13 studies, 1388 participants, moderate-quality evidence) and likewise in the long-term interval (g 0.32, 95% CI 0.10 to 0.53, 14 studies, 1586 participants, moderate-quality evidence). Psychological interventions did not improve mobility in the medium-term interval (g 0.23, 95% CI -0.22 to 0.67, 3 studies, 444 participants, low-quality evidence), nor in the long-term interval (g 0.09, 95% CI -0.10 to 0.28, 4 studies, 458 participants, moderate-quality evidence). Only two studies reported data on time to extubation, indicating that psychological interventions reduced the time to extubation (g 0.56, 95% CI 0.08 to 1.03, 2 studies, 154 participants, low-quality evidence). Overall, the very low to moderate quality of the body of evidence on the efficacy of psychological interventions for acute pain after open heart surgery cannot be regarded as sufficient to draw robust conclusions. Most 'Risk of bias' assessments were low or unclear. We judged selection bias (random sequence generation) and attrition bias to be mostly low risk for included studies. However, we judged the risk of selection bias (allocation concealment), performance bias, detection bias and reporting bias to be mostly unclear. In line with the conclusions of our previous review, there is a lack of evidence to support or refute psychological interventions in order to reduce postoperative pain in participants undergoing open heart surgery. We found moderate-quality evidence that psychological interventions reduced mental distress in participants undergoing open heart surgery. Given the small numbers of studies, it is not possible to draw robust conclusions on the efficacy of psychological interventions on outcomes such as analgesic use, mobility, and time to extubation respectively on adverse events or harms of psychological interventions.

We found 23 studies, including a total of 2669 participants, which reported effects of psychological treatment compared to a control group without psychological treatment on pain intensity, use of pain medication, mental distress, mobility, or time to extubation after surgery. 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. We do not know if psychological treatment reduces pain intensity, enhances mobility, or decreases intubation time after open heart surgery. This is because there were not enough data to answer some parts of our review question, because there were problems with the design of some studies, or because results were conflicting. We only found very low to moderate-quality evidence for these outcomes. We found moderate-quality evidence that psychological treatment could reduce mental distress. This means that we are moderately certain about the results because there were psychological treatments that clearly reduced distress whereas others did not. The evidence in our review is current to February 2017.

10.1002/14651858.CD009984.pub3

cochrane-simplification-train-610

cochrane-simplification-train-610

A total of 185 studies were included. The average sodium intake was reduced from 201 mmol/day (corresponding to high usual level) to 66 mmol/day (corresponding to the recommended level). The effect of sodium reduction on blood pressure (BP) was as follows: white people with normotension: SBP: mean difference (MD) -1.09 mmHg (95% confidence interval (CI): -1.63 to -0.56; P = 0.0001); 89 studies, 8569 participants; DBP: + 0.03 mmHg (MD 95% CI: -0.37 to 0.43; P = 0.89); 90 studies, 8833 participants. High-quality evidence. Black people with normotension: SBP: MD -4.02 mmHg (95% CI:-7.37 to -0.68; P = 0.002); seven studies, 506 participants; DBP: MD -2.01 mmHg (95% CI:-4.37 to 0.35; P = 0.09); seven studies, 506 participants. Moderate-quality evidence. Asian people with normotension: SBP: MD -0.72 mmHg (95% CI: -3.86 to 2.41; P = 0.65); DBP: MD -1.63 mmHg (95% CI:-3.35 to 0.08; P =0.06); three studies, 393 participants. Moderate-quality evidence. White people with hypertension: SBP: MD -5.51 mmHg (95% CI: -6.45 to -4.57; P < 0.00001); 84 studies, 5925 participants; DBP: MD -2.88 mmHg (95% CI: -3.44 to -2.32; P < 0.00001); 85 studies, 6001 participants. High-quality evidence. Black people with hypertension: SBP MD -6.64 mmHg (95% CI:-9.00 to -4.27; P = 0.00001); eight studies, 619 participants; DBP -2.91 mmHg (95% CI:-4.52, -1.30; P = 0.0004); eight studies, 619 participants. Moderate-quality evidence. Asian people with hypertension: SBP: MD -7.75 mmHg (95% CI:-11,44 to -4.07; P < 0.0001) nine studies, 501 participants; DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15; P = 0.0006). Moderate-quality evidence. In plasma or serum, there was a significant increase in renin (P < 0.00001), aldosterone (P < 0.00001), noradrenaline (P < 0.00001), adrenaline (P < 0.03), cholesterol (P < 0.0005) and triglyceride (P < 0.0006) with low sodium intake as compared with high sodium intake. All effects were stable in 125 study populations with a sodium intake below 250 mmol/day and a sodium reduction intervention of at least one week. Sodium reduction from an average high usual sodium intake level (201 mmol/day) to an average level of 66 mmol/day, which is below the recommended upper level of 100 mmol/day (5.8 g salt), resulted in a decrease in SBP/DBP of 1/0 mmHg in white participants with normotension and a decrease in SBP/DBP of 5.5/2.9 mmHg in white participants with hypertension. A few studies showed that these effects in black and Asian populations were greater. The effects on hormones and lipids were similar in people with normotension and hypertension. Renin increased 1.60 ng/mL/hour (55%); aldosterone increased 97.81 pg/mL (127%); adrenalin increased 7.55 pg/mL (14%); noradrenalin increased 63.56 pg/mL: (27%); cholesterol increased 5.59 mg/dL (2.9%); triglyceride increased 7.04 mg/dL (6.3%).

One hundred and eighty-five intervention studies of 12,210 individuals lasting four to 1100 days were included, which evaluated at least one of the effect measures. Participants were healthy or had elevated blood pressure. Longitudinal studies have shown that the effect of reduced salt intake on BP is stable after at maximum seven days and population studies have shown that very few people eat more than 14.5 g salt per day. Therefore, we also perfomed subgroup sub-analyses of 125 studies with a duration of at least seven days and a salt intake of maximum 14.5 g. Forty-four studies did not mention support. One hundred and twenty-two studies were supported by public foundations. Twelve studies were supported by the pharmaceutical industry and one study by an electronic company. Six studies were supported by food industry organisations. The mean dietary sodium intake was reduced from 11.5 g per day to 3.8 g per day. The reduction in SBP/DBP in people with normotension was about 1/0 mmHg, and in people with hypertension about 5.5/2.9 mmHg. In contrast, the effect on hormones and lipids were similar in people with normotension and hypertension. Renin increased 1.60 ng/mL/hour (55%); aldosterone increased 97.81 pg/mL (127%); adrenalin increased 7.55 pg/mL (14%); noradrenalin increased 63.56 pg/mL (27%); cholesterol increased 5.59 mg/dL (2.9%); triglyceride increased 7.04 mg/dL (6.3%). Only randomised controlled trials were included and the basic grade of evidence was therefore considered to be high, although the grade of evidence was downgraded in some of the smaller analyses. In general, the description of the randomisation procedure was insufficient, introducing a bias which could exaggerate the effects, but many of the studies were published in a period where it was not customary to report such descriptions. The majority of studies were open, but the outcomes of these did not differ from the outcomes of the double-blind studies. Almost all individual studies of participants with normal blood pressure (BP) show no significant effect of sodium reduction on BP, whereas a large number of studies in people with hypertension did show significant effect of sodium reduction on BP. Thus, there was a high grade of consistency between the outcomes of the individual studies and the outcomes of the meta-analyses. Sensitivity analyses of studies lasting at least one week (the time of maximal efficacy) confirmed the primary analyses. Finally, the impact of commercial interests on the outcomes was negligible.

10.1002/14651858.CD004022.pub4

cochrane-simplification-train-611

cochrane-simplification-train-611

1162 people from 13 studies were randomised to trifluoperazine or placebo. For global improvement, small short-term studies favoured trifluoperazine (n=95, 3 RCTs, RR 0.62 CI 0.49 to 0.78 NNT 3 CI 2 to 4). Loss to follow up was about 12% in both groups (n=280, 7 RCTs, RR 0.99 CI 0.62 to 1.57) and more people allocated trifluoperazine used antiparkinson drugs to alleviate movements disorders compared with placebo (n=195, 4 RCTs, RR 5.06 CI 2.49 to 10.27, NNH 4 CI 2 to 9). 2230 people from 49 studies were randomised to trifluoperazine or another older generation antipsychotic. Trifluoperazine was not clearly different in terms of 'no substantial improvement' (n=1016, 27 RCTs, RR 1.06 CI 0.98 to 1.14) or leaving the study early (n=930, 22 RCTs, RR 1.15 CI 0.83 to 1.58). Almost identical numbers of people reported at least one adverse event (˜60%) in each group (n=585, 14 RCTs, RR 0.99 CI 0.87 to 1.13), although trifluoperazine was more likely to cause extrapyramidal adverse effects overall when compared to low potency antipsychotics such as chlorpromazine (n=130, 3 RCTs, RR 1.66 CI 1.03 to 2.67, NNH 6 CI 3 to 121). One small study (n=38) found no clear differences between trifluoperazine and the atypical drug, sulpiride. Although there are shortcomings and gaps in the data, there appears to be enough consistency over different outcomes and periods to confirm that trifluoperazine is an antipsychotic of similar efficacy to other commonly used neuroleptics for people with schizophrenia. Its adverse events profile is similar to that of other drugs. It has been claimed that trifluoperazine is effective at low doses for patients with schizophrenia but this does not appear to be based on good quality trial based evidence.

Thousands of people with schizophrenia have participated in studies and therefore we are reasonably sure that it is a potent antipsychotic drug and as good as similar older drugs. Most people taking it do experience adverse effects, but this also applies to other older drugs. Not enough comparisons with newer generations of drugs have been undertaken to be sure of how trifluoperazine compares to them.

10.1002/14651858.CD003545.pub2

cochrane-simplification-train-612

cochrane-simplification-train-612

We included 16 trials involving 4759 participants. Analysis did not show a significant overall difference for subjective health status (standardised mean difference (SMD) -0.03, 95% confidence interval (CI) -0.11 to 0.04, P = 0.34) or extended activities of daily living (SMD 0.04, 95% CI -0.03 to 0.11, P = 0.22). There was no overall significant effect for the outcome of carer subjective health status (SMD 0.04, 95% CI -0.05 to 0.14, P = 0.37). Patients with mild to moderate disability (Barthel 15 to 19) had a significant reduction in dependence (odds ratio (OR) 0.62, 95% CI 0.44 to 0.87, P = 0.006). This would equate to 10 fewer dependent patients (95% CI 17 fewer to 4 fewer) for every 100 patients seen by the stroke liaison worker. Similar results were seen for the outcome of death or dependence for the subgroup with Barthel 15 to 19 (OR 0.55, 95% CI 0.38 to 0.81, P = 0.002). This risk difference equates to 11 fewer dead or dependent patients (95% CI 17 fewer to 4 fewer) for every 100 patients seen by the stroke liaison worker. There is no evidence for the effectiveness of this multifaceted intervention in improving outcomes for all groups of patients or carers. Patients with mild to moderate disability benefit from a reduction in death and disability. Patients and carers do report improved satisfaction with some aspects of service provision.

In this review, we evaluated 16 studies (involving 4759 participants) of healthcare workers or volunteers (a 'stroke liaison worker') providing education and social support (including counselling) and liaison with services. Overall, there do not appear to be any significant benefits for patients in terms of their perceived health, mood, activities or participation. Patients appeared to be more satisfied that someone had really listened to them, and carers appeared to be more satisfied with aspects of the care provided. It also appears that patients with mild to moderate disability may benefit from a reduction in disability and death as a result of the input from the stroke liaison worker. The reason for this is not yet clear and further research is required.

10.1002/14651858.CD005066.pub2

cochrane-simplification-train-613

cochrane-simplification-train-613

Four trials are now included in the review, with 753 participants. They were different in many ways including the intervention, duration, outcomes and control group so pooling of data was not possible. Overall, the quality of the evidence was rated as very low. Re-analysis of outcomes using data from the published studies found no significant effects of respite care compared to no respite care on any caregiver variable. When respite care was compared to polarity therapy a significant effect was found in favour of polarity therapy for caregiver perceived stress (n = 38, MD 5.80, 95% CI 1.43 to 10.17), but not for other measures of psychological health and other caregiver outcomes. No studies reported evaluable data on outcomes related to the people with dementia. Current evidence does not demonstrate any benefits or adverse effects from the use of respite care for people with dementia or their caregivers. These results should be treated with caution, however, as they may reflect the lack of high quality research in this area rather than an actual lack of benefit. Given the frequency with which respite care is advocated and provided, well-designed trials are needed in this area.

Four studies with 753 participants were included in this review. Three compared respite care to no respite care and one compared respite care to polarity therapy, a type of touch therapy. All studies included people with dementia and their caregivers. We were not able to pool the results of the studies as there were so few studies and they measured the outcomes in different ways. All the studies reported outcomes for the caregiver, but only one reported outcomes for the person with dementia. The three studies that compared respite care to no respite care found no evidence of any benefit of respite care for people with dementia or for their caregivers for any outcome, including rates of institutionalisation and caregiver burden. The study that compared respite care to polarity therapy found that polarity therapy decreased caregiver perceived stress but that there was no difference between polarity therapy and respite care for other measures of psychological health and other caregiver outcomes. A host of methodological problems were identified in the available trials. One study did not report data that could be analysed, the remaining three studies were very small and had a very short duration. Further methodologically sound research is needed before any firm conclusions can be drawn.

10.1002/14651858.CD004396.pub3

cochrane-simplification-train-614

cochrane-simplification-train-614

We found no RCTs comparing ICS and LABA combination with either placebo or usual care. We included one RCT that compared combined ICS and LABA with high-dose ICS in 40 adults with non-CF bronchiectasis without co-existent asthma. All participants received three months of high-dose budesonide dipropionate treatment (1600 micrograms). After three months, participants were randomly assigned to receive either high-dose budesonide dipropionate (1600 micrograms per day) or a combination of budesonide with formoterol (640 micrograms of budesonide and 18 micrograms of formoterol) for three months. The study was not blinded. We assessed it to be an RCT with overall high risk of bias. Data analysed in this review showed that those who received combined ICS-LABA (in stable state) had a significantly better transition dyspnoea index (mean difference (MD) 1.29, 95% confidence interval (CI) 0.40 to 2.18) and cough-free days (MD 12.30, 95% CI 2.38 to 22.2) compared with those receiving ICS after three months of treatment. No significant difference was noted between groups in quality of life (MD -4.57, 95% CI -12.38 to 3.24), number of hospitalisations (odds ratio (OR) 0.26, 95% CI 0.02 to 2.79) or lung function (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)). Investigators reported 37 adverse events in the ICS group versus 12 events in the ICS-LABA group but did not mention the number of individuals experiencing adverse events. Hence differences between groups were not included in the analyses. We assessed the overall evidence to be low quality. In adults with bronchiectasis without co-existent asthma, during stable state, a small single trial with a high risk of bias suggests that combined ICS-LABA may improve dyspnoea and increase cough-free days in comparison with high-dose ICS. No data are provided for or against, the use of combined ICS-LABA in adults with bronchiectasis during an acute exacerbation, or in children with bronchiectasis in a stable or acute state. The absence of high quality evidence means that decisions to use or discontinue combined ICS-LABA in people with bronchiectasis may need to take account of the presence or absence of co-existing airway hyper-responsiveness and consideration of adverse events associated with combined ICS-LABA.

Key results: A single study showed some benefit of the inhaled ICS-LABA combination over high-dose ICS in terms of indices of clinical stability such as dyspnoea (shortness of breath), cough-free days and number of exacerbations but failed to show significant improvement in lung function or microbiology. No data are available on children with bronchiectasis or adults with bronchiectasis during an exacerbation phase. Until further evidence becomes available, we recommend that use of combined ICS-LABA should be individualised according to the presence or likelihood of co-existing asthma features and risks of medications. Quality of the evidence: This review is based on a single study, hence the quality of evidence is substantially limited. Bottom line: The decision to use combined ICS-LABA in bronchiectasis must be made for individual patients on the basis of the presence or absence of bronchial hyperreactivity, until further randomised controlled trials are conducted to answer this important question.

10.1002/14651858.CD010327.pub2

cochrane-simplification-train-615

cochrane-simplification-train-615

The previous version of this review included one randomised controlled trial involving 327 patients and 159 healthcare providers at baseline. It compared an email to physicians containing patient-specific osteoporosis risk information and guidelines for evaluation and treatment versus usual care (no email). This study was at high risk of bias for the allocation concealment and blinding domains. The email reminder changed health professional actions significantly, with professionals more likely to provide guideline-recommended osteoporosis treatment (bone density measurement or osteoporosis medication, or both) when compared with usual care. The evidence for its impact on patient behaviours or actions was inconclusive. One measure found that the electronic medical reminder message impacted patient behaviour positively (patients had a higher calcium intake), and two found no difference between the two groups. The study did not assess health service outcomes or harms. No new studies were identified for this update. Only one study was identified for inclusion, providing insufficient evidence for guiding clinical practice in regard to the use of email for clinical communication between healthcare professionals. Future research should aim to utilise high-quality study designs that use the most recent developments in information technology, with consideration of the complexity of email as an intervention.

In this review, we found only one study that focused on the effects of healthcare professionals using email to communicate with each other. This study included 327 patients and 159 healthcare providers, and compared an email reminder for physicians with usual care. It found that healthcare professionals who received an email reminder were more likely to provide guideline-recommended osteoporosis treatment than those who did not, and this may or may not have improved patient care. We were unable to properly assess its impact on patient behaviours or actions as the results were mixed. The study did not measure how email affects health services, or whether email can cause harms. This evidence is current to August 2013. As there is a lack of evidence for the effects of healthcare professionals using email to communicate with each other, high-quality research is needed to evaluate the use of email for this purpose. Future research should look at the costs of using email and take into account ongoing changes in technology.

10.1002/14651858.CD007979.pub3

cochrane-simplification-train-616

cochrane-simplification-train-616

This updated review included a total of 22 trials which randomised 76,864 people with CHD to an education intervention or a 'no education' comparator. Nine new trials (8215 people) were included for this update. We judged most included studies as low risk of bias across most domains. Educational 'dose' ranged from one 40 minute face-to-face session plus a 15 minute follow-up call, to a four-week residential stay with 11 months of follow-up sessions. Control groups received usual medical care, typically consisting of referral to an outpatient cardiologist, primary care physician, or both. We found no difference in effect of education-based interventions on total mortality (13 studies, 10,075 participants; 189/5187 (3.6%) versus 222/4888 (4.6%); random effects risk ratio (RR) 0.80, 95% CI 0.60 to 1.05; moderate quality evidence). Individual causes of mortality were reported rarely, and we were unable to report separate results for cardiovascular mortality or non-cardiovascular mortality. There was no evidence of a difference in effect of education-based interventions on fatal and/or non fatal myocardial infarction (MI) (2 studies, 209 participants; 7/107 (6.5%) versus 12/102 (11.8%); random effects RR 0.63, 95% CI 0.26 to 1.48; very low quality of evidence). However, there was some evidence of a reduction with education in fatal and/or non-fatal cardiovascular events (2 studies, 310 studies; 21/152 (13.8%) versus 61/158 (38.6%); random effects RR 0.36, 95% CI 0.23 to 0.56; low quality evidence). There was no evidence of a difference in effect of education on the rate of total revascularisations (3 studies, 456 participants; 5/228 (2.2%) versus 8/228 (3.5%); random effects RR 0.58, 95% CI 0.19 to 1.71; very low quality evidence) or hospitalisations (5 studies, 14,849 participants; 656/10048 (6.5%) versus 381/4801 (7.9%); random effects RR 0.93, 95% CI 0.71 to 1.21; very low quality evidence). There was no evidence of a difference between groups for all cause withdrawal (17 studies, 10,972 participants; 525/5632 (9.3%) versus 493/5340 (9.2%); random effects RR 1.04, 95% CI 0.88 to 1.22; low quality evidence). Although some health-related quality of life (HRQoL) domain scores were higher with education, there was no consistent evidence of superiority across all domains. We found no reduction in total mortality, in people who received education delivered as part of cardiac rehabilitation, compared to people in control groups (moderate quality evidence). There were no improvements in fatal or non fatal MI, total revascularisations or hospitalisations, with education. There was some evidence of a reduction in fatal and/or non-fatal cardiovascular events with education, but this was based on only two studies. There was also some evidence to suggest that education-based interventions may improve HRQoL. Our findings are supportive of current national and international clinical guidelines that cardiac rehabilitation for people with CHD should be comprehensive and include educational interventions together with exercise and psychological therapy. Further definitive research into education interventions for people with CHD is needed.

We searched the scientific literature for randomised controlled trials (experiments that randomly allocate participants to one of two or more treatment groups) looking at the effectiveness of education-based treatments compared with no education in people of all ages with CHD. We included nine new trials which involved 8215 people with coronary heart disease that compared patient education with no education. We included a total of 22 trials that studied 76,864 people with heart disease, most of whom had survived heart attack, and had undergone heart bypass surgery or angioplasty (a procedure which opens blocked vessels that supply blood to heart muscle). Sixteen studies reported sources of funding; six did not report funding sources. One study was funded by an industrial sponsor, four by health insurance companies and 11 by government or public sources. Findings of this update are similar to the last review version (2011). Patient education, as part of a cardiac rehabilitation programme, does not contribute to fewer deaths, further heart attacks, heart by-pass or angioplasty, or admission to hospital for heart-related problems. There is some evidence of fewer other heart-related events and improvements in health-related quality of life with education-based interventions. Individual causes of death were not reported, so we were unable to determine how many people in the studies died from heart-related causes or other causes of death. Although there is insufficient information at present to fully understand the benefits or harms of patient education for people with heart disease, our findings broadly support current guidelines that people with heart disease should receive comprehensive rehabilitation that includes education. Further research is needed to evaluate the most clinically and cost-effective ways of providing education for people with heart disease. Overall, evidence was assessed as very low to moderate quality.

10.1002/14651858.CD008895.pub3

cochrane-simplification-train-617

cochrane-simplification-train-617

Two RCTs were included in the review (106 participants). Neither study reported live birth rate. Vitrification was associated with an increased clinical pregnancy rate compared to slow freezing (RR 3.86, 95% CI 1.63 to 9.11, P = 0.002, 2 RCTs, 106 women, I2 = 8%, moderate quality evidence). The effect of vitrification compared to slow freezing on ongoing pregnancy rates was only reported in one small study, with inconclusive findings (RR 6.07, 95% CI 0.86 to 43.04, P = 0.07, one RCT, 28 women, low quality evidence). No data were reported on adverse effects, nor were any other outcomes reported in the included trials. The evidence was limited by imprecision. We assessed the included studies as at low to unclear risk of bias as the methods were not well described. Oocyte vitrification compared to slow freezing probably increases clinical pregnancy rates in women undergoing assisted reproduction. However, the total number of women and pregnancies were low and the imprecision is high which limits applicability. The effect on ongoing pregnancy is uncertain as data were sparse. No data were available on live births or adverse effects.

Characteristics of the included studies. The search of the medical literature was done in March 2014. We found two randomised controlled trials (RCTs) with 106 participants comparing oocyte vitrification versus slow freezing. Neither study reported live births or adverse events as outcomes. One reported ongoing pregnancy and both reported clinical pregnancy. Key results. The clinical pregnancy rate was higher in the oocyte vitrification group than in the slow freezing group. The effect of vitrification compared to slow freezing on ongoing pregnancy rates was only reported in the one small study, with inconclusive findings. Quality of the evidence. The quality of the evidence was rated as moderate for clinical pregnancy and low for ongoing pregnancy. The evidence was limited by imprecision.

10.1002/14651858.CD010047.pub2

cochrane-simplification-train-618

cochrane-simplification-train-618

We found 51 studies (52 papers), mostly from high-income countries and mostly describing women's perspectives. We assessed our level of confidence in each finding using the GRADE-CERQual approach. We had high or moderate confidence in many of our findings. Where we only had low or very low confidence in a finding, we have indicated this. Labour companions supported women in four different ways. Companions gave informational support by providing information about childbirth, bridging communication gaps between health workers and women, and facilitating non-pharmacological pain relief. Companions were advocates, which means they spoke up in support of the woman. Companions provided practical support, including encouraging women to move around, providing massage, and holding her hand. Finally, companions gave emotional support, using praise and reassurance to help women feel in control and confident, and providing a continuous physical presence. Women who wanted a companion present during labour and childbirth needed this person to be compassionate and trustworthy. Companionship helped women to have a positive birth experience. Women without a companion could perceive this as a negative birth experience. Women had mixed perspectives about wanting to have a male partner present (low confidence). Generally, men who were labour companions felt that their presence made a positive impact on both themselves (low confidence) and on the relationship with their partner and baby (low confidence), although some felt anxious witnessing labour pain (low confidence). Some male partners felt that they were not well integrated into the care team or decision-making. Doulas often met with women before birth to build rapport and manage expectations. Women could develop close bonds with their doulas (low confidence). Foreign-born women in high-income settings may appreciate support from community-based doulas to receive culturally-competent care (low confidence). Factors affecting implementation included health workers and women not recognising the benefits of companionship, lack of space and privacy, and fearing increased risk of infection (low confidence). Changing policies to allow companionship and addressing gaps between policy and practice were thought to be important (low confidence). Some providers were resistant to or not well trained on how to use companions, and this could lead to conflict. Lay companions were often not integrated into antenatal care, which may cause frustration (low confidence). We compared our findings from this synthesis to the companionship programmes/approaches assessed in Bohren’s review of effectiveness. We found that most of these programmes did not appear to address these key features of labour companionship. We have high or moderate confidence in the evidence contributing to several of these review findings. Further research, especially in low- and middle-income settings and with different cadres of healthcare providers, could strengthen the evidence for low- or very low-confidence findings. Ahead of implementation of labour companionship, researchers and programmers should consider factors that may affect implementation, including training content and timing for providers, women and companions; physical structure of the labour ward; specifying clear roles for companions and providers; integration of companions; and measuring the impact of companionship on women’s experiences of care. Implementation research or studies conducted on labour companionship should include a qualitative component to evaluate the process and context of implementation, in order to better interpret results and share findings across contexts.

We found 51 studies, mostly from high-income countries and mostly describing women's perspectives. We assessed our level of confidence in each finding using the GRADE-CERQual approach. We had high or moderate confidence in many of our findings. Where we only had low or very low confidence in a finding, we have indicated this. Labour companions supported women in four different ways. Companions gave informational support by providing information about childbirth, bridging communication gaps between health workers and women, and facilitating non-pharmacological pain relief. Companions were advocates, which means they spoke up in support of the woman. Companions provided practical support, including encouraging women to move around, providing massage, and holding her hand. Finally, companions gave emotional support, using praise and reassurance to help women feel in control and confident, and providing a continuous physical presence. Women who wanted a companion present during labour and childbirth needed this person to be compassionate and trustworthy. Companionship helped women to have a positive birth experience. Women without a companion could perceive this as a negative birth experience. Women had mixed perspectives about wanting to have a male partner present (low confidence). Generally, men who were labour companions felt that their presence made a positive impact on both themselves (low confidence) and on the relationship with their partner and baby (low confidence), although some felt anxious witnessing labour pain (low confidence). Some male partners felt that they were not well integrated into the care team or decision-making. Doulas often met with women before birth to build rapport and manage expectations. Women could develop close bonds with their doulas (low confidence). Foreign-born women in high-income settings may appreciate support from community-based doulas to receive culturally-competent care (low confidence). Factors affecting implementation included health workers and women not recognising the benefits of companionship, lack of space and privacy, and fearing increased risk of infection (low confidence). Changing policies to allow companionship and addressing gaps between policy and practice were thought to be important (low confidence). Some providers were resistant to or not well trained on how to use companions, and this could lead to conflict. Lay companions were often not integrated into antenatal care, which may cause frustration (low confidence). We compared our findings from this synthesis to the companionship programmes/approaches assessed in Bohren’s review of effectiveness. We found that most of these programmes did not appear to address these key features of labour companionship. We searched for studies published before 9 September 2018.

10.1002/14651858.CD012449.pub2

cochrane-simplification-train-619

cochrane-simplification-train-619

Five studies were included, of which four with a total of 282 participants provided data. No meta-analysis was possible due to heterogeneity of comparisons within included studies as well as inadequate reporting of data. All studies were considered to be at either moderate or high risk of bias. The results of this systematic review indicate that there is no clinical or statistical difference between systematic desensitisation and any of the control interventions (either waiting list control, systematic desensitisation combined with group therapy or in vitro (with women under instruction by the therapist) desensitisation) for the treatment of vaginismus. The drop-out rates were higher in the waiting list groups. A clinically relevant effect of systematic desensitisation when compared with any of the control interventions cannot be ruled out. None of the included trials compared other behaviour therapies (e.g. cognitive behaviour therapy, sex therapy) to pharmacological interventions. The findings are limited by the evidence available and as such conclusions about the efficacy of interventions for the treatment of vaginismus should be drawn cautiously.

This review found five poor to moderate quality studies, of which four with a total of 282 women provided data. There was not enough evidence to say if systematic desensitisation worked better than another treatment. Further studies including larger numbers of women are needed to show if systematic desensitisation if effective for the treatment of women with vaginismus.

10.1002/14651858.CD001760.pub2

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cochrane-simplification-train-620

The review included 16 RCTs. Fourteen RCTs (1745 women) were included in the meta-analysis. Only three studies reported live birth per couple. No evidence of a statistically significant difference was noted between IUI and FSP in live birth (OR 0.94, 95% CI 0.59 to 1.49, three RCTs, 633 women, I2 = 0%, low-quality evidence) or clinical pregnancy (OR 0.75, 95% CI 0.49 to 1.12, 14 RCTs, 1745 women, I2 = 52%, low-quality evidence). These findings suggest that for a couple with a 13% chance of live birth using FSP, the chance when using IUI will be between 8% and 19%; and that for a couple with a 19% chance of pregnancy using FSP, the chance of pregnancy when using IUI will be between 10% and 20%. Nor was evidence found of a statistically significant difference between IUI and FSP in per-pregnancy of multiple pregnancy (OR 0.96, 95% CI 0.44 to 2.07, eight RCTs, 197 women, I2 = 0%, low-quality evidence), miscarriage (OR 1.23, 95% CI 0.60 to 2.53, seven RCTs, 199 women, I2 = 0%, low-quality evidence) or ectopic pregnancy (OR 1.71, 95% CI 0.42 to 6.88, four RCTs, 111 women, I2 = 0%, very low quality evidence). Substantial heterogeneity was noted for the outcome of clinical pregnancy (I2 = 54%), for which no clear explanation was provided. Currently no clear evidence suggests any difference between IUI and FSP with respect to their effectiveness and safety for treating couples with non-tubal subfertility. However, a high level of uncertainty is evident in the findings, and additional research may be useful.

The review included 16 randomised controlled trials (more than 1800 women) that compared these procedures for treating couples with non-tubal subfertility. Only three trials reported live birth. The evidence is current to September 2013. No trial reported its funding source, but one reported no conflict of interest, and one stated that it had received no commercial funding. No clear evidence suggests any difference between IUI and FSP with respect to their effectiveness and safety in the treatment of couples with non-tubal subfertility. However, a high level of uncertainty due to lack of data is evident in the findings. The overall quality of the evidence was rated as low for most outcomes, largely because of the small quantity of available data.

10.1002/14651858.CD001502.pub4

cochrane-simplification-train-621

cochrane-simplification-train-621

We identified two trials comparing pancreatic resection versus other treatments for patients with locally advanced pancreatic cancer. Ninety eight patients were randomised to pancreatic resection (n = 47) or palliative treatment (n = 51) in the two trials included in this review. Both trials were at high risk of bias. Both trials included patients who had locally advanced pancreatic cancer which involved the serosa anteriorly or retroperitoneum posteriorly or involved the blood vessels. Such pancreatic cancers would be considered generally unresectable. One trial included patients with pancreatic cancer in different locations of the pancreas including the head, neck and body (n = 42). The patients allocated to the pancreatic resection group underwent partial pancreatic resection (pancreatoduodenectomy with lymph node clearance or distal pancreatic resection with lymph node clearance) in this trial; the control group received palliative treatment with chemoradiotherapy. In the other trial, only patients with cancer in the head or neck of the pancreas were included (n = 56). The patients allocated to the pancreatic resection group underwent en bloc total pancreatectomy with splenectomy and vascular reconstruction in this trial; the control group underwent palliative bypass surgery with chemoimmunotherapy. The pancreatic resection group had lower mortality than the palliative treatment group (HR 0.38; 95% CI 0.25 to 0.58, very low quality evidence). Both trials followed the survivors up to at least five years. There were no survivors at two years in the palliative treatment group in either trial. Approximately 40% of the patients who underwent pancreatic resection were alive in the pancreatic resection group at the end of three years. This difference in survival was statistically significant (RR 22.68; 95% CI 3.15 to 163.22). The difference persisted at five years of follow-up (RR 8.65; 95% CI 1.12 to 66.89). Neither trial reported severe adverse events but it is likely that a significant proportion of patients suffered from severe adverse events in both groups. The overall peri-operative mortality in the resection group in the two trials was 2.5%. None of the trials reported quality of life. The estimated difference in the length of total hospital stay (which included all admissions of the patient related to the treatment) between the two groups was imprecise (MD -23.00 days; 95% CI -59.05 to 13.05, very low quality evidence). The total treatment costs were significantly lower in the pancreatic resection group than the palliative treatment group (MD -10.70 thousand USD; 95% CI -14.11 to -7.29, very low quality evidence). There is very low quality evidence that pancreatic resection increases survival and decreases costs compared to palliative treatments for selected patients with locally advanced pancreatic cancer and venous involvement. When sufficient expertise is available, pancreatic resection could be considered for selected patients with locally advanced pancreatic cancer who are willing to accept the potentially increased morbidity associated with the procedure. Further randomised controlled trials are necessary to increase confidence in the estimate of effect and to assess the quality of life of patients and the cost-effectiveness of pancreatic resection versus palliative treatment for locally advanced pancreatic cancer.

Overall, the trials were at high risk of bias (that is, there is a potential to arrive at wrong conclusions). This was because it was not clear how the randomisation was performed, whether the people assessing the outcomes were aware of the group to which the participants belonged, and whether all participants were included in the analysis. The overall quality of evidence was very low as the trials were at high risk of bias and there were few trials to assess whether only studies with negative results were published. There is very low quality evidence that surgical resection increases survival and decreases costs compared to palliative treatments for patients with locally advanced pancreatic cancer with involvement of veins. In selected patients pancreatic resection could be considered for patients with locally advanced pancreatic cancer who are willing to accept the potentially increased complications associated with the surgical procedure and when sufficient expertise is available. Further randomised controlled trials are necessary to obtain more precise results and to assess the quality of life of patients and the value for money of surgical removal versus other treatments for locally advanced pancreatic cancer.

10.1002/14651858.CD010244.pub2

cochrane-simplification-train-622

cochrane-simplification-train-622

One study was identified that compared protein containing synthetic surfactants (PCSS) to protein free synthetic surfactants. Infants who received protein containing synthetic surfactant compared to protein free synthetic surfactant did not demonstrate significantly different risks of prespecified primary outcomes: mortality at 36 weeks postmenstrual age (PMA) [RR 0.89 (95% CI 0.71, 1.11)], chronic lung disease at 36 weeks PMA [RR 0.89 (95% CI 0.78, 1.03)], or the combined outcome of mortality or chronic lung disease at 36 weeks PMA [RR 0.88 (95% CI 0.77, 1.01)]. Among the secondary outcomes, a decrease in the incidence of respiratory distress syndrome at 24 hours of age was demonstrated in the group that received PCSS [RR 0.83 (95% CI 0.72, 0.95). In the one trial comparing protein containing synthetic surfactants compared to protein free synthetic surfactant for the prevention of RDS, no statistically different clinical differences in death and chronic lung disease were noted. Clinical outcomes between the two groups were generally similar although the group receiving protein containing synthetic surfactants did have decreased incidence of respiratory distress syndrome. Further well designed studies comparing protein containing synthetic surfactant to the more widely used animal derived surfactant extracts are indicated.

A recent trial of protein containing synthetic surfactant compared to protein free synthetic surfactant suggests that these protein containing synthetic surfactants help prevent respiratory distress syndrome and may or may not lead to a decrease in lung injury (chronic lung disease). Other clinical outcomes were similar. Further studies will help refine recommendations concerning use of protein containing synthetic surfactants.

10.1002/14651858.CD006180.pub2

cochrane-simplification-train-623

cochrane-simplification-train-623

The review currently includes one randomised trial from mainland China with 153 participants that lasted two months and compared flupenthixol with chlorpromazine. The exact methods of sequence generation and allocation concealment were not reported, and medication was provided in an open manner. There were no data on the outcomes that we had a priori selected for a 'Summary of findings' table. There was no significant difference between flupenthixol and chlorpromazine in the participants' general mental state at endpoint as measured by the Brief Psychiatric Rating Scale (BPRS) total score (1 randomised controlled trial (RCT), n = 153, MD 2.20 95% confidence interval (CI) -1.25 to 5.65). Chlorpromazine was associated with significantly less dizziness (1 RCT, n = 153, MD 0.12 95% CI 0.01 to 0.23); dystonia (1 RCT, n = 153, MD 0.29 95% CI 0.13 to 0.45); unsteady gait (1 RCT, n = 153, MD 0.46 95% CI 0.28 to 0.64); reduced facial expression (1 RCT, n = 153, MD 0.27 95% CI 0.09 to 0.45); restlessness (1 RCT, n = 153, MD 0.69 95% CI 0.45 to 0.93); rigidity (elbow) (1 RCT, n = 153, MD 0.48 95% CI 0.28 to 0.68); and tremor (1 RCT, n = 153, MD 0.56 95% CI 0.34 to 0.78). Chlorpromazine produced more dryness of mouth than flupenthixol (1 RCT, n = 153, MD -0.14 95% CI -0.25 to -0.03). The evidence base of flupenthixol versus low-potency first-generation antipsychotics is currently restricted to one randomised comparison with chlorpromazine. The few reported data do not suggest a difference in efficacy, but flupenthixol appeared to produce more movement disorders and dizziness, while chlorpromazine was associated with the anticholinergic side effect - dryness of mouth. More trials are needed to make conclusions about the relative effects of flupenthixol and low-potency antipsychotics.

Flupenthixol was first made available in the UK in 1965 and it has been used to treat schizophrenia for nearly five decades. It is available both as a tablet and a long-acting injection. Having been investigated in numerous studies, flupenthixol was found to be effective and well tolerated by people with schizophrenia. The main side effects are shaking, restlessness or the inability to sit still, a dry mouth and some weight gain. Although this drug has been available for decades, few systematic reviews exist on flupenthixol. The effects of this drug in helping people cope with the symptoms of schizophrenia are not currently measured, quantified and known. The review could include only one small study, which was limited and 13 years old. The number as well as the quality of the study was low; for the main outcomes of interest the authors could not rate the quality of evidence at all, as the study did not report on the outcomes of interest for the 'Summary of findings' table. Flupenthixol was compared with chlorpromazine. There was no clear difference in efficacy, nor was there clear information on: increasing their use of services; people’s satisfaction with treatment; quality of life; or costs and cost effectiveness. Flupenthixol is widely available and inexpensive. It is perhaps understandable that it remains one of many drugs used for treating people with serious mental illnesses. This is because the use of flupenthixol is based more on clinical experience, and the decisions of psychiatrists are based on large scale research studies and evidence-based information. The effectiveness and benefits of flupenthixol over chlorpromazine remain largely unknown and incomplete. Large randomised trials could be helpful in increasing knowledge about this drug. This plain language summary has been written by Benjamin Gray, Service User Expert, Rethink Mental Illness.

10.1002/14651858.CD009227.pub2

cochrane-simplification-train-624

cochrane-simplification-train-624

We included one RCT which was a pilot study with 19 participants that compared HFNC therapy with oxygen delivery via a head box. In this study, we judged the risk of selection, attrition and reporting bias to be low, and we judged the risk of performance and detection bias to be unclear due to lack of blinding. The median oxygen saturation (SpO2) was higher in the HFNC group at eight hours (100% versus 96%, P = 0.04) and at 12 hours (99% versus 96%, P = 0.04) but similar at 24 hours. There was no clear evidence of a difference in total duration of oxygen therapy, time to discharge or total length of stay between groups. No adverse events were reported in either group and no participants in either group required further respiratory support. Five ongoing trials were identified but no data were available in May 2013. We were not able to perform a meta-analysis. There is insufficient evidence to determine the effectiveness of HFNC therapy for treating infants with bronchiolitis. The current evidence in this review is of low quality, from one small study with uncertainty about the estimates of effect and an unclear risk of performance and detection bias. The included study provides some indication that HFNC therapy is feasible and well tolerated. Further research is required to determine the role of HFNC in the management of bronchiolitis in infants. The results of the ongoing studies identified will contribute to the evidence in future updates of this review.

One study (19 participants) met our inclusion criteria. It showed that high-flow nasal cannula therapy is well tolerated as a treatment for bronchiolitis. Oxygen saturations (blood oxygen levels) were better at eight and 12 hours in participants receiving high-flow nasal cannula therapy than in those receiving oxygen therapy via a head box, but were similar between groups at 24 hours, although this may have been due to higher oxygen flow rates in the high-flow nasal cannula group. There was no clear evidence of a difference between the two groups in the duration of oxygen therapy, length of hospitalisation and time to discharge. No adverse events were reported in either group. There is insufficient evidence to determine the effectiveness of high-flow nasal cannula therapy for treating bronchiolitis in infants. The included study provides some indication that HFNC therapy is feasible and well tolerated. However, our evidence is based on one low-quality, small study with uncertainty about the effects and some possibility of bias arising from the study methods. Further research is required to determine the role of high-flow nasal cannula therapy in the management of bronchiolitis in infants. The results of six ongoing studies identified will contribute to the evidence in future updates of this review. The evidence is current to May 2013.

10.1002/14651858.CD009609.pub2

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cochrane-simplification-train-625

We included 45 studies, and based on the criteria for PET-CT positivity, we categorised the included studies into three groups: Activity > background (18 studies, N = 2823, prevalence of N2 and N3 nodes = 679/2328), SUVmax ≥ 2.5 (12 studies, N = 1656, prevalence of N2 and N3 nodes = 465/1656), and Other/mixed (15 studies, N = 1616, prevalence of N2 to N3 nodes = 400/1616). None of the studies reported (any) adverse events. Under-reporting generally hampered the quality assessment of the studies, and in 30/45 studies, the applicability of the study populations was of high or unclear concern. The summary sensitivity and specificity estimates for the 'Activity > background PET-CT positivity criterion were 77.4% (95% CI 65.3 to 86.1) and 90.1% (95% CI 85.3 to 93.5), respectively, but the accuracy estimates of these studies in ROC space showed a wide prediction region. This indicated high between-study heterogeneity and a relatively large 95% confidence region around the summary value of sensitivity and specificity, denoting a lack of precision. Sensitivity analyses suggested that the overall estimate of sensitivity was especially susceptible to selection bias; reference standard bias; clear definition of test positivity; and to a lesser extent, index test bias and commercial funding bias, with lower combined estimates of sensitivity observed for all the low 'Risk of bias' studies compared with the full analysis. The summary sensitivity and specificity estimates for the SUVmax ≥ 2.5 PET-CT positivity criterion were 81.3% (95% CI 70.2 to 88.9) and 79.4% (95% CI 70 to 86.5), respectively.In this group, the accuracy estimates of these studies in ROC space also showed a very wide prediction region. This indicated very high between-study heterogeneity, and there was a relatively large 95% confidence region around the summary value of sensitivity and specificity, denoting a clear lack of precision. Sensitivity analyses suggested that both overall accuracy estimates were marginally sensitive to flow and timing bias and commercial funding bias, which both lead to slightly lower estimates of sensitivity and specificity. Heterogeneity analyses showed that the accuracy estimates were significantly influenced by country of study origin, percentage of participants with adenocarcinoma, (¹⁸F)-2-fluoro-deoxy-D-glucose (FDG) dose, type of PET-CT scanner, and study size, but not by study design, consecutive recruitment, attenuation correction, year of publication, or tuberculosis incidence rate per 100,000 population. This review has shown that accuracy of PET-CT is insufficient to allow management based on PET-CT alone. The findings therefore support National Institute for Health and Care (formally 'clinical') Excellence (NICE) guidance on this topic, where PET-CT is used to guide clinicians in the next step: either a biopsy or where negative and nodes are small, directly to surgery. The apparent difference between the two main makes of PET-CT scanner is important and may influence the treatment decision in some circumstances. The differences in PET-CT accuracy estimates between scanner makes, NSCLC subtypes, FDG dose, and country of study origin, along with the general variability of results, suggest that all large centres should actively monitor their accuracy. This is so that they can make reliable decisions based on their own results and identify the populations in which PET-CT is of most use or potentially little value.

We included 45 studies, and based on the criteria for a positive PET-CT scan, we performed two main analyses. In the 18 studies (2823 participants) in the Activity > background group, PET-CT was found to accurately identify 77.4% (95% CI 65.3 to 86.1) of the participants with NSCLC spread beyond the N1 nodes and 90.1% (95% CI 85.3 to 93.5) of the participants without spread beyond the N1 nodes. In the 12 studies (1656 participants) in the SUVmax of ≥ 2.5 group, PET-CT accurately identified 81.3% (95% CI 70.2 to 88.9) of the participants with spread beyond the N1 nodes and 79.4% (95% CI 70 to 86.5) of the participants without spread beyond the N1 nodes. However, the results varied a lot between the studies in each analysis, and the quality and size of the studies themselves, country of study origin, percentage of participants with adenocarcinoma, FDG dose, and type of PET-CT scanner influenced the results. We believe that the results of this review show that the accuracy of PET-CT is insufficient to allow management based on PET-CT alone.

10.1002/14651858.CD009519.pub2

cochrane-simplification-train-626

cochrane-simplification-train-626

Ten new studies have been added to this update; 18 studies with a total 1215 participants are now included. These examined effects of music therapy over the short, medium, and long-term, with treatment dosage varying from seven to 240 sessions. Overall, most information is from studies at low or unclear risk of bias A positive effect on global state was found for music therapy compared to standard care (medium term, 2 RCTs, n = 133, RR 0.38 95% confidence interval (CI) 0.24 to 0.59, low-quality evidence, number needed to treat for an additional beneficial outcome NNTB 2, 95% CI 2 to 4). No binary data were available for other outcomes. Medium-term continuous data identified good effects for music therapy on negative symptoms using the Scale for the Assessment of Negative Symptoms (3 RCTs, n = 177, SMD - 0.55 95% CI -0.87 to -0.24, low-quality evidence). General mental state endpoint scores on the Positive and Negative Symptoms Scale were better for music therapy (2 RCTs, n = 159, SMD -0.97 95% CI -1.31 to -0.63, low-quality evidence), as were average endpoint scores on the Brief Psychiatric Rating Scale (1 RCT, n = 70, SMD -1.25 95% CI -1.77 to -0.73, moderate-quality evidence). Medium-term average endpoint scores using the Global Assessment of Functioning showed no effect for music therapy on general functioning (2 RCTs, n = 118, SMD -0.19 CI -0.56 to 0.18, moderate-quality evidence). However, positive effects for music therapy were found for both social functioning (Social Disability Screening Schedule scores; 2 RCTs, n = 160, SMD -0.72 95% CI -1.04 to -0.40), and quality of life (General Well-Being Schedule scores: 1 RCT, n = 72, SMD 1.82 95% CI 1.27 to 2.38, moderate-quality evidence). There were no data available for adverse effects, service use, engagement with services, or cost. Moderate- to low-quality evidence suggests that music therapy as an addition to standard care improves the global state, mental state (including negative and general symptoms), social functioning, and quality of life of people with schizophrenia or schizophrenia-like disorders. However, effects were inconsistent across studies and depended on the number of music therapy sessions as well as the quality of the music therapy provided. Further research should especially address the long-term effects of music therapy, dose-response relationships, as well as the relevance of outcome measures in relation to music therapy.

We ran electronic searches up to January 2015 for trials randomising people with schizophrenia or schizophrenia-like disorders to receive music therapy or standard care. We found and checked 176 potential studies. Eighteen trials with a total of 1215 participants met the review requirements and provided useful data. The evidence currently available is of low to moderate quality. The results of these studies suggest that music therapy improves global state and may also improve mental state, functioning, and quality of life if a sufficient number of music therapy sessions are provided. Music therapy seems to help people with schizophrenia but further research is needed to confirm the positive effects found in this review. This research should especially address the long-term effects of music therapy, the quality of music therapy provided and measure outcomes relevant to music therapy.

10.1002/14651858.CD004025.pub4

cochrane-simplification-train-627

cochrane-simplification-train-627

We identified 40 RCTs of various pharmacological interventions including intravenous ketamine (14 RCTs), oral gabapentin (10 RCTs), oral pregabalin (5 RCTs), non-steroidal anti-inflammatories (3 RCTs), intravenous steroids (3 RCTs), oral N-methyl-D-aspartate (NMDA) blockers (3 RCTs), oral mexiletine (2 RCTs), intravenous fentanyl (1 RCT), intravenous lidocaine (1 RCT), oral venlafaxine (1 RCT) and inhaled nitrous oxide (1 RCT). Meta-analysis suggested a modest but statistically significant reduction in the incidence of chronic pain after surgery following treatment with ketamine but not gabapentin or pregabalin. Results with ketamine should be viewed with caution since most of the included trials were small (that is < 100 participants per treatment arm), which could lead to the overestimation of treatment effect. Additional evidence from better, well designed, large-scale trials is needed in order to more rigorously evaluate pharmacological interventions for the prevention of chronic pain after surgery. Furthermore, available evidence does not support the efficacy of gabapentin, pregabalin, non-steroidal anti-inflammatories, intravenous steroids, oral NMDA blockers, oral mexiletine, intravenous fentanyl, intravenous lidocaine, oral venlafaxine or inhaled nitrous oxide for the prevention of chronic postoperative pain.

Researchers have studied the ability of various drug treatments to prevent the development of chronic pain after surgery and this systematic review evaluated published studies in this field. Available studies suggest a modest effect of ketamine, compared to placebo, for prevention of chronic pain after surgery, however small study size could lead to an overestimation of this effect. Studies of other drugs such as gabapentin and pregabalin did not suggest the same preventative effect. Additional large studies using improved research methods are necessary to more clearly identify treatments that are beneficial for preventing chronic postsurgical pain.

10.1002/14651858.CD008307.pub2

cochrane-simplification-train-628

cochrane-simplification-train-628

Seventeen trials satisfied the inclusion criteria. Four trials evaluated preventative interventions for HSV lesions, three trials for viral isolates, and eight trials evaluated both outcome measures. A single trial reported on the cost of prophylaxis for HSV. Two trials evaluating treatment reported on time to healing, duration of viral shedding and relief of pain. No trials reported on duration of hospital stay, amount of analgesia or patient quality of life. In placebo controlled trials, aciclovir was found to be effective for the prevention of HSV infections as measured by oral lesions or viral isolates (RR = 0.16, 95% confidence interval (CI) 0.08 to 0.31 nine trials; RR = 0.17, 95% CI 0.07 to 0.37 nine trials). There is no evidence that valaciclovir is more efficacious than aciclovir, or that higher doses of valaciclovir are more effective than lower doses. Placebo was found to be more effective than prostaglandin E for prevention of viral isolates (RR = 1.87, 95% CI 1.12 to 3.14 one trial). Aciclovir was also found to be effective for the treatment of HSV in terms of duration of viral shedding (median of 2.5 days versus 17.0 days, P = 0.0002; 2 days compared to more than 9, P = 0.0008), time to first decrease in pain (median 3 days compared to 16, P = 0.04), complete resolution of pain (9.9 days compared to 13.6 days, P = 0.01; median of 6 days compared to 16, P = 0.05), 50% healing (median of 6 days compared to 11, P = 0.01) and total healing (median 13.9 days compared to 20.7 days, P = 0.08; median of 8 days compared to 21, P = 0.0). There is evidence that aciclovir is efficacious in the prevention and treatment of herpes simplex virus infections. There is no evidence that valaciclovir is more efficacious than aciclovir, or that a high dose of valaciclovir is better than a low dose of valaciclovir. There is evidence that as a prophylaxis, placebo is more efficacious than prostaglandin E. However, in all included trials, risk of bias is unclear.

This review of 17 trials found evidence that aciclovir is efficacious in the prevention and treatment of HSV infections, in terms of preventing clinical/culture positive HSV infections, reduction in healing time, duration of viral shedding and relief of pain. There is no evidence that valaciclovir is more efficacious than aciclovir, or that a high dose of valaciclovir is better than a low dose of valaciclovir. There is evidence that for prevention, placebo is more efficacious than prostaglandin E. However, in all included trials, risk of bias is unclear. No trials reported on duration of hospital stay, amount of analgesia or patient quality of life.

10.1002/14651858.CD006706.pub2

cochrane-simplification-train-629

cochrane-simplification-train-629

We included eleven studies (523 participants) in this review. Ten studies had two arms and one had three arms that were all relevant to this review. Three studies compared a hydrogel dressing with a basic wound contact dressing; three studies compared a hydrogel dressing with a hydrocolloid dressing; three studies compared a hydrogel dressing with another hydrogel dressing; one study compared a hydrogel dressing with a foam dressing; one study compared a hydrogel dressing with a dextranomer paste dressing and one study compared a hydrogel dressing with a topical treatment (collagenase). Limited data were available for analyses in this review: we conducted no meta-analyses. Where data were available there was no evidence of a difference between hydrogel and alternative treatments in terms of complete wound healing or adverse events. One small study reported that using hydrogel dressings was, on average, less costly than hydrocolloid dressings, but this estimate was imprecise and its methodology was not clear. All included studies were small, had short follow-up times and were at unclear risk of bias. It is not clear if hydrogel dressings are more or less effective than other treatments in healing pressure ulcers or if different hydrogels have different effects, Most trials in this field are very small and poorly reported so that risk of bias is unclear.

In June 2014 we searched for as many relevant medical studies as we could find that had a robust design (randomised controlled trials) that had compared hydrogel dressings with other treatments for pressure ulcers. We found 11 studies involving a total of 539 participants. From the results of these studies we could not tell whether hydrogel wound dressings heal pressure ulcers more quickly or slowly than other types of dressing or topical treatments. Generally, the studies we found were small and the results inconclusive. Some studies lacked information about how they were conducted and it was difficult to tell whether the results presented were robust. More research of better quality is needed before it can be determined whether hydrogel dressings are better or worse at healing pressure ulcers than other types of dressings or topical treatments.

10.1002/14651858.CD011226.pub2

cochrane-simplification-train-630

cochrane-simplification-train-630

We now have included 174 trials involving 17,244 participants. Aripiprazole was compared with clozapine, quetiapine, risperidone, ziprasidone and olanzapine. The overall number of participants leaving studies early was 30% to 40%, limiting validity (no differences between groups). When compared with clozapine, there were no significant differences for global state (no clinically significant response, n = 2132, 29 RCTs, low quality evidence); mental state (BPRS, n = 426, 5 RCTs, very low quality evidence); or leaving the study early for any reason (n = 240, 3 RCTs, very low quality evidence). Quality of life score using the WHO-QOL-100 scale demonstrated significant difference, favouring aripiprazole (n = 132, 2 RCTs, RR 2.59 CI 1.43 to 3.74, very low quality evidence). General extrapyramidal symptoms (EPS) were no different between groups (n = 520, 8 RCTs,very low quality evidence). No study reported general functioning or service use. When compared with quetiapine, there were no significant differences for global state (n = 991, 12 RCTs, low quality evidence); mental state (PANSS positive symptoms, n = 583, 7 RCTs, very low quality evidence); leaving the study early for any reason (n = 168, 2 RCTs, very low quality evidence), or general EPS symptoms (n = 348, 4 RCTs, very low quality evidence). Results were significantly in favour of aripiprazole for quality of life (WHO-QOL-100 total score, n = 100, 1 RCT, MD 2.60 CI 1.31 to 3.89, very low quality evidence). No study reported general functioning or service use. When compared with risperidone, there were no significant differences for global state (n = 6381, 80 RCTs, low quality evidence); or leaving the study early for any reason (n = 1239, 12 RCTs, very low quality evidence). Data were significantly in favour of aripiprazole for improvement in mental state using the BPRS (n = 570, 5 RCTs, MD 1.33 CI 2.24 to 0.42, very low quality evidence); with higher adverse effects seen in participants receiving risperidone of general EPS symptoms (n = 2605, 31 RCTs, RR 0.39 CI 0.31 to 0.50, low quality evidence). No study reported general functioning, quality of life or service use. When compared with ziprasidone, there were no significant differences for global state (n = 442, 6 RCTs, very low quality evidence); mental state using the BPRS (n = 247, 1 RCT, very low quality evidence); or leaving the study early for any reason (n = 316, 2 RCTs, very low quality evidence). Weight gain was significantly greater in people receiving aripiprazole (n = 232, 3 RCTs, RR 4.01 CI 1.10 to 14.60, very low quality evidence). No study reported general functioning, quality of life or service use. When compared with olanzapine, there were no significant differences for global state (n = 1739, 11 RCTs, very low quality evidence); mental state using PANSS (n = 1500, 11 RCTs, very low quality evidence); or quality of life using the GQOLI-74 scale (n = 68, 1 RCT, very low quality of evidence). Significantly more people receiving aripiprazole left the study early due to any reason (n = 2331, 9 RCTs, RR 1.15 CI 1.05 to 1.25, low quality evidence) and significantly more people receiving olanzapine gained weight (n = 1538, 9 RCTs, RR 0.25 CI 0.15 to 0.43, very low quality evidence). None of the included studies provided outcome data for the comparisons of 'service use' or 'general functioning'. Information on all comparisons is of limited quality, is incomplete and problematic to apply clinically. The quality of the evidence is all low or very low. Aripiprazole is an antipsychotic drug with an important adverse effect profile. Long-term data are sparse and there is considerable scope for another update of this review as new data emerge from ongoing larger, independent pragmatic trials.

In many countries in the industrialised world there has been a huge growth in the prescription of medication for people with mental health problems, taken orally as a tablet or by injection. Atypical and second generation antipsychotic drugs have become ever more popular, because they are thought to help people with mental health problems who do not respond quite so well to initial treatment. These newer drugs hold the promise of both reducing symptoms, such as hearing voices or seeing things, and reducing problematic side effects, such as sleepiness, weight gain, and shaking. However, there is little research and comparison of the ways in which drugs differ from one another. This review examines the effectiveness of aripiprazole with other new antipsychotics. Originally the review included 12 research trials. After an update search carried out in November 2012, 162 trials were added. Most of these trials were from China and although new data were added to the review, overall conclusions did not change. The review now has five comparisons with aripiprazole being compared with clozapine, olanzapine, quetiapine, risperidone and ziprasidone. For people with schizophrenia it may be important to know that aripiprazole may not be as good or effective as olanzapine but that it has less side effects. Aripiprazole is similar in effectiveness to risperidone and somewhat better than ziprasidone. Aripiprazole had less side- effects than olanzapine and risperidone (such as weight gain, sleepiness, heart problems, shaking and increased cholesterol levels). Aripiprazole was not as good as ziprasidone for dealing with restlessness or people’s inability to sit still. Comparison with other antipsychotic drugs as a group showed that people preferred taking aripiprazole. However, people with schizophrenia as well as mental health professionals and policy makers should know that the evidence is limited and mostly of low or very low quality. More trials and research is required, including on outcomes such as: quality of life; the views of service users and carers; and patient preference. This plain language summary has been written by a consumer from Rethink Mental Illness, Benjamin Gray. Email: [email protected]

10.1002/14651858.CD006569.pub5

cochrane-simplification-train-631

cochrane-simplification-train-631

Twenty-nine studies were included. Twenty-three studies on 3189 participants compared self management versus usual care; six studies on 499 participants compared different components of self management on a head-to-head basis. Although we included non-randomised controlled clinical trials as well as RCTs in this review, we restricted the primary analysis to RCTs only and reported these trials in the abstract. In the 23 studies with a usual care control group, follow-up time ranged from two to 24 months. The content of the interventions was diverse. A statistically relevant effect of self management on HRQoL was found (St George's Respiratory Questionnaire (SGRQ) total score, mean difference (MD) -3.51, 95% confidence interval (CI) -5.37 to -1.65, 10 studies, 1413 participants, moderate-quality evidence). Self management also led to a lower probability of respiratory-related hospitalisations (odds ratio (OR) 0.57, 95% CI 0.43 to 0.75, nine studies, 1749 participants, moderate-quality evidence) and all cause hospitalisations (OR 0.60; 95% CI 0.40 to 0.89, 6 studies, 1365 participants, moderate-quality evidence). Over one year of follow-up, eight (95% CI 5 to 14) participants with a high baseline risk of respiratory-related hospital admission needed to be treated to prevent one participant with at least one hospital admission, and 20 (95% CI 15 to 35) participants with a low baseline risk of hospitalisation needed to be treated to prevent one participant with at least one respiratory-related hospital admission. No statistically significant effect of self management on mortality (OR 0.79, 95% CI 0.58 to 1.07, 8 studies, 2134 participants, very low-quality evidence) was detected. Also, dyspnoea measured by the (modified) Medical Research Council Scale ((m)MRC) was reduced in individuals who participated in self management (MD -0.83, 95% CI -1.36 to -0.30, 3 studies, 119 participants, low-quality evidence). The difference in exercise capacity as measured by the six-minute walking test was not statistically significant (MD 33.69 m, 95% CI -9.12 to 76.50, 6 studies, 570 participants, very low-quality evidence). Subgroup analyses depending on the use of an exercise programme as part of the intervention revealed no statistically significant differences between studies with and without exercise programmes in our primary outcomes of HRQoL and respiratory-related hospital admissions. We were unable to pool head-to-head trials because of heterogeneity among interventions and controls; thus results are presented narratively within the review. Self management interventions in patients with COPD are associated with improved health-related quality of life as measured by the SGRQ, a reduction in respiratory-related and all cause hospital admissions, and improvement in dyspnoea as measured by the (m)MRC. No statistically significant differences were found in other outcome parameters. However, heterogeneity among interventions, study populations, follow-up time and outcome measures makes it difficult to formulate clear recommendations regarding the most effective form and content of self management in COPD.

In this review, we assessed 29 studies that evaluated the effects of self management. Patients in these studies were followed for two to 24 months. Twenty-three studies had a control group that received usual care. A total of 3189 patients participated in these studies. In six studies, different components of self management were compared on a head-to-head basis. Content and duration of the self management programmes were diverse. Analysis of the studies revealed that self management training improved health-related quality of life in patients with COPD compared with usual care. Also, the number of patients with at least one hospital admission related to lung disease and other causes was reduced among those who participated in a self management intervention. These patients also experienced less shortness of breath. We found trials that compared different types of self management interventions versus each other. We had hoped that these trials would help us identify the most effective components of self management. However, all interventions were different, and we were unable to draw out the key themes. The studies assessed in this review were diverse. Self management programmes differed in content and duration. Also, types of participants differed across studies. Therefore, no clear recommendations on the most effective content of self management training can be made at this time.

10.1002/14651858.CD002990.pub3

cochrane-simplification-train-632

cochrane-simplification-train-632

Only two underpowered trials (reporting 36 and 40 patients) were identified. These differed markedly in their inclusion criteria and treatment protocols. Both stated that they used placebo. However, allocation concealment was unclear. Only one trial reported any patient deaths. No significant improvement in mortality was identified (odds ratio (OR) 0.42, 95% confidence interval (CI) 0.10 to 1.76). Improvements in serum markers of liver inflammation and liver histology were identified. Potentially prognostically linked markers such as bilirubin and albumin were incompletely reported. Bone mineral density (weighted mean difference -2.84%, 95% CI -4.16 to -1.53) and the number of patients with any adverse event (OR 8.99, 95% CI 2.15 to 37.58) were significantly increased in the glucocorticosteroid group. There is insufficient data to support or reject the use of glucocorticosteroids for patients with primary biliary cirrhosis. It may be appropriate to consider a large prospective randomised clinical trial on this topic.

Only two small randomised clinical trials on this topic were identified. The trials were not large enough in terms of sample size or length of follow up to allow changes in mortality to be adequately evaluated. Glucocorticosteroids were associated with improvement in serum markers of inflammation and liver histology, both of which were of uncertain clinical significance. Glucocorticosteroids were also associated with adverse events, including reduced bone mineral density. Further trials are necessary if the effectiveness of glucocorticosteroids is to be properly evaluated.

10.1002/14651858.CD003778.pub2

cochrane-simplification-train-633

cochrane-simplification-train-633

Among 22 eligible trials, 17 pairs of groups comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 μg) versus low to medium (200 μg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X2 = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, body mass index and skeletal maturation reported with low quality of evidence due to imprecision. In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents’ and physicians’ concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma.

We studied whether a difference could be seen in the growth of children with persistent asthma who were using different doses of the same ICS molecule and the same delivery device. We found 22 eligible trials, but only 10 of them measured growth or other measures of interest. Overall, 3394 children included in the review combined 17 group comparisons (i.e. 17 pairs of groups of children with mild to moderate asthma using a particular dose and type of steroid in 10 trials). Trials used different ICS molecules (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) either on their own or in combination with a long-acting beta2-agonist (a drug used to open up the airways) and generally compared low doses of corticosteroids (50 to 100 μg) with low to medium (200 μg) doses of corticosteroids (converted in μg HFA-beclomethasone equivalent) over 12 to 52 weeks. We found a small but statistically significant group difference in growth over 12 months between these different doses clearly favouring the lower dose of ICS. The type of corticosteroid among newer molecules (ciclesonide, fluticasone, mometasone) did not seem to influence the impact on growth over one year. Differences in corticosteroid doses did not seem to affect the change in height, the gain in weight, the gain in body mass index and the maturation of bones. This review is based on a small number of trials that reported data and were conducted on children with mild to moderate asthma. Only 10 of 22 studies measured the few outcomes of interest for this review, and only four comparisons reported growth over 12 months. Our confidence in the quality of evidence is high for this outcome, however it is low to moderate for several other outcomes, depending on the number of trials reporting these outcomes. Moreover, a few outcomes were reported only by a single trial; as these findings have not been confirmed by other trials, we downgraded the evidence for these outcomes to low quality. An insufficient number of trials have compared the effect of a larger difference in dose, for example, between a high dose and a low dose of ICS and of other popular molecules such as budesonide and beclomethasone over a year or longer of treatment. We report an ICS dose–dependent reduction in growth velocity in prepubescent school-aged children with mild to moderate persistent asthma. The choice of ICS molecule (mometasone, ciclesonide or fluticasone) was not found to affect the level of growth velocity response over a year. The effect of corticosteroids on growth was not consistently reported: among 22 eligible trials, only four comparisons reported the effects of corticosteroids on growth over one year. In view of parents' and clinicians' concerns, lack of or incomplete reporting of growth is a matter of concern given the importance of the topic. We recommend that growth be systematically reported in all trials involving children taking ICS for three months or longer. Until further data comparing low versus high ICS dose and trials of longer duration are available, we recommend that the minimal effective ICS dose be used in all children with asthma.

10.1002/14651858.CD009878.pub2

cochrane-simplification-train-634

cochrane-simplification-train-634

Unfortunately, we did not find any relevant studies to include. One non-randomised trial, published in 1961, suggested beneficial effects for those admitted to mother and baby units. For the experimental group, more women were able to care for their baby on their own and experienced fewer early relapses on their return home compared with standard care. Care practices for people with schizophrenia have changed dramatically over the past 40 years and a sensitively designed pragmatic trial is possible and justified. Mother and bay units are reportedly common in the UK but less common in other countries and rare or non-existent in the developing world. However, there does not appear to be any trial-based evidence for the effectiveness of these units. This lack of data is of concern as descriptive studies have found poor outcomes such as anxious attachment and poor development for children of mothers with schizophrenia and a greater risk of the children being placed under supervised or foster care. Effective care of both mothers and babies during this critical time may be crucial to prevent poor clinical and parenting outcomes. Good, relevant research is urgently needed.

To assess the efficacy of MBUs we systematically searched for any randomised trials of MBUs compared to standard care. We found no trials involving either mothers suffering from post partum psychosis or severe post natal depression. Anecdotal results from a 1961 trial did suggest a beneficial effect, but non-randomised data from over 40 years ago is difficult to apply to today's care. Such lack of data is of concern as MBUs are expensive to set up and run. If they are to be the 'gold standard' of care for mothers and their babies, their effectiveness needs to validated. Good quality, relevant research is urgently needed.

10.1002/14651858.CD006333

cochrane-simplification-train-635

cochrane-simplification-train-635

We included five studies involving 266 participants (136 intervention; 130 control). All participants were adult stroke survivors, living in the community or a care home. Programmes to improve community ambulation consisted of walking practice in a variety of settings and environments in the community, or an indoor activity that mimicked community walking (including virtual reality or mental imagery). Three studies were funded by government agencies, and two had no funding. From two studies of 198 people there was low quality evidence for the effect of intervention on participation compared with control (SMD, 0.08, 95% confidence interval (CI) -0.20 to 0.35 (using inverse variance). The CI for the effect of the intervention on gait speed was wide and does not exclude no difference (MD 0.12, 95% CI -0.01 to 0.24; four studies, 98 participants, low quality evidence). We considered the quality of the evidence to be low for all the remaining outcomes in our review: Community Walk Test (MD -6.35, 95% CI -21.59 to 8.88); Walking Ability Questionnaire (MD 0.53, 95% CI -5.59 to 6.66); Six-Minute Walk Test (MD 39.62 metres, 95% CI -8.26 to 87.51) and self-efficacy (SMD 0.32, 95% CI -0.09 to 0.72). We downgraded the quality of the evidence because of a high risk of bias and imprecision. There is currently insufficient evidence to establish the effect of community ambulation interventions or to support a change in clinical practice. More research is needed to determine if practicing outdoor or community walking will improve participation and community ambulation skills for stroke survivors living in the community.

The evidence in this review is current to November 2013. We included five studies with a total of 266 participants. All participants were adult stroke survivors who lived in the community or a care home. Programmes to improve community ambulation consisted of walking practice in a variety of settings and environments in the community (three studies), or an activity indoors that mimicked community walking (three studies). Three studies were funded by government agencies, and two had no funding. The term 'participation' refers to the ability of a person to engage in activities that are meaningful to them, such as leisure activities, paid or volunteer work, or socialising with others. For the primary outcome of participation we could not be sure whether the intervention improved participation compared with control (two studies). When considering how fast a person walks, it is unclear if the speed of walking may increase with a community ambulation intervention ( four studies). Based on the included studies, the effect of the intervention on the ability to walk, how far people could walk in six minutes or their confidence in walking is unclear. There is currently insufficient evidence to establish the effect of community ambulation interventions or to support a change in clinical practice. No adverse effects of the interventions were reported in any of the included studies. We considered the quality of the evidence to be low across the studies for both the participation and walking speed outcomes. There were some study design considerations which led to the low score, such as who knew what group the participants were in, and the number of people who dropped out of the studies. Also, we included a small number of studies in this review, which limits how the results can be interpreted. More research is needed in this area.

10.1002/14651858.CD010200.pub2

cochrane-simplification-train-636

cochrane-simplification-train-636

We included 13 studies, involving 920 randomised participants. There was considerable heterogeneity among study designs, including the comparator arms (placebo, opioid, another NSAID, or a different regimen of ketorolac), dosing regimens (routes and timing of administration, single versus multiple dose), outcome assessment methods, and types of surgery. Mean study population ages ranged from 356 days to 13.9 years. The majority of studies chose a dose of either 0.5 mg/kg (as a single or multiple dose regimen) or 1 mg/kg (single dose with 0.5 mg/kg for any subsequent doses). One study administered interventions intraoperatively; the remainder administered interventions postoperatively, often after the participant reported moderate to severe pain. There were insufficient data to perform meta-analysis for either of our primary outcomes: participants with at least 50% pain relief; or mean postoperative pain intensity. Four studies individually reported statistically significant reductions in pain intensity when comparing ketorolac with placebo, but the studies were small and had various risks of bias, primarily due to incomplete outcome data and small sample sizes. We found limited data available for the secondary outcomes of participants requiring rescue medication and opioid consumption. For the former, we saw no clear difference between ketorolac and placebo; 74 of 135 (55%) participants receiving ketorolac required rescue analgesia in the post-anaesthesia care unit (PACU) versus 81 of 127 (64%) receiving placebo (relative risk (RR) 0.85, 95% confidence interval (CI) 0.71 to 1.00, P = 0.05; 4 studies, 262 participants). For opioid consumption in the PACU, we saw no clear difference between ketorolac and placebo (P = 0.61). For the time period zero to four hours after administration of the interventions, participants receiving ketorolac received 1.58 mg less intravenous morphine equivalents than those receiving placebo (95% CI -2.58 mg to -0.57 mg, P = 0.002; 2 studies, 129 participants). However, we are uncertain whether ketorolac has an important effect on opioid consumption, as the data were sparse and the results were inconsistent. Only one study reported data for opioid consumption when comparing ketorolac with an opioid. There were no clear differences between the ketorolac and opioid group at any time point. There were no data assessing this outcome for the comparison of ketorolac with another NSAID. There were insufficient data to allow us to analyze overall adverse event or serious adverse event rates. Although the majority of serious adverse events reported in those receiving ketorolac involved bleeding, the number of events was too low to conclude that bleeding risk was increased in those receiving ketorolac perioperatively. There was not a statistically significant increase in event rates for any specific adverse event, either in pooled analysis or in single studies, when comparing ketorolac and placebo. When comparing ketorolac with opioids or other NSAIDs, there were too few data to make any conclusions regarding event rates. Lastly, withdrawals due to adverse events were vary rare in all groups, reflecting the acute nature of such studies. We assessed the quality of evidence for all outcomes for each comparison (placebo or active) as very low, due to issues with risk of bias in individual studies, imprecision, heterogeneity between studies, and low overall numbers of participants and events. Due to the lack of data for our primary outcomes, and the very low-quality evidence for secondary outcomes, the efficacy and safety of ketorolac in treating postoperative pain in children were both uncertain. The evidence was insufficient to support or reject its use.

In November 2017, we searched for clinical trials where ketorolac was used to treat pain after surgery in children. We found 13 studies, enrolling 920 children, that met our requirements for the review. The studies were quite different in their design, the dose of ketorolac, the timing (during or after surgery) and number of doses given, the type of surgery, and to what ketorolac was compared (either a placebo (a dummy treatment, such as a bag of fluid) or another drug). There was not enough information for a statistical analysis of the assessments in which we were most interested, that is, the number of children with at least 50% pain relief; or the average pain intensity (a measure of a patient's pain that asks the patient to rate how much pain they have, often on a scale of 0 for 'no pain' to 10 for 'worst pain imaginable'). Four studies individually reported that ketorolac was better at reducing pain intensity than placebo, but the studies were small and had various design issues. There was more information for other assessments, such as the number of children who needed rescue medication (additional pain medication that is given if the study medication is not helping the person's pain sufficiently), and how much of this rescue medication was used. Fewer children needed rescue medication in the ketorolac group than those who received placebo, although the result was not statistically different. During the four hours after they received study medications, children receiving ketorolac needed slightly less rescue pain medication than those who had received placebo. There was not enough information about ketorolac in direct comparisons with other medications. There was also not enough information in the studies for us to make a good assessment of side effects and serious side effects when ketorolac was used in this setting. Serious side effects in those receiving ketorolac included bleeding, but it didn't occur often enough for us to make any firm conclusions. Very few children dropped out of the studies because of side effects. This is normal in studies where participants are only in the study for a short period of time. We rated the quality of the evidence as very low, due to methodological issues with many of the studies, differences in study designs, and low overall numbers of children enrolled. Very low-quality evidence means that we are very uncertain about the results.

10.1002/14651858.CD012294.pub2

cochrane-simplification-train-637

cochrane-simplification-train-637

One study fulfilled the review criteria. In this study, 150 preterm infants of less than 32 weeks' gestation undergoing 60 second DCC were randomized to a group who received respiratory support in the form of continuous positive airway pressure (CPAP) or positive pressure ventilation during DCC and a group that did not receive respiratory support during the procedure. Mortality during hospital admission was not significantly different between groups with wide confidence intervals (CI) for magnitude of effect (risk ratio (RR) 1.67, 95% CI 0.41 to 6.73). The study did not report neurodevelopmental disability and death or disability at two to three years of age. There were no significant differences between groups in condition at birth (Apgar scores or intubation in the delivery room), use of inotropic agents (RR 1.25, CI 0.63 to 2.49), and receipt of blood transfusion (RR 1.03, 95% CI 0.70 to 1.54). In addition, there were no significant differences in the incidences of any intraventricular haemorrhage (RR 1.50, 95% CI 0.65 to 3.46) and severe intraventricular haemorrhage (RR 1.33, 95% CI 0.31 to 5.75). Several continuous variables were reported in subgroups depending on method of delivery. Unpublished data for each group as a whole was made available and showed peak haematocrit in the first 24 hours and duration of phototherapy did not differ significantly. Overall, the quality of evidence for several key neonatal outcomes (e.g. mortality and intraventricular haemorrhage) was low because of lack of precision with wide CIs. The results from one study with wide CIs for magnitude of effect do not provide evidence either for or against the use of respiratory support before clamping the umbilical cord. A greater body of evidence is required as many of the outcomes of interest to the review occurred infrequently. Similarly, the one included study cannot answer the question of whether the intervention is or is not harmful.

we searched medical databases and found one study for inclusion in this review. Preterm infants born before 32 weeks' gestation (32 weeks from the first day of the woman's last period (menstruation) to the current date) who had clamping of the umbilical cord delayed for 60 seconds after birth were selected at random to enter a group of babies who received breathing support and a group of babies who did not receive breathing support. The breathing support was given after birth of the baby and before the cord was clamped. Breathing support was the use of CPAP for infants breathing on their own or applying intermittent airwaypressureto expand the lungs in babies not breathing well on their own. Most of the study infants (83%) were delivered by caesarean section. the single study included in the review did not provide sufficient evidence either for or against the use of breathing support before cord clamping. the quality of evidence was low, mainly because more infants need to be studied for definite conclusions.

10.1002/14651858.CD012491.pub2

cochrane-simplification-train-638

cochrane-simplification-train-638

A total of four studies (305 participants) met the inclusion criteria. All of these studies sought to determine the effectiveness of different acupuncture techniques in the treatment of persistent and intractable hiccups. All four studies had a high risk of bias, did not compare the intervention with placebo, and failed to report side effects or adverse events for either the treatment or control groups. Due to methodological differences we were unable to perform a meta-analysis of the results. No studies investigating pharmacological interventions for persistent and intractable hiccups met the inclusion criteria. There is insufficient evidence to guide the treatment of persistent or intractable hiccups with either pharmacological or non-pharmacological interventions. The paucity of high quality studies indicate a need for randomised placebo-controlled trials of both pharmacological and non-pharmacological treatments. As the symptom is relatively rare, trials would need to be multi-centred and possibly multi-national.

This review aimed to find out whether there is good evidence that any of these work. We searched for good quality studies that involved adult patients (18 or older) who had experienced hiccups for 48 hours or more. Our conclusion is that there is insufficient evidence to recommend a particular treatment for hiccups. There is a need for randomised controlled studies to identify which treatments might be effective or harmful in treating persistent hiccups.

10.1002/14651858.CD008768.pub2

cochrane-simplification-train-639

cochrane-simplification-train-639

We included three trials with a total of 128 participants in this review. The duration of zinc supplementation ranged between four and 12 weeks. Risk of bias was unclear for most studies regarding selection bias (random sequence generation, allocation concealment) and detection bias (blinding of outcome assessment). No study reported on our key outcome measures (incidence of type 2 diabetes mellitus, adverse events, health-related quality of life, all-cause mortality, diabetic complications, socioeconomic effects). Evaluation of insulin resistance as measured by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) showed neutral effects when comparing zinc supplementation with control (two trials; 114 participants). There were neutral effects for trials comparing zinc supplementation with placebo for total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides (2 studies, 70 participants). The one trial comparing zinc supplementation with exercise also showed neutral effects for total cholesterol, HDL and LDL cholesterol, and a mean difference in triglycerides of -30 mg/dL (95% confidence interval (CI) -49 to -10) in favour of zinc supplementation (53 participants). Various surrogate laboratory parameters were also analysed in the included trials. There is currently no evidence on which to base the use of zinc supplementation for the prevention of type 2 diabetes mellitus. Future trials should investigate patient-important outcome measures such as incidence of type 2 diabetes mellitus, health-related quality of life, diabetic complications, all-cause mortality and socioeconomic effects.

We included three randomised controlled studies with a total of 128 participants in this review. The duration of zinc supplementation ranged between four and 12 weeks. No study reported on our patient-important key outcomes (new onset of type 2 diabetes mellitus, side effects, health-related quality of life, all-cause mortality, diabetic complications, socioeconomic effects). The effects of zinc supplementation are uncertain regarding insulin resistance and lipid levels in the blood (mainly cholesterol and triglycerides). The overall quality of the included studies was unclear because study authors did not provide important information for us to judge how the studies were performed (unclear risk of bias in most cases). In addition, the number of studies and participants is low and the study authors did not investigate important outcomes such as new onset of type 2 diabetes mellitus or side effects of zinc supplementation. This evidence is up to date as of March 2015.

10.1002/14651858.CD005525.pub3

cochrane-simplification-train-640

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Eighty-six studies met the inclusion criteria, recruiting 16,160 participants. In non-oral steroid treated asthmatics with mild and moderate disease FP resulted in improvements from baseline compared with placebo across all dose ranges (100 to 1000 mcg/d) in FEV1 (between 0.1 to 0.43 litres); morning PEF (between 23 and 46 L/min); symptom scores (based on a standardised scale, between 0.44 and 0.7); reduction in rescue beta-2 agonist use (between 1 and 1.4 puffs/day). High dose FP increased the number of patients who could withdraw from prednisolone: FP 1000-1500 mcg/day Peto Odds Ratio 14.07 (95% CI 7.17 to 27.57). FP at all doses led to a greater likelihood of sore throat, hoarseness and oral Candidiasis. Doses of FP in the range 100-1000 mcg/day are effective. In most patients with mild-moderate asthma improvements with low dose FP are only a little less than those associated with high doses when compared with placebo. High dose FP appears to have worthwhile oral-corticosteroid reducing properties. FP use is accompanied by an increased likelihood of oropharyngeal side effects.

This review found that it is highly effective even in low doses. The effect does appear to increase with higher doses, but these improvements are small. This drug is associated with symptoms such a thrush, sore throat and hoarseness and these get worse with higher doses. In people with severe asthma who need oral steroid tablets to control their asthma, it can reduce the dose of oral steroids they need and improve their asthma at the same time. However, high or very high doses are needed for this effect. The drug appears to work in children and adults.

10.1002/14651858.CD003135.pub4

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We included eight studies involving 353 children in the review. These studies reported different types of interventions (lignocaine or bupivacaine), observation times, and forms of measuring and describing the outcomes, making it difficult to conduct meta-analyses. In the comparison of infraorbital nerve block versus placebo, there was a large effect in mean postoperative pain scores (our first primary outcome) favouring the intervention group (standardised mean difference (SMD) -3.54, 95% confidence interval (CI) -6.13 to -0.95; very low-quality evidence; 3 studies; 120 children). Only one study reported the duration of analgesia (in hours) (second primary outcome) with a difference favouring the intervention group (mean difference (MD) 8.26 hours, 95% CI 5.41 to 11.11; very low-quality evidence) and less supplemental analgesic requirements in the intervention group (risk ratio (RR) 0.05, 95% CI 0.01 to 0.18; low-quality evidence). In the comparison of infraorbital nerve block versus intravenous analgesia, there was a difference favouring the intervention group in mean postoperative pain scores (SMD -1.50, 95% CI -2.40 to -0.60; very low-quality evidence; 2 studies; 107 children) and in the time to feeding (MD -9.45 minutes, 95% CI -17.37 to -1.53; moderate-quality evidence; 2 studies; 128 children). No significant adverse events (third primary outcome) were associated with the intervention, although three studies did not report this outcome. Five out of eight studies found no unwanted side effects after the nerve blocks. Overall, the included studies were at low or unclear risk of bias. The reasons for downgrading the quality of the evidence using GRADE related to the lack of information about randomisation methods and allocation concealment in the studies, very small sample sizes, and heterogeneity of outcome reporting. There is low- to very low-quality evidence that infraorbital nerve block with lignocaine or bupivacaine may reduce postoperative pain more than placebo and intravenous analgesia in children undergoing cleft lip repair. Further studies with larger samples are needed. Future studies should standardise the observation time and the instruments used to measure outcomes, and stratify children by age group.

We included eight studies with a total of 353 boys and girls, who ranged in age from 1 month to 13 years. These studies had been published up to June 2015. Three studies compared nerve block with sham block. Three studies compared nerve block with injected analgesics, and two studies compared nerve block with local anaesthesia. The children who received the infraorbital nerve block (with lignocaine or bupivacaine) had less pain and more time between finishing surgery and needing more analgesics. These children also had less need for analgesics than those who received the sham block. The children who received the infraorbital nerve block also had less pain and were able to eat sooner than those who received injected (intravenous) analgesics. The nerve block did not appear to alter heart rate, breath rate, and blood pressure. Five out of eight studies found no unwanted side effects after the nerve blocks; the other three studies did not mention side effects. The overall quality of the evidence was low or very low due to the small number of children included in the studies and differences between the studies (heterogeneity) regarding the types of intervention, the observation time, and the forms of measuring and describing the outcomes. Further studies with larger numbers of children are needed.

10.1002/14651858.CD011131.pub2

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We included 13 studies involving 4229 participants (six RCTs, n = 1096, five RCTs of intermediate risk of bias, one RCT of high risk of bias; four non-randomised experiments, n = 1639 and three observational studies, n = 1494). Ten studies tested nitroderivative drugs nifurtimox or benznidazole (three exposed participants to allopurinol, one to itraconazole). Five studies were conducted in Brazil, five in Argentina, one in Bolivia, one in Chile and one in Venezuela. TT was associated with substantial, but heterogeneous reductions on parasite-related outcomes such as positive serology (9 studies, OR 0.21, 95% CI 0.10 to 0.44, I2 = 76%), positive PCR (2 studies, OR 0.50, 95% CI 0.27 to 0.92, I2 = 0%), positive xenodiagnosis after treatment (6 studies, OR 0.35, 95% CI 0.14 to 0.86, I2 = 79%), or reduction on antibody titres (3 studies, SMD -0.56, 95% CI -0.89 to -0.23, I2 = 28%). Efficacy data on patient-related outcomes was largely from non-RCTs. TT with nitroderivatives was associated with potentially important, but imprecise and inconsistent reductions in progression of CCC (4 studies, 106 events, OR 0.74, 95% CI 0.32 to 1.73, I2 = 66%) and mortality after TT (6 studies, 99 events, OR 0.55, 95% CI 0.26 to 1.14, I2 = 48%). The overall median incidence of any severe side effects among 1475 individuals from five studies exposed to TT was 2.7%, and the overall discontinuation of this two-month therapy in RCTs (5 studies, 134 events) was 20.5% (versus 4.3% among controls) and 10.4% in other five studies (125 events). Despite the evidence that TT reduced parasite-related outcomes, the low quality and inconsistency of the data for patient-important outcomes must be treated with caution. More geographically diverse RCTs testing newer forms of TT are warranted in order to 1. estimate efficacy more precisely, 2. explore factors potentially responsible for the heterogeneity of results and 3. increase knowledge on the efficacy/tolerance balance of conventional TT.

We searched scientific databases for studies comparing TT versus a placebo (an inactive or pretend treatment) or no treatment in people with Trypanosoma cruzi infection. The search is current to February 2014. We identified 13 studies comparing the outcomes of 4229 people after receiving TT or placebo. Five of these studies were from Argentina, five from Brazil, one from Venezuela, one from Chile and one from Bolivia. Receiving TT was associated with a 50% to 90% smaller chance of having circulating antibodies or parasitic material, as compared with non-treated people. However, the results on progression towards Chagas disease or death indicate smaller benefits. Furthermore, the results were also statistically inconclusive, did not rule out potential harm and had substantial variation across studies conducted in different countries or testing different drugs. About one in five individuals treated abandoned the treatment and one in 40 treated individuals had a severe reaction (needing hospitalisation, additional treatments or interruption of this treatment). We conclude that although TT may reduce the progression of Chagas disease, better quality studies are warranted before its use can be generally recommended for chronically infected individuals. New data should bring more certainty of the efficacy of TT and provide a precise evaluation of the balance between benefits and harms. Because of the variations across studies, these studies should include populations from more regions and test newer drugs. Only 25% of these data came from good-quality studies. Although most studies were published since 2000, all studies tested drugs developed in the 1960s.

10.1002/14651858.CD003463.pub2

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Overall, there appeared to be an improvement in CVI related signs and symptoms with HCSE compared with placebo. Leg pain was assessed in seven placebo-controlled trials. Six reported a significant reduction of leg pain in the HCSE groups compared with the placebo groups, while another reported a statistically significant improvement compared with baseline. One trial suggested a weighted mean difference (WMD) of 42.4 mm (95% confidence interval (CI) 34.9 to 49.9) measured on a 100 mm visual analogue scale. Leg volume was assessed in seven placebo-controlled trials. Six trials (n = 502) suggested a WMD of 32.1ml (95% CI 13.49 to 50.72) in favour of HCSE compared with placebo. One trial indicated that HCSE may be as effective as treatment with compression stockings. Adverse events were usually mild and infrequent. The evidence presented suggests that HCSE is an efficacious and safe short-term treatment for CVI. However, several caveats exist and larger, definitive RCTs are required to confirm the efficacy of this treatment option.

Overall, the trials suggested an improvement in the symptoms of leg pain, oedema and pruritus with horse chestnut seed extract when taken as capsules over two to 16 weeks. Six placebo-controlled studies (543 participants) reported a clear reduction of leg pain when the herbal extract was compared with placebo. Similar results were reported for oedema, leg volume, leg circumference and pruritis. The other studies which compared the extract with rutosides (four trials), pycnogenol (one trial) or compression stockings (two trials) reported no significant differences between the therapies for leg pain or a symptom score that included leg pain. The herbal extract was equivalent to rutosides, pycnogenol and compression on the other symptoms with the exception that it was inferior to pycnogenol on oedema. The adverse events reported (14 trials) were mild and infrequent. They included gastrointestinal complaints, dizziness, nausea, headache and pruritus, from six studies.

10.1002/14651858.CD003230.pub4

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We included nine studies involving 1044 randomised participants. The studies took place in several countries and had different funding sources. No study was at low risk of bias in all domains. We classified all included studies as at unclear or high risk of bias in two or more domains. Seven included studies focused mainly on obstetric outcomes. One study included non-pregnancy-related cases, and one study included both pregnancy-related cases and other patients with positive results for aPL antibodies. The remaining studies concerned women with aPL antibodies and a history of pregnancy failure. Four studies compared anticoagulant with or without acetylsalicylic acid (ASA) versus ASA only and observed no clear difference in thrombosis risk (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.25 to 3.77; 4 studies; 493 participants; low-quality evidence). No major bleeding was reported, but minor bleeding risk (nasal bleeding, menorrhagia) was higher in the anticoagulant with ASA group as compared with ASA alone in one study (RR 22.45, 95% CI 1.34 to 374.81; 1 study; 164 participants; low-quality evidence). In one study ASA was compared with placebo, and there were no clear differences in thrombosis (RR 5.21, 95% CI 0.63 to 42.97; 1 study; 98 participants; low-quality evidence) or minor bleeding risk between the groups (RR 3.13, 95% CI 0.34 to 29.01; 1 study; 98 participants; low-quality evidence), and no major bleeding was observed. Two studies compared ASA with low molecular weight heparin (LMWH) versus placebo or intravenous immunoglobulin (IVIG), and no thrombotic events were observed in any of the groups. Moreover, there were no clear differences in the risk of bleeding requiring transfusion (RR 9.0, 95% CI 0.49 to 164.76; 1 study; 180 participants; moderate-quality evidence) or postpartum bleeding (RR 1.30, 95% CI 0.60 to 2.81; 1 study; 180 participants; moderate-quality evidence) between the groups. Two studies compared ASA with high-dose LMWH versus ASA with low-dose LMWF or unfractionated heparin (UFH); no thrombotic events or major bleeding was reported. Mortality and quality of life data were not reported for any of the comparisons. There is insufficient evidence to demonstrate benefit or harm of using anticoagulants with or without ASA versus ASA alone in people with aPL antibodies and a history of recurrent pregnancy loss and with no such history; ASA versus placebo in people with aPL antibodies; and ASA with LMWH versus placebo or IVIG, and ASA with high-dose LMWH versus ASA with low-dose LMWH or UFH, in women with aPL antibodies and a history of recurrent pregnancy loss, for the primary prevention of thrombotic events. In a mixed population of people with a history of previous pregnancy loss and without such a history treated with anticoagulant combined with ASA, the incidence of minor bleeding (nasal bleeding, menorrhagia) was increased when compared with ASA alone. Studies that are adequately powered and that focus mainly on thrombotic events are needed to draw any firm conclusions on the primary prevention of thrombotic events in people with antiphospholipid antibodies.

The evidence is current as of December 2017. We searched for studies that randomly allocated people with aPL antibodies and without any previous thrombotic event to different treatments, including anticoagulants, antiplatelet drugs, or both. We identified nine studies involving 1044 participants. The studies took place in several different countries. One study was multicentred and had a variety of funding sources. In two studies aspirin was compared with placebo (dummy treatment). Four studies compared an anticoagulant with or without aspirin with aspirin alone. The remaining studies compared combinations of antiplatelet agents, anticoagulants, other treatments, or two different doses of the same drug. The majority of the studies concerned women with aPL antibodies and a history of pregnancy failure. One study included non-pregnancy-related cases, and one study included pregnancy-related cases and other patients with positive results for aPL antibodies. We summarised the effects of the treatments using the following comparisons: aspirin only versus placebo, anticoagulant only or with aspirin versus aspirin only, aspirin with anticoagulant versus placebo or other treatment. We found no clear differences in the number of individuals with thrombotic events in the compared groups. One study revealed an increased risk of minor bleeding (such as nasal bleeding or intensified menstruation) in participants receiving aspirin and anticoagulant. All other analyses did not show any meaningful differences in the number of participants with bleeding. None of the studies reported on risk of death or quality of life. We found no clear difference between the groups in any of the comparisons for unwanted effects other than bleeding, where this information was reported; the more common of these effects included mild gastrointestinal symptoms in the aspirin group and allergic reactions in the aspirin with anticoagulant group. We assessed none of the studies as at low risk of bias because of methodological concerns or reporting of the results. We judged the overall quality of evidence to be low to moderate, it was downgraded due to unclear or high risk of bias, small number of studies and imprecise results.

10.1002/14651858.CD012534.pub2

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We identified 31 studies, and 13 fulfilled the criteria for inclusion. We described trials that were not eligible for the review in the Discussion. The included studies involved a total of 85 participants, but the number in each individual trial was small; the largest treatment trial included 19 participants and the smallest study included only one participant. There was no benefit with: D-ribose, glucagon, verapamil, vitamin B6, branched chain amino acids, dantrolene sodium, and high-dose creatine. Minimal subjective benefit was found with low dose creatine and ramipril only for patients with a polymorphism known as the D/D angiotensin converting enzyme (ACE) phenotype. A carbohydrate-rich diet resulted in better exercise performance compared with a protein-rich diet. Two studies of oral sucrose given at different times and in different amounts before exercise showed an improvement in exercise performance. Four studies reported adverse effects. Oral ribose caused diarrhoea and symptoms suggestive of hypoglycaemia including light-headedness and hunger. In one study, branched chain amino acids caused a deterioration of functional outcomes. Dantrolene was reported to cause a number of adverse effects including tiredness, somnolence, dizziness and muscle weakness. Low dose creatine (60 mg/kg/day) did not cause side-effects but high-dose creatine (150 mg/kg/day) worsened the symptoms of myalgia. Although there was low quality evidence of improvement in some parameters with creatine, oral sucrose, ramipril and a carbohydrate-rich diet, none was sufficiently strong to indicate significant clinical benefit.

After a wide search, we identified 13 randomised studies that included 85 participants with McArdle disease. This is an update of a review first published in 2004. We found no new trials at this update. The review found no benefit compared with placebo with the following treatments: D-ribose, glucagon, verapamil, vitamin B6, oral branched chain amino acids, dantrolene sodium, high-dose creatine and ramipril. Low dose creatine and ramipril produced minimal benefit for patients who also have the D/D angiotensin converting enzyme (ACE) phenotype. Taking low dose creatine supplements had a minor benefit in improving exercise tolerance in a small number of people with the condition. Taking a sugary drink before planned strenuous exercise can improve performance but this treatment is not practical for day-to-day living. A diet rich in carbohydrate may be superior to a diet rich in protein. Adverse effects were reported in four studies. Oral ribose caused symptoms suggestive of a low blood sugar including light-headedness, hunger and diarrhoea. One study of branched chain amino acids resulted in a deterioration in participants. Dantrolene was reported to cause a number of side-effects including tiredness, sleepiness, dizziness and muscle weakness. Low dose creatine (60 mg/kg/day) did not cause any side-effects but high-dose creatine (150 mg/kg/day) worsened the symptoms of muscle pain. The quality of these studies was low due to the small number of participants; the largest number in one trial was 19 and one trial had only one participant. The evidence is current to August 2014.

10.1002/14651858.CD003458.pub5

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This updated review includes 260 trials and 68 different antibiotics, including 24 cephalosporins and 43,451 participants. Many studies had multiple variables that separated the two study groups; these could not be compared to other studies that tested one antibiotic and had a single variable separating the two groups. We did not consider the risk of bias arising from attrition and lack of blinding of outcome assessors to affect the results for surgical wound infection. Meta-analyses demonstrated a statistically significant difference in postoperative surgical wound infection when prophylactic antibiotics were compared to placebo/no treatment (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.28 to 0.41, high quality evidence). This translates to a reduction in risk from 39% to 13% with prophylactic antibiotics. The slightly higher risk of wound infection with short-term compared with long-term duration antibiotic did not reach statistical significance (RR 1.10, 95% CI 0.93 to 1.30). Similarly risk of would infection was slightly higher with single-dose antibiotics when compared with multiple dose antibiotics, but the results are compatible with benefit and harm (RR 1.30, 95% CI 0.81 to 2.10). Additional aerobic coverage and additional anaerobic coverage both showed statistically significant improvements in surgical wound infection rates (RR 0.44, 95% CI 0.29 to 0.68 and RR 0.47, 95% CI 0.31 to 0.71, respectively), as did combined oral and intravenous antibiotic prophylaxis when compared to intravenous alone (RR 0.56, 95% CI 0.43 to 0.74), or oral alone (RR 0.56, 95% CI 0.40 to 0.76). Comparison of an antibiotic with anaerobic specificity to one with aerobic specificity showed no significant advantage for either one (RR 0.84, 95% CI 0.30 to 2.36). Two small studies compared giving antibiotics before or after surgery and no significant difference in this timing was found (RR 0.67, 95% CI 0.21 to 2.15). Established gold-standard regimens recommended in major guidelines were no less effective than any other antibiotic choice. This review has found high quality evidence that antibiotics covering aerobic and anaerobic bacteria delivered orally or intravenously (or both) prior to elective colorectal surgery reduce the risk of surgical wound infection. Our review shows that antibiotics delivered within this framework can reduce the risk of postoperative surgical wound infection by as much as 75%. It is not known whether oral antibiotics would still have these effects when the colon is not empty. This aspect of antibiotic dosing has not been tested. Further research is required to establish the optimal timing and duration of dosing, and the frequency of longer-term adverse effects such as Clostridium difficile pseudomembranous colitis.

The review found 260 studies which had recruited over 43 thousand people undergoing abdominal surgery. The studies had some limitations in relation to the number of people who remained in the studies and the possibility that the results were affected because some of the researchers in the studies knew which people had received antibiotics before surgery. However, when the results were analysed effect of prophylactic antibiotics was consistently beneficial meaning that these limitations were unlikely to have had a major impact on the nature of the overall results. Abdominal surgical wound infection in patients having operations on the large intestine occurs in about 40% of patients if antibiotics are not given. This risk can be greatly diminished by the administration of antibiotics prophylactically before surgery. The antibiotic(s) given usuallly needs to cover different types of bacteria some of which need oxygen (aerobic bacteria) and others which do not need oxygen (anaerobic bacteria).. They are usually given via a canula injected into a vein, though there is evidence that a combination of oral and intravenous antibiotics may provide more protection. This last finding raises a problem in that current clinical practice is to avoid mechanical cleansing of the colon because it is not thought to be necessary before surgery (and not popular with patients). Studies that found a benefit to oral antibiotics were done at a time when mechanical cleansing of the colon was routinely done. In the light of current practice regarding mechanical cleansing before surgery of the colon, the benefit of oral antibiotics is uncertain.

10.1002/14651858.CD001181.pub4

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We screened 3028 titles, and included one Italian cluster RCT with 16 general medicine wards (inpatient units in hospitals) and 232 carers of cancer patients in this updated review. We judged the study to be at a high risk of bias overall, mainly due to a lack of blinding and rates of attrition. Only 34% of the participants (range 14% to 75% on individual wards) were cared for in accordance with the care pathway as planned. However, these issues were to be expected due to the nature of the intervention and condition. The study population was all cancer patients in their last days of life. Participants were allocated to care using the Liverpool Care Pathway (LCP-I, Italian version of a continuous quality improvement programme of end-of-life care) or to standard care. The primary outcomes of this review were physical symptom severity, psychological symptom severity, quality of life, and any adverse effects. Physical symptom severity was assessed as overall control of pain, breathlessness, and nausea and vomiting. There was very low quality evidence of a difference in overall control of breathlessness that favoured the Liverpool Care Pathway group compared to usual care: the study reported an odds ratio (OR) of 2.0 with 95% confidence intervals (CIs) 1.1 to 3.8. Very low quality evidence of no difference was found for pain (OR 1.3, 95% CI 0.7 to 2.6, P = 0.461) and nausea and vomiting (OR 1.5, 95% CI 0.7 to 3.2, P = 0.252). None of the other primary outcomes were assessed by the study. Limited data on advance care planning were collected by the study authors, making results for this secondary outcome unreliable. None of our other secondary outcomes were assessed by the study. There is limited available evidence concerning the clinical, physical, psychological or emotional effectiveness of end-of-life care pathways.

In July 2015, we searched scientific databases for clinical trials in which the effect of the end-of-life care pathway was compared with a control group that received usual care, or with trials comparing one end-of-life care pathway with another end-of-life care pathway. Participants were patients, carers and families who received care guided by an end-of-life care pathway. There were no restrictions on age of the patient, diagnosis or setting (hospital, home, nursing home). In the current review we found one Italian study, in which information about 232 patients who were dying was provided by their informal carers (friends or family). Only 34% of the participants were cared for in accordance with the pathway. Breathlessness was better controlled for patients on the Liverpool Care Pathway compared to patients not on the pathway, but this is based on evidence from one small trial. The study did not report on important outcomes such as the severity of other physical or psychological symptoms or quality of life, or if there were any side effects associated with using the end-of-life care pathway. Nor were there questions about satisfaction with care, costs of the intervention, or quality of communication between carers and healthcare providers. We judged the included study to be of very low quality due to potential biases, including: not being able to prevent participants from knowing which group they were in (usual care or the care pathway group); the large number of carers who were initially enrolled, but who did not respond to follow-up questionnaires (this was particularly true for carers of patients in the wards where the care pathway was not used (control wards)); the low proportion of patients who actually received the care pathway (intervention) as planned; and that the study only included cancer patients in Italian hospitals; therefore, results might not apply to patients with other diseases.

10.1002/14651858.CD008006.pub4

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We included 11 trials in this review with a total of 1228 participants, ranging from age 45 to 94. The studies were generally at unclear risk of bias due to poorly reported trial methods. No study reported presenting visual acuity, so we report both uncorrected (UCVA) and best corrected visual acuity (BCVA). Studies varied in visual acuity assessment methods and time frames at which outcomes were reported. Participants in the phacoemulsification group were more likely to achieve UCVA of 6/12 or more at three months (risk ratio (RR) 1.81, 95% confidence interval (CI) 1.36 to 2.41, two studies, 492 participants) and one year (RR 1.99, 95% CI 1.45 to 2.73, one study, 439 participants). People in the phacoemulsification group were also more likely to achieve BCVA of 6/12 or more at three months (RR 1.12, 95% CI 1.03 to 1.22, four studies, 645 participants) and one year (RR 1.06, 95% CI 0.99 to 1.14, one study, 439 participants), but the difference between the two groups was smaller. No trials reported BCVA less than 6/60 but three trials reported BCVA worse than 6/9 and 6/18: there were fewer events of this outcome in the phacoemulsification group than the ECCE group at both the three-month (RR 0.33, 95% CI 0.20 to 0.55, three studies, 604 participants) and 12-month time points (RR 0.62, 95% CI 0.36 to 1.05, one study, 439 participants). Three trials reported posterior capsule rupture: this occurred more commonly in the ECCE group than the phacoemulsification group but small numbers of events mean the true effect is uncertain (Peto odds ratio (OR) 0.56, 95% CI 0.26 to 1.22, three studies, 688 participants). Iris prolapse, cystoid macular oedema and posterior capsular opacification were also higher in the ECCE group than the phacoemulsification group. Phacoemulsification surgical costs were higher than ECCE in two studies. A third study reported similar costs for phacoemulsification and ECCE up to six weeks postoperatively, but following this time point ECCE incurred additional costs due to additional visits, spectacles and laser treatment to achieve a similar outcome. Removing cataract by phacoemulsification may result in a better visual acuity compared to ECCE, with a lower complication rate. The review is currently underpowered to detect differences for rarer outcomes, including poor visual outcome. The lower cost of ECCE may justify its use in a patient population where high-volume surgery is a priority, however, there are a lack of data comparing phacoemulsification and ECCE in lower-income settings.

A search was performed of the literature in May 2013 for studies comparing the two techniques and 11 randomised controlled trials were identified which included a total of 1228 participants. These trials included participants with age-related cataract and were conducted in Europe, South America and the Far East. We evaluated these for any biases that may have affected the data, extracted data according to pre-determined criteria and performed analyses of the pooled data from all studies where possible. There were few studies that reported outcomes which met our pre-defined criteria. The studies were generally at unclear risk of bias due to poorly reported trial methods and the overall quality of the evidence for different outcomes ranged from moderate to very low. Phacoemulsification gave superior results at both three and 12-month time points. Complications were higher in the ECCE group than the phacoemulsification group. However, two out of three studies that reported costs indicated that ECCE was cheaper than phacoemulsification. In summary, on the basis of the few studies that reported outcomes that we could include in our analysis, visual outcomes were better with phacoemulsification and complications were lower with this technique. However, ECCE was cheaper and in lower income countries ECCE may therefore have a role in maximising the number of people that can be treated with limited resources.

10.1002/14651858.CD008812.pub2

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Our search identified no RCTs investigating the role of increased water intake for the prevention of urinary stone formation in participants with no history of urinary stones (primary prevention). We found one RCT assessing the effects of increased water intake versus standard water intake for the prevention of urinary stone formation in people with a history of urinary stones (secondary prevention). This trial randomised 220 participants (110 participants in the intervention group with increased water intake and 110 in the control group with standard water intake). Increased water intake was defined as achieving a urine volume of at least 2.0 L per day by drinking water. Based on this study, increased water intake may decrease stone recurrences (RR 0.45, 95% CI 0.24 to 0.84; 199 participants; low-certainty evidence); this corresponds to 149 fewer (43 fewer to 205 fewer) stone recurrences per 1000 participants with 270 stone recurrence per 1000 participants over five years in the control group. Increased water intake may also prolong the time to urinary stone recurrence compared to standard water intake (HR 0.40, 95% CI 0.20 to 0.79; 199 participants; low-certainty evidence); based on a stone recurrence rate of 270 per 1000 participants over five years, this corresponds to 152 fewer (209 fewer to 50 fewer) recurrences per 1000 participants. For both outcomes we downgraded the certainty of evidence for study limitations and imprecision. We found no evidence for the outcome of adverse events We found no RCT evidence on the role of increased water intake for primary prevention of urinary stones. For secondary prevention, increased water intake achieving a urine volume of at least 2.0 L/day may reduce urinary stone recurrence and prolong time to recurrence for people with a history of urinary stone disease. However, our confidence in these findings is limited. We did not find evidence for adverse events.

We examined research published up to October 2019. We included studies which by chance decided whether people were asked to drink more water (to produce at least 2 litres of urine) or were given no special instructions. We found no studies of people who had never had kidney stones. We found one study, performed in 220 people who had calcium-containing stones in the past, but were stone-free when they started the study. The average age was approximately 41 years, and two-thirds of participants were men. We found that drinking more water may reduce the risk of stones coming back. It may also prolong the time it takes for stones to come back. We found no evidence of unwanted effects. The certainty of evidence for both outcomes for which we found evidence was low. This means that the true results may be quite different.

10.1002/14651858.CD004292.pub4

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All studies were retrospective, and the majority reported consecutive sampling of cases. Sensitivity and specificity results were available from 38 studies involving 11,181 participants (3200 with invasive cancer, 1055 with borderline tumours and 6926 with benign tumours, determined by paraffin section as the reference standard). The median prevalence of malignancy was 29% (interquartile range (IQR) 23% to 36%, range 11% to 63%). We assessed test performance using two thresholds for the frozen section test. Firstly, we used a test threshold for frozen sections, defining positive test results as invasive cancer and negative test results as borderline and benign tumours. The average sensitivity was 90.0% (95% confidence interval (CI) 87.6% to 92.0%; with most studies typically reporting range of 71% to 100%), and average specificity was 99.5% (95% CI 99.2% to 99.7%; range 96% to 100%). Similarly, we analysed sensitivity and specificity using a second threshold for frozen section, where both invasive cancer and borderline tumours were considered test positive and benign cases were classified as negative. Average sensitivity was 96.5% (95% CI 95.5% to 97.3%; typical range 83% to 100%), and average specificity was 89.5% (95% CI 86.6% to 91.9%; typical range 58% to 99%). Results were available from the same 38 studies, including the subset of 3953 participants with a frozen section result of either borderline or invasive cancer, based on final diagnosis of malignancy. Studies with small numbers of disease-negative cases (borderline cases) had more variation in estimates of specificity. Average sensitivity was 94.0% (95% CI 92.0% to 95.5%; range 73% to 100%), and average specificity was 95.8% (95% CI 92.4% to 97.8%; typical range 81% to 100%). Our additional analyses showed that, if the frozen section showed a benign or invasive cancer, the final diagnosis would remain the same in, on average, 94% and 99% of cases, respectively. In cases where the frozen section diagnosis was a borderline tumour, on average 21% of the final diagnoses would turn out to be invasive cancer. In three studies, the same pathologist interpreted the index and reference standard tests, potentially causing bias. No studies reported blinding pathologists to index test results when reporting paraffin sections. In heterogeneity analyses, there were no statistically significant differences between studies with pathologists of different levels of expertise. In a hypothetical population of 1000 patients (290 with cancer and 80 with a borderline tumour), if a frozen section positive test result for invasive cancer alone was used to diagnose cancer, on average 261 women would have a correct diagnosis of a cancer, and 706 women would be correctly diagnosed without a cancer. However, 4 women would be incorrectly diagnosed with a cancer (false positive), and 29 with a cancer would be missed (false negative). If a frozen section result of either an invasive cancer or a borderline tumour was used as a positive test to diagnose cancer, on average 280 women would be correctly diagnosed with a cancer and 635 would be correctly diagnosed without. However, 75 women would be incorrectly diagnosed with a cancer and 10 women with a cancer would be missed. The largest discordance is within the reporting of frozen section borderline tumours. Investigation into factors leading to discordance within centres and standardisation of criteria for reporting borderline tumours may help improve accuracy. Some centres may choose to perform surgical staging in women with frozen section diagnosis of a borderline ovarian tumour to reduce the number of false positives. In their interpretation of this review, readers should evaluate results from studies most typical of their population of patients.

We included 38 studies (11,181 women), reporting three types of diagnoses from the frozen section test. 1. Cancer, which occurred in an average of 29% of women. 2. Borderline tumour, which occurred in 8% of women. 3. Benign mass. In a hypothetical group of 1000 patients where 290 have cancer and 80 have a borderline tumour, 261 women would receive a correct diagnosis of a cancer and 706 women would be correctly diagnosed without a cancer based on a frozen section result. However, 4 women would be incorrectly diagnosed as having a cancer where none existed (false positive), and 29 women with cancer would be missed and potentially need further treatment (false negative). If surgeons used a frozen section result of either a cancer or a borderline tumour to diagnose cancer, 280 women would be correctly diagnosed with a cancer and 635 women would be correctly diagnosed without a cancer. However, 75 women would be incorrectly diagnosed as having a cancer, and 10 women with cancer would be missed on the initial test and found to have a cancer after surgery. If the frozen section result reported the mass as benign or malignant, the final diagnosis would remain the same in, on average, 94% and 99% of the cases, respectively. In cases where the frozen section diagnosis was a borderline tumour, there is a chance that the final diagnosis would turn out to be a cancer in, on average, 21% of women. Where the frozen section diagnosis is a borderline tumour, the diagnosis is less accurate than for benign or malignant tumours. Surgeons may choose to perform additional surgery in this group of women at the time of their initial surgery in order to reduce the need for a second operation if the final diagnosis turns out to be a cancer, as it would on average in one out of five of these women.

10.1002/14651858.CD010360.pub2

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cochrane-simplification-train-651

We included twenty-six studies (2726 infants) in the analysis. The heterogeneity of participants, methods and results precluded an extensive quantitative synthesis. Of the 21 studies comparing iron supplementation with controls, none evaluated neurodevelopmental status as an outcome. Of thirteen studies reporting at least one growth parameter as an outcome, only one study of poor quality found a significant benefit of iron supplementation. Regarding haematological outcomes, no benefit for iron supplementation was demonstrated within the first 8.5 weeks of postnatal life (16 trials), except by two poor quality studies. After this age, most studies reported a higher mean haemoglobin in iron-supplemented infants. We were only able to include a limited number of studies in a quantitative meta-analysis, which suggested the haemoglobin concentration in iron-supplemented infants was higher by about 6 g/L at six to nine months. One study comparing high dose and low dose iron supplementation monitored neurodevelopmental outcome for one year, without finding any significant difference between the groups. One study comparing early versus late commencement of iron supplementation found no difference in cognitive outcome, but an increased rate of abnormal neurological examination in the late iron group at five years of age. The studies comparing high and low doses of iron indicated that there was no discernible haematological benefit in exceeding 'standard' doses of iron (i.e. 2 mg/kg/day to 3 mg/kg/day). The available data suggest that infants who receive iron supplementation have a slightly higher haemoglobin level, improved iron stores and a lower risk of developing iron deficiency anaemia when compared with those who are unsupplemented. However, it is unclear whether iron supplementation in preterm and low birth weight infants has long term benefits in terms of neurodevelopmental outcome and growth. The optimum timing and duration of iron supplementation remains unclear.

This review examined whether providing iron supplementation is beneficial for preterm and low birth weight infants. The potential benefits included improvements in the level of red blood cells and stored iron in their blood. In the longer term, it was thought that iron supplementation might improve the babies' growth and development. We identified 25 randomised controlled trials (RCTs) which were relevant to this topic. We concluded that the long term benefits of iron supplementation for preterm and low birth weight babies remain uncertain. Regarding red blood cell and iron levels, it was found that in the first year of life, after two months of age, iron supplementation may result in slightly higher iron stores and red blood cell levels, and lower rates of iron deficiency anaemia. However, there was a lot of variability between different studies. More RCTs are needed, using well defined patient groups.

10.1002/14651858.CD005095.pub2

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cochrane-simplification-train-652

Seventeen studies were not randomised and this increases the potential for selection bias. In addition, there was imbalance in the baseline characteristics of the participants included in all studies. All studies were classified as having a elevate risk of bias. The assessment of methodological quality of all non-randomized studies included in meta-analysis performed by the STROBE checklist has allowed us to identify several methodological limits in most of the analysed studies. At present, the information from the single RCT included (Ruers 2010) comes from an abstract of 2010 ASCO Annual Meeting where the allocation concealment was not reported; however in original protocol allocation concealment was adequately reported (EORTC 40004 protocol). The heterogeneity regarding interventions, comparisons and outcomes rendered the data not suitable. This systematic review gathers information from several controlled clinical trials and observational studies which are vulnerable to different types of bias. The imbalance between characteristics of patients in the allocated groups appears to be the main concern. Only one randomised clinical trial (published as an abstract), comparing 60 patients receiving RFA plus CT versus 59 patients receiving CT alone, was identified. This study showed that PFS was significantly higher in the group that received RFA. However, it was not able to provide information on overall survival. In conclusion, evidence from the included studies are insufficient to recommend RFA for a radical oncological treatment of CRLMs.

According to several studies RFA is technically feasible and safe for the treatment of CRLMs, however little is known about its efficacy in terms of overall survival (OS), disease free survival (DFS) and local recurrence. The aim of this review was to see if the treatment of CRLMs with RFA provides more benefit in terms of overall survival, disease free survival and local recurrence. This review include 18 studies (10 observational studies, 7 CCTs and an additional 1 RCT) comparing radiofrequency ablation with any other treatment. The heterogeneity regarding interventions, comparisons and outcomes rendered the data unusable and unsuitable for drawing conclusions. There is insufficient evidence to recommend the use of radiofrequency ablation for a radical treatment of liver metastases from colorectal cancer. High quality randomised clinical trials are required to answer on the potential benefit and harms associated with the use of radiofrequency ablation in the treatment of liver metastases from colorectal cancer.

10.1002/14651858.CD006317.pub3

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cochrane-simplification-train-653

Six studies are included in this review. Three studies were mainly conducted in adults, two were conducted in older children (5 to16 years) and one in infants (18 to 25 months). Trial duration was 4 to 52 weeks. Doses of oxatomide varied between studies, ranging from 1 mg/kg/day for infants to 180 mg/day for adults. Only data on adverse events was suitable for meta-analysis. Although PEF did not change significantly in any of the studies, the FVC and FEV1 improved significantly in two. There was no uniform change in symptom scores. There was no significant difference between oxatomide and placebo treatment in use of inhaled corticosteroid or bronchodilator. Two studies showed significant improvement with oxatomide as judged subjectively by physicians. Adverse events, analysed using data from four parallel and one cross over study, showed oxatomide to be associated with a significantly higher risk of any adverse event (OR: 2.97, 95%CI: 1.69 to 5.22) and drowsiness (OR: 5.22,95%CI: 2.53 to 10.74). There is no evidence to show that oxatomide has a significant effect on the control of stable asthma. Some studies reported significant benefits in subjective parameters. There was improvement in some lung function outcomes reported, but this were not consistent across measures or studies and may represent reporting bias. Adverse events, including drowsiness, were significantly greater with oxatomide than placebo.

Six randomised controlled studies of the effect of oxatomide were identified. All studies compared oxatomide with placebo. Two studies showed significant improvement with oxatomide as judged subjectively by the doctor. There was significant difference shown between oxatomide and placebo on objective outcomes (outcomes that are not influenced by people's opinions such as lung function or the amount of regular asthma medication taken by participants during the course of the study). Adverse effects were the only outcome able to be combined in a meta-analysis, and these were significantly more likely with oxatomide than with placebo treatment.

10.1002/14651858.CD002179

cochrane-simplification-train-654

cochrane-simplification-train-654

We found three RCTs with a total of 58 participants that were eligible for inclusion. There was significant variability between the trials in interventions, methodology and outcome measures and therefore we did not perform meta-analysis. One study reported on the use of 2% CsA in maize oil and two on the use of a commercial emulsion of 0.05% CsA. Of these three studies, one showed a beneficial effect of topical CsA in controlling signs and symptoms of AKC, one in controlling signs of AKC and one did not show evidence of an improvement. Only two studies analysed the effect of topical CsA in reducing topical steroid use; one showed a significant reduction in topical steroid use with CsA, but the other did not show evidence of this improvement. No serious adverse events were reported in the trials. This systematic review highlights the relative scarcity of controlled clinical trials assessing the efficacy of topical CsA therapy in AKC and suggests that evidence on the efficacy and safety of topical CsA treatment in patients with CsA remains limited. However, the data suggest that topical CsA may provide clinical and symptomatic relief in AKC and may help to reduce topical steroid use in patients with steroid-dependent or steroid-resistant AKC. No serious adverse events were reported. Reported adverse events in patients treated with topical CsA include intense stinging and eyelid skin maceration. One patient in the placebo group developed a severe allergic response to maize antigens. However, the total number of patients in the trials was too small to assess the safety of this treatment. Additional well-designed and powered RCTs of topical CsA in AKC are needed. Ideal study designs should include adequate randomisation and concealment of allocation; masking of participants, personnel and outcome assessors; adequate follow-up periods and minimisation of attrition bias; and comparison groups with similar clinical and epidemiologic characteristics. Samples should be large enough to provide sufficient statistical power to assess the safety of CsA and to detect clinically relevant treatment effect sizes of the primary outcomes. Analyses should be appropriate to the study’s design and outcome measures. Moreover, standardisation of outcome measures and follow-up periods across studies would be beneficial to maximise study comparability.

Three eligible studies with a total of 58 participants were included in this review. One study was conducted in the UK, one in Australia and one had multicentre sites in the UK and US. These studies varied significantly in interventions, methodology and reported outcomes. One study used 2% CsA in maize oil, and two used a commercial emulsion of 0.05% CsA. Of these three studies, two showed a beneficial effect of topical CsA in controlling signs of AKC, and one did not find evidence of this improvement. One study showed a beneficial effect of topical CsA in controlling symptoms of AKC, but the other two did not find evidence of this improvement. Only two studies analysed the effect of topical CsA in reducing topical steroid use; one showed a significant reduction in topical steroid use with CsA, but the other could not find evidence of this improvement. The data suggest that topical CsA may provide clinical and symptomatic relief in AKC and may help to reduce topical steroid use in patients with steroid-dependent or steroid-resistant AKC. Moreover, no serious adverse events were detected. However, this review has identified a need for more randomised controlled trials to provide further reliable evidence on the efficacy and safety of topical treatment with CsA eyedrops for patients with AKC. These trials should include larger samples of patients with AKC, and their follow-up periods should be long enough to draw conclusions on the long-term efficacy and safety of this therapy.

10.1002/14651858.CD009078.pub2

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cochrane-simplification-train-655

Two randomized controlled trials, for a total of 182 infants, met the inclusion criteria of this review. Both trials compared antithrombin with placebo. We found no significant differences in the rates of intraventricular hemorrhage (typical RR 1.30, CI 95% 0.87 to 1.93, typical RD 0.09, 95% CI −0.05 to 0.23; 2 studies, 175 infants; I² = 18% for RR and I² = 42% for RD) and severe intraventricular hemorrhage (typical RR 1.04, CI 95% 0.55 to 1.94; typical RD 0.01, 95% CI −0.11 to 0.12; 2 studies, 175 infants; I² = 0% for RR and I² = 0% for RD). Among secondary outcomes, we found no significant differences in terms of neonatal mortality (typical RR 2.00, CI 95% 0.62 to 6.45; typical RD 0.04, 95% CI −0.03 to 0.12; 2 studies, 182 infants; I² = 46% for RR and I² = 61% for RD) and in the other specified outcomes, such as bronchopulmonary dysplasia. The quality of the evidence supporting these findings is limited due to the imprecision of the estimates. The administration of antithrombin seems not to reduce the incidence and severity of intraventricular hemorrhage in very preterm infants. Limited evidence is available on other clinically relevant outcomes. Given the imprecision of the estimate, the results of this systematic review are consistent with either a benefit or a detrimental effect of antithrombin and do not provide a definitive answer to the review question.

We included two trials for a total of 182 newborn infants comparing antithrombin with placebo (sugar or albumin solution). The use of antithrombin does not reduce the risks of bleeding in the brain, mortality or any other relevant outcomes in very preterm neonates when compared to placebo. However, the data collected are too limited to draw definitive conclusions on the use of antithrombin in the prevention of intraventricular hemorrhage (i.e. bleeding in the brain). The results of this systematic review are consistent with either a benefit or a detrimental effect of antithrombin and do not provide a definitive answer to the review question.

10.1002/14651858.CD011636.pub2

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cochrane-simplification-train-656

Ninety-eight studies, involving 2,605,044 people, are included in this review. Fifty-four studies involving 812,705 people were comparable enough to be included in at least one meta-analysis. Thirty-five (65%) studies were RCTs. Nineteen (35%) of the studies included in the meta-analysis provided IPD. There was a lack of evidence that home safety interventions reduced rates of thermal injuries or poisoning. There was some evidence that interventions may reduce injury rates after adjusting CBA studies for baseline injury rates (IRR 0.89, 95% CI 0.78 to 1.01). Greater reductions in injury rates were found for interventions delivered in the home (IRR 0.75, 95% CI 0.62 to 0.91), and for those interventions not providing safety equipment (IRR 0.78, 95% CI 0.66 to 0.92). Home safety interventions were effective in increasing the proportion of families with safe hot tap water temperatures (OR 1.41, 95% CI 1.07 to 1.86), functional smoke alarms (OR 1.81, 95% CI 1.30 to 2.52), a fire escape plan (OR 2.01, 95% CI 1.45 to 2.77), storing medicines (OR 1.53, 95% CI 1.27 to 1.84) and cleaning products (OR 1.55, 95% CI 1.22 to 1.96) out of reach, having syrup of ipecac (OR 3.34, 95% CI 1.50 to 7.44) or poison control centre numbers accessible (OR 3.30, 95% CI 1.70 to 6.39), having fitted stair gates (OR 1.61, 95% CI 1.19 to 2.17), and having socket covers on unused sockets (OR 2.69, 95% CI 1.46 to 4.96). Interventions providing free, low cost or discounted safety equipment appeared to be more effective in improving some safety practices than those interventions not doing so. There was no consistent evidence that interventions were less effective in families whose children were at greater risk of injury. Home safety interventions most commonly provided as one-to-one, face-to-face education, especially with the provision of safety equipment, are effective in increasing a range of safety practices. There is some evidence that such interventions may reduce injury rates, particularly where interventions are provided at home. Conflicting findings regarding interventions providing safety equipment on safety practices and injury outcomes are likely to be explained by two large studies; one clinic-based study provided equipment but did not reduce injury rates and one school-based study did not provide equipment but did demonstrate a significant reduction in injury rates. There was no consistent evidence that home safety education, with or without the provision of safety equipment, was less effective in those participants at greater risk of injury. Further studies are still required to confirm these findings with respect to injury rates.

Injuries are the leading cause of childhood death in industrialised countries. People living in disadvantaged circumstances are at greater risk of injury than those who are more advantaged. This review examined whether home safety education and providing safety equipment reduced injuries and increased safety behaviours and safety equipment use. It also looked at whether home safety education was more or less effective in disadvantaged families. The review authors found 98 studies involving 2,605,044 participants which reported many different safety behaviours, but relatively few studies included information on injuries. The authors found that home safety interventions provided in the home may reduce injury rates, but more research is needed to confirm this finding. The results often varied between studies but, overall, families who received home safety interventions were more likely to have a safe hot tap water temperature, a working smoke alarm, a fire escape plan, fitted stair gates, socket covers on unused sockets, syrup of ipecac, poison control centre numbers accessible, and to store medicines and cleaning products out of reach of children. The authors found that home safety education was equally effective in the families whose children were at greater risk of injury.

10.1002/14651858.CD005014.pub3

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cochrane-simplification-train-657

Eighteen RCTs with 1250 participants met our inclusion criteria. The studies were conducted in hospital settings in low, middle and high income countries. Blood loss We found significant reductions in blood loss with the following interventions: vaginal misoprostol (2 RCTs, 89 women: MD -97.88 ml, 95% CI -125.52 to -70.24; I2 = 43%; moderate-quality evidence); intramyometrial vasopressin (3 RCTs, 128 women: MD -245.87 ml, 95% CI -434.58 to -57.16; I2 = 98%; moderate-quality evidence); intramyometrial bupivacaine plus epinephrine (1 RCT, 60 women: MD -68.60 ml, 95% CI -93.69 to -43.51; low-quality evidence); intravenous tranexamic acid (1 RCT, 100 women: MD -243 ml, 95% CI -460.02 to -25.98; low-quality evidence); gelatin-thrombin matrix (1 RCT, 50 women: MD -545.00 ml, 95% CI -593.26 to -496.74; low-quality evidence); intravenous ascorbic acid (1 RCT, 102 women: MD -411.46 ml, 95% CI -502.58 to -320.34; low-quality evidence); vaginal dinoprostone (1 RCT, 108 women: MD -131.60 ml, 95% CI -253.42 to -9.78; low-quality evidence); loop ligation of the myoma pseudocapsule (1 RCT, 70 women: MD -305.01 ml, 95% CI -354.83 to -255.19; low-quality evidence); a fibrin sealant patch (1 RCT, 70 women: MD -26.50 ml, 95% CI -44.47 to -8.53; low-quality evidence), a Foley catheter tied around the cervix (1 RCT, 93 women: MD -240.70 ml, 95% CI -359.61 to -121.79; low-quality evidence), and a polyglactin suture round both cervix and infundibulopelvic ligament (1 RCT, 28 women: MD -1870.0 ml, 95% CI -2547.16 to 1192.84; low-quality evidence). There was no good evidence of an effect on blood loss with oxytocin, morcellation or clipping of the uterine artery. Need for blood transfusion We found significant reductions in the need for blood transfusion with vasopressin (2 RCTs, 90 women: OR 0.15, 95% CI 0.03 to 0.74; I2 = 0%; moderate-quality evidence); tourniquet tied round the cervix (1 RCT, 98 women: OR 0.22, 95% CI 0.09 to 0.55; low-quality evidence); tourniquet tied round both cervix and infundibulopelvic ligament (1 RCT, 28 women: OR 0.02, 95% CI 0.00 to 0.23; low-quality evidence); gelatin-thrombin matrix (1 RCT, 100 women: OR 0.01, 95% CI 0.00 to 0.10; low-quality evidence) and dinoprostone (1 RCT, 108 women: OR 0.17, 95% CI 0.04 to 0.81; low-quality evidence), but no evidence of effect on the need for blood transfusion with misoprostol, oxytocin, tranexamic acid, ascorbic acid, loop ligation of the myoma pseudocapsule and a fibrin sealant patch. There were insufficient data on the adverse effects and costs of the different interventions. At present there is moderate-quality evidence that misoprostol or vasopressin may reduce bleeding during myomectomy, and low-quality evidence that bupivacaine plus epinephrine, tranexamic acid, gelatin-thrombin matrix, ascorbic acid, dinoprostone, loop ligation, a fibrin sealant patch, a peri-cervical tourniquet or a tourniquet tied round both cervix and infundibulopelvic ligament may reduce bleeding during myomectomy. There is no evidence that oxytocin, morcellation and temporary clipping of the uterine artery reduce blood loss. Further well designed studies are required to establish the effectiveness, safety and costs of different interventions for reducing blood loss during myomectomy.

The evidence is current to June 2014. The review included 18 studies with a total of 1250 women who had myomectomy for uterine fibroids. All studies compared an intervention to reduce bleeding during myomectomy with either a placebo or no such treatment. The data available suggest that vaginal insertion of misoprostol and infiltration of vasopressin into the uterine muscle are effective in reducing bleeding during myomectomy. Limited data available also suggest that chemical dissection (such as with mesna), vaginal insertion of dinoprostone, a gelatin-thrombin matrix, tranexamic acid, infusion of vitamin C (ascorbic acid) during surgery, infiltration of a mixture of bupivacaine and epinephrine into the uterine muscles, the use of fibrin sealant patch (a surgical patch that improves blood clotting) or a tourniquet around the cervix or around both the cervix and the infundibulopelvic ligamentmay be effective in reducing bleeding during myomectomy. We found limited information on the harms (adverse effects) of the different interventions. There is moderate-quality evidence that misoprostol reduces blood loss by between 70.24 ml and 125.52 ml; with a laparotomy vasopressin reduces blood loss by between 392.51 and 507.49 ml during myomectomy, and by between 121.73 ml and 172.17 ml during laparoscopic myomectomy. There is low-quality evidence for the rest of the interventions (chemical dissection, dinoprostone, gelatin-thrombin matrix, tranexamic acid, vitamin C, mixture of bupivacaine and epinephrine, a fibrin sealant patch and the two types of tourniquet).

10.1002/14651858.CD005355.pub5

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cochrane-simplification-train-658

53 trials were included, most of which were cluster-randomised. The reporting quality of trials was poor, only 3.8% of them reporting adequate method of randomisation and program allocation concealment. Incomplete data was adequately addressed in 23% of the trials. Due to extensive heterogeneity across interventions, populations, and outcomes, the results were summarized only qualitatively. Six of the 11 trials evaluating alcohol-specific interventions showed some evidence of effectiveness compared to a standard curriculum. In 14 of the 39 trials evaluating generic interventions, the program interventions demonstrated significantly greater reductions in alcohol use either through a main or subgroup effect. Gender, baseline alcohol use, and ethnicity modified the effects of interventions. Results from the remaining 3 trials with interventions targeting cannabis, alcohol, and/or tobacco were inconsistent. This review identified studies that showed no effects of preventive interventions, as well as studies that demonstrated statistically significant effects. There was no easily discernible pattern in characteristics that would distinguish trials with positive results from those with no effects. Most commonly observed positive effects across programs were for drunkenness and binge drinking. Current evidence suggests that certain generic psychosocial and developmental prevention programs can be effective and could be considered as policy and practice options. These include the Life Skills Training Program, the Unplugged program, and the Good Behaviour Game. A stronger focus of future research on intervention program content and delivery context is warranted.

We conducted a Cochrane systematic review of 53 well-designed experimental studies that examined the effectiveness of school-based universal programs for the prevention of alcohol misuse in young people. The studies were divided into two major groups based on the nature of the prevention program: 1) programs targeting specifically prevention or reduction of alcohol misuse and 2) generic programs with wider focus for prevention (e.g., other drug use/abuse, antisocial behavior). In the review we found studies that showed no effects of the preventive program, as well as studies that demonstrated statistically significant effects. There was no easily discernible pattern in program characteristics that would distinguish studies with positive results from those with no effects. Most commonly observed positive effects across programs were for drunkenness and binge drinking. In conclusion, current evidence suggests that certain generic psychosocial and developmental prevention programs can be effective and could be considered as policy and practice options. These include the Life Skills Training Program, the Unplugged program, and the Good Behaviour Game.

10.1002/14651858.CD009113

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cochrane-simplification-train-659

Four studies (187 children) met the inclusion criteria. Three studies were carried out in children with cystic fibrosis and one study included children with paediatric malignant disease. Overall there was a low risk of bias for blinding and incomplete outcome data.Two studies had a high risk of bias for allocation concealment. Few statistical differences were found in the outcomes we assessed between treatment and control groups, except change in total energy intake at six and 12 months, mean difference 304.86 kcal per day (95% confidence interval 5.62 to 604.10) and mean difference 265.70 kcal per day (95% confidence interval 42.94 to 485.46), respectively. However, these were based on the analysis of just 58 children in only one study. Only two chronic diseases were included in these analyses, cystic fibrosis and paediatric malignant disease. No other studies were identified which assessed the effectiveness of oral protein calorie supplements in children with other chronic diseases. Oral protein calorie supplements are widely used to improve the nutritional status of children with a number of chronic diseases. We identified a small number of studies assessing these products in children with cystic fibrosis and paediatric malignant disease, but were unable to draw any conclusions based on the limited data extracted. We recommend a series of large, randomised controlled trials be undertaken investigating the use of these products in children with different chronic diseases. Until further data are available, we suggest these products are used with caution.

We looked for trials of oral protein calorie supplements compared to usual treatment or no alternative treatment where the children took the supplements for at least one month. The review included four trials with 187 children; in three of these the children had cystic fibrosis and in one they had cancer. Studies lasted from three months to one year. We recorded the results and judged whether the trials were at risk of being biased based on the design or the way it was run. We looked at outcomes such as weight and height, calorie intake, behaviour and also side effects. One study (with 58 children) showed increases in the total calories consumed at both six and 12 months. None of the other outcomes we looked at showed any difference between treatments. This is an updated version of the review, which found no conclusive evidence to support the use of oral protein supplements. We suggest that at least one high quality trial be conducted.Therefore, we suggest that these products are used sparingly and with caution. Overall the included studies had a low risk of bias, except for two studies in which it was possible that the organisers knew which treatment group in which the children would be placed. These issues are unlikely to change the results as knowing which treatment one receives is unlikely to affect the results of body measurements (e.g. weight, height outcomes). All planned outcomes were reported on, with the exception of one study that did not report on eating behaviour and lipase intake which were measured. The quality of the results for the eating behaviour assessment was questionable and many of the children did not return the food diaries from which the lipase intake could be calculated.

10.1002/14651858.CD001914.pub2

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cochrane-simplification-train-660

Eight studies involving 22,018 participants met our eligibility criteria. Five studies (n = 18,962) assessed the safety and effectiveness of surgical abortion procedures administered by mid-level providers compared to doctors. Three studies (n = 3056) assessed the safety and effectiveness of medical abortion procedures. The surgical abortion studies (one RCT and four cohort studies) were carried out in the United States, India, South Africa and Vietnam. The medical abortion studies (two RCTs and one cohort study) were carried out in India, Sweden and Nepal. The studies included women with gestational ages up to 14 weeks for surgical abortion and nine weeks for medical abortion. Risk of selection bias was considered to be low in the three RCTs, unclear in four observational studies and high in one observational study. Concealment bias was considered to be low in the three RCTs and high in all five observational studies. Although none of the eight studies performed blinding of the participants to the provider type, we considered the performance bias to be low as this is part of the intervention. Detection bias was considered to be high in all eight studies as none of the eight studies preformed blinding of the outcome assessment. Attrition bias was low in seven studies and high in one, with over 20% attrition. We considered six studies to have unclear risk of selective reporting bias as their protocols had not been published. The remaining two studies had published their protocols. Few other sources of bias were found. Based on an analysis of three cohort studies, the risk of surgical abortion failure was significantly higher when provided by mid-level providers than when procedures were administered by doctors (RR 2.25, 95% CI 1.38 to 3.68), however the quality of evidence for this outcome was deemed to be very low. For surgical abortion procedures, we found no significant differences in the risk of complications between mid-level providers and doctors (RR 0.99, 95% CI 0.17 to 5.70 from RCTs; RR 1.38, 95% CI 0.70 to 2.72 from observational studies). When we combined the data for failure and complications for surgical abortion we found no significant differences between mid-level providers and doctors in both the observational study analysis (RR 1.36, 95% CI 0.86 to 2.14) and the RCT analysis (RR 3.07, 95% CI 0.16 to 59.08). The quality of evidence of the outcome for RCT studies was considered to be low and for observational studies very low. For medical abortion procedures the risk of failure was not different for mid-level providers or doctors (RR 0.81, 95% CI 0.48 to 1.36 from RCTs; RR 1.09, 95% CI 0.63 to 1.88 from observational studies). The quality of evidence of this outcome for the RCT analysis was considered to be high, although the quality of evidence of the observational studies was considered to be very low. There were no complications reported in the three medical abortion studies. There was no statistically significant difference in the risk of failure for medical abortions performed by mid-level providers compared with doctors. Observational data indicate that there may be a higher risk of abortion failure for surgical abortion procedures administered by mid-level providers, but the number of studies is small and more robust data from controlled trials are needed. There were no statistically significant differences in the risk of complications for first trimester surgical abortions performed by mid-level providers compared with doctors.

We carried out searches for studies that compared medical abortion (using pills) or surgical abortion provided by either mid-level providers or doctors. We also wrote to researchers to find more studies. The studies could compare how safe the abortions were or how effective they were (whether they actually worked). The evidence we found is up to date as of the 15th of August 2014. We found eight studies with a total of 22,018 participants. Five studies compared surgical abortion provided by doctors or mid-level providers and three studies compared medical abortion provided by doctors or mid-level providers. Of the five surgical abortion studies only one had a high-quality study design. Of the three medical abortion studies, two had a high-quality study design. Three of these studies were carried out in America, two in India, one in was carried out in both South Africa and Vietnam the remaining two were from Sweden and Nepal. The results from the analyses of the medical abortion studies showed that there does not seem to be an advantage when these are provided by doctors. The results from most of the analyses of the surgical abortion studies showed that we cannot be sure that there is a difference in how safe and how effective mid-level providers are compared to doctors. One analysis of three low-quality studies of surgical abortion showed that there was more chance of the abortion being ineffective if it was provided by mid-level providers. Most of the studies did not show a difference between mid-level providers and doctors in how safe the abortions were and how well they worked. Training mid-level providers to give medical or surgical abortions could reduce the number of deaths and the disability caused by unsafe abortion. Studies in the future should focus on what types of mid-level providers can provide safe and effective abortions. They should also look at whether mid-level providers are as safe and effective as doctors for providing abortions in rural developing country settings.

10.1002/14651858.CD011242.pub2

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cochrane-simplification-train-661

We included eight studies involving 4488 participants. Regarding quality of evidence, trials showed differences in study population, study design, type of antibiotic, and definition of infection; however, primary outcomes among the included studies were consistent. Mortality rate in the preventive antibiotic group was not significantly different from that in the control group (373/2208 (17%) vs 360/2214 (16%); RR 1.03, 95% confidence interval (CI) 0.87 to 1.21; high-quality evidence). The number of participants with a poor functional outcome (death or dependency) in the preventive antibiotic therapy group was also not significantly different from that in the control group (1158/2168 (53%) vs 1182/2164 (55%); RR 0.99, 95% CI 0.89 to 1.10; moderate-quality evidence). However, preventive antibiotic therapy did significantly reduce the incidence of 'overall' infections in participants with acute stroke from 26% to 19% (408/2161 (19%) vs 558/2156 (26%); RR 0.71, 95% CI 0.58 to 0.88; high-quality evidence). This finding was highly significant for urinary tract infections (81/2131 (4%) vs 204/2126 (10%); RR 0.40, 95% CI 0.32 to 0.51; high-quality evidence), whereas no preventive effect for pneumonia was found (222/2131 (10%) vs 235/2126 (11%); RR 0.95, 95% CI 0.80 to 1.13; high-quality evidence). No major side effects of preventive antibiotic therapy were reported. Only two studies qualitatively assessed the occurrence of elevated body temperature; therefore, these results could not be pooled. Only one study reported length of hospital stay. Preventive antibiotics had no effect on functional outcome or mortality, but significantly reduced the risk of 'overall' infections. This reduction was driven mainly by prevention of urinary tract infection; no effect for pneumonia was found.

We included eight studies on preventive antibiotic therapy, with a total of 4488 people with stroke: 2230 participants were randomised to preventive antibiotic therapy, and 2258 to control. The mean age of participants in the preventive antibiotics group was 74.2 years, and in the control group 74.8 years. In both groups, the percentage of men was 52%. Study interventions differed in all eight studies; in two studies, trialists selected the (type of) antibiotic according to local antibiotic policy, with the aim of treating pneumonia. Preventive antibiotic treatment did not reduce the risk of dependency or death. However, preventive antibiotic therapy did significantly reduce the occurrence of 'overall' infections from 26% to 19%. Regarding type of infection, findings were highly significant for urinary tract infections (4% vs 10%) but showed no effect on pneumonia (10% vs 11%). No major side effects of preventive antibiotic therapy were reported. It has become possible to draw first 'overall' conclusions on the net effect of preventive antibiotic therapy in stroke; however, the decision of whether to use preventive antibiotic therapy in acute stroke should be reached with care. Studies were heterogeneous, and despite the large numbers of participants, results from a total of eight studies are limited. In two of these studies, risk of bias was considered to be high for three out of six criteria. Overall, reviewers considered the quality of evidence for the main outcomes of this review - looking at 'any' preventive antibiotic therapy, in 'any' dose, at any length of treatment - as high to moderate.

10.1002/14651858.CD008530.pub3

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cochrane-simplification-train-662

We included 63 studies with 7768 participants; six studies were quasi-randomized and the remaining were RCTs. All participants were undergoing cardiac surgery, and in most studies, at least some of the participants were previously taking beta-blockers. Types of beta-blockers were: propranolol, metoprolol, sotalol, esmolol, landiolol, acebutolol, timolol, carvedilol, nadolol, and atenolol. In twelve studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in nine studies this was before surgery, in 20 studies during surgery, and in the remaining studies beta-blockers were started postoperatively. Overall, we found that most studies did not report sufficient details for us to adequately assess risk of bias. In particular, few studies reported methods used to randomize participants to groups. In some studies, participants in the control group were given beta-blockers as rescue therapy during the study period, and all studies in which the control was standard care were at high risk of performance bias because of the open-label study design. No studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. We judged 68% studies to be at high risk of bias in at least one domain. Study authors reported few deaths (7 per 1000 in both the intervention and control groups), and we found low-certainty evidence that beta-blockers may make little or no difference to all-cause mortality at 30 days (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.47 to 1.90; 29 studies, 4099 participants). For myocardial infarctions, we found no evidence of a difference in events (RR 1.05, 95% CI 0.72 to 1.52; 25 studies, 3946 participants; low-certainty evidence). Few study authors reported cerebrovascular events, and the evidence was uncertain (RR 1.37, 95% CI 0.51 to 3.67; 5 studies, 1471 participants; very low-certainty evidence). Based on a control risk of 54 per 1000, we found low-certainty evidence that beta-blockers may reduce episodes of ventricular arrhythmias by 32 episodes per 1000 (RR 0.40, 95% CI 0.25 to 0.63; 12 studies, 2296 participants). For atrial fibrillation or flutter, there may be 163 fewer incidences with beta-blockers, based on a control risk of 327 incidences per 1000 (RR 0.50, 95% CI 0.42 to 0.59; 40 studies, 5650 participants; low-certainty evidence). However, the evidence for bradycardia and hypotension was less certain. We found that beta-blockers may make little or no difference to bradycardia (RR 1.63, 95% CI 0.92 to 2.91; 12 studies, 1640 participants; low-certainty evidence), or hypotension (RR 1.84, 95% CI 0.89 to 3.80; 10 studies, 1538 participants; low-certainty evidence). We used GRADE to downgrade the certainty of evidence. Owing to studies at high risk of bias in at least one domain, we downgraded each outcome for study limitations. Based on effect size calculations in the previous review, we found an insufficient number of participants in all outcomes (except atrial fibrillation) and, for some outcomes, we noted a wide confidence interval; therefore, we also downgraded outcomes owing to imprecision. The evidence for atrial fibrillation and length of hospital stay had a moderate level of statistical heterogeneity which we could not explain, and we, therefore, downgraded these outcomes for inconsistency. We found no evidence of a difference in early all-cause mortality, myocardial infarction, cerebrovascular events, hypotension and bradycardia. However, there may be a reduction in atrial fibrillation and ventricular arrhythmias when beta-blockers are used. A larger sample size is likely to increase the certainty of this evidence. Four studies awaiting classification may alter the conclusions of this review.

The evidence is current to 28 June 2019. We included 63 studies with 7768 adults who were undergoing heart surgery, including coronary artery bypass graft and valve replacement surgery. Studies were mostly randomized controlled studies, and six were quasi-randomized (participants were allocated to groups by methods such as using hospital record numbers or dates of birth). The types of beta-blockers were: propranolol, metoprolol, sotalol, esmolol, landiolol, acebutolol, timolol, carvedilol, nadolol, and atenolol. These beta-blockers were compared with either a placebo (disguised to look like a beta-blocker but containing no medicine) or with standard care. Beta-blockers were started before surgery, during surgery or at the latest by the end of the first day after surgery. The length of time beta-blockers were given varied between studies. In most studies, at least some of the people were already taking beta-blockers, which would be expected for people who had conditions that needed heart surgery. Key results Beta-blockers probably make little or no difference to the number of people who die (29 studies, 4099 participants) or have a heart attack (25 studies, 3946 participants) within 30 days of surgery. This was supported by low-certainty evidence. Few studies reported on people who had a stroke, and we were uncertain whether or not beta-blockers reduced strokes because the certainty of the evidence was very low (5 studies, 1471 participants). Beta-blockers may reduce atrial fibrillation, which is an irregular heartbeat starting in the atrial chambers of the heart that increases the risk of stroke if untreated (40 studies, 5650 participants; low-certainty evidence). Beta-blockers may also reduce ventricular arrhythmias, which are potentially life-threatening irregular heartbeat rhythms originating in the main chambers of the heart, and which may need immediate medical treatment (12 studies, 2296 participants). We found that beta-blockers may make little or no difference to whether people experience a very low heart rate or very low blood pressure. We were uncertain whether beta-blockers made a difference to the number of deaths up to a year after surgery (3 studies, 511 participants), to death because of the heart (4 studies, 320 participants), or to people who had heart failure (3 studies, 311 participants). The certainty of this evidence was very low. People who took beta-blockers had a shorter hospital stay by about half a day (14 studies, 2450 participants; low-certainty evidence). No studies assessed whether people on beta-blockers had a better quality of life after heart surgery. Certainty of the evidence The certainty of the evidence in this review was mostly low. We found that many studies reported methods that we believed could influence the results. For example, many studies did not use a placebo-control and the doctors might, therefore, have treated people differently in each group. We were unable to explain some of the differences that we found in the data for atrial fibrillation. We also needed to have evidence from a larger number of participants to be very confident in our findings. Conclusion Beta-blockers may be beneficial for people who are undergoing cardiac surgery because they may reduce the number of people who experience atrial fibrillation and ventricular arrhythmias. Beta-blockers may make little or no difference to the other outcomes in this review, including death, heart attacks or stroke.

10.1002/14651858.CD013435

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cochrane-simplification-train-663

We included four RCTs (N = 238 participants) that explored: a two-day workshop-based transition preparation training for adolescents with spina bifida; a nurse-led, one-on-one, teaching session with the additional support of a ‘health passport’ for adolescents with heart disease; a web- and SMS-based educational intervention for adolescents with a range of different conditions; and a structured comprehensive transition programme with a transition co-ordinator for adolescents with type 1 diabetes. One study evaluating a one-on-one nurse-led intervention, and one evaluating a technology-based intervention suggested that these interventions may lead to slight improvements in transitional readiness and chronic disease self-management measured at six- to eight-month follow-ups (low certainty evidence). Results with the TRAQ self-management tool were: MD 0.20; 95% CI -0.16 to 0.56 and MD 0.43; 95% CI; -0.09 to 0.95; with the TRAQ self-advocacy tool: MD 0.37; 95% CI -0.06 to 0.80; and with the PAM tool were: MD 10; 95% CI 2.96 to 17.04. In contrast, transition-preparation training delivered via a two-day workshop for patients with spina bifida may lead to little or no difference in measures of self-care practice and general health behaviours when measured using the DSCPI-90©. Two studies evaluated the use of health services. One study evaluated a technology-based intervention and another a comprehensive transition programme; these interventions may lead to slightly more young people taking positive steps to initiate contact with health professionals themselves (Relative risk (RR): 4.87; 95% CI 0.24 to 98.12 and RR 1.50; 95% CI 0.32 to 6.94, respectively; low certainty evidence. Young people’s knowledge of their disease may slightly improve with a nurse-led, one-on-one intervention to prepare young people for transition to an adult congenital heart programme (MD 14; 95% CI 2.67 to 25.33; one study; low certainty evidence). Disease-specific outcome measures were reported in two studies, both of which led to little or no difference in outcomes (low certainty evidence). One study found little or no difference between intervention and control groups. A second study found that follow-up HbA1c in young people with type 1 diabetes mellitus increased by 1.2% for each percentage increase in baseline HbA1c, independent of treatment group (1.2%; 95% CI 0.4 to 1.9; P = 0.01). Transition interventions may lead to little or no difference in well-being or quality of life as measured with the PARS III or PedsQ (two studies; low certainty evidence). Both the technology-based intervention and the two-day workshop for young people with spina bifida found little or no difference between intervention and control groups (MD 1.29; 95% CI -4.49 to 7.07). One study did not report the data. Four telephone support calls from a transition co-ordinator may lead to little or no difference in rates of transfer from paediatric to adult diabetes services (one study; low certainty evidence). At 12-month follow-up, there was little or no difference between groups of young people receiving usual care or a telephone support (RR 0.80; 95% CI 0.59 to 1.08)). They may slightly reduce the risk of disease-related hospital admissions at 12-month follow-up (RR 0.29; 95% CI 0.03 to 2.40). The available evidence (four small studies; N = 238), covers a limited range of interventions developed to facilitate transition in a limited number of clinical conditions, with only four to 12 months follow-up. These follow-up periods may not be long enough for any changes to become apparent as transition is a lengthy process. There was evidence of improvement in patients' knowledge of their condition in one study, and improvements in self-efficacy and confidence in another, but since few studies were eligible for this review, and the overall certainty of the body of this evidence is low, no firm conclusions can be drawn about the effectiveness of the evaluated interventions. Further research is very likely to have an important impact on our confidence in the intervention effect and likely could change our conclusions. There is considerable scope for the rigorous evaluation of other models of transitional care, reporting on clinical outcomes with longer term follow-up.

We searched the literature up to 19 June 2015 and found four studies (N = 238 participants) for this review. The studies evaluated four different types of educational interventions, all targeting adolescents with different clinical conditions. All sought to improve knowledge and self-management skills of adolescents in preparation for transition to adult care. Three of the transitional-care programmes found that the intervention may slightly improve transitional readiness in young people, enabling them to better self-manage and adjust to using adult health services. One transitional-care programme that evaluated a two-day workshop for young people with spina bifida found little or no difference in measures of transitional readiness. Transitional-care programmes may slightly improve a young persons knowledge of their condition and their own appropriate use of health services. Transitional-care programmes led to little or no difference in health status, quality of life or well-being, or rates of transfer from child to adult health services. While there is a wide range of transition programmes that are being developed in different countries, often within particular clinical specialties, this review only identified four small studies that provided low certainty evidence about educational interventions targeting participating adolescents, and no studies of interventions that targeted the organisation of care (for example, joint clinics or provision of a key worker). Other limitations with the evidence are the small number of adolescents recruited, the limited number of clinical conditions studied, the short follow up (12 months or less), and the fact that only two of the included studies reported on the primary outcome (that is, condition-specific clinical outcomes). Despite the challenges in designing studies that can test these types of interventions, such as evaluating a complex intervention, a stronger evidence base is needed to inform the development of these services.

10.1002/14651858.CD009794.pub2

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cochrane-simplification-train-664

We retrieved 28,098 references, from which we identified 29 potential articles. Four RCTs (in 11 reports) met the inclusion criteria.The sample sizes ranged from 27 to 135 (total 245 participants). Time poststroke varied from less than one week (n = 1), to one to three months (n = 2), or a median of 51 months (n = 1). Stroke severity ranged from a median of one to six on the National Institutes of Health Stroke Scale (NIHSS). Three studies were conducted in inpatient rehabilitation, and one was in a university laboratory. All studies compared use of activity monitor plus another intervention (e.g. a walking retraining programme or an inpatient rehabilitation programme) versus the other intervention alone. Three studies reported on the primary outcome of daily step counts. There was no clear effect for the use of activity monitors in conjunction with other interventions on step count in a community setting (mean difference (MD) -1930 steps, 95% confidence interval (CI) -4410 to 550; 1 RCT, 27 participants; very low-quality evidence), or in an inpatient rehabilitation setting (MD 1400 steps, 95% CI -40 to 2840; 2 RCTs, 83 participants; very low-quality evidence). No studies reported the primary outcome moderate-to-vigorous physical activity, but one did report time spent in moderate and vigorous intensity activity separately: this study reported that an activity monitor in addition to usual inpatient rehabilitation increased the time spent on moderate intensity physical activity by 4.4 minutes per day (95% CI 0.28 to 8.52; 1 RCT, 48 participants; low-quality evidence) compared with usual rehabilitation alone, but there was no clear effect for the use of an activity monitor plus usual rehabilitation for increasing time spent in vigorous intensity physical activity compared to usual rehabilitation (MD 2.6 minutes per day, 95% CI -0.8 to 6; 1 RCT, 48 participants; low-quality evidence). The overall risk of bias was low, apart from high-risk for blinding of participants and study personnel. None of the included studies reported any information relating to adverse effects. Only four small RCTs with 274 participants (three in inpatient rehabilitation and one in the community) have examined the efficacy of activity monitors for increasing physical activity after stroke. Although these studies showed activity monitors could be incorporated into practice, there is currently not enough evidence to support the use of activity monitors to increase physical activity after stroke.

We included four trials in this review, comprising 245 participants, ranging in age from 22 to 92 years. Three trials measured physical activity outcomes after the treatment period. Trials were conducted in hospital and community settings. All participants were able to communicate and provide informed consent, and all were able to walk at least five steps without supervision or assistance. The experimental groups in the trials received feedback at least daily on the number of steps taken. We searched for studies up to 3 March 2018. We found that the use of wearable activity monitors to provide feedback on physical activity did not increase physical activity levels in people with stroke. No conclusions could be drawn regarding the influence of stroke severity, walking ability, stroke survivor age, or time poststroke on the outcomes. The four included studies were conducted in different settings, and used different outcome measures, which limited the ability to combine data. No study reported whether the use of physical activity monitors was harmful. More research is needed to determine if they are effective. Using the GRADE approach, the quality of the evidence was low to very low, due to the small number of studies, small sample sizes, and because no study was able to blind the participants or the therapists delivering the intervention (they were aware that a device was being used and aware of the feedback that was being provided by the device).

10.1002/14651858.CD012543.pub2

cochrane-simplification-train-665

cochrane-simplification-train-665

There were nine studies (total 366 participants randomised) included in this review of non-pharmacological interventions for dry mouth which were divided into three comparisons. Eight studies were assessed at high risk of bias in at least one domain and the remaining study was at unclear risk of bias. Five small studies (total 153 participants, with dry mouth following radiotherapy treatment) compared acupuncture with placebo. Four were assessed at high risk and one at unclear risk of bias. Two trials reported outcome data for dry mouth in a form suitable for meta-analysis. The pooled estimate of these two trials (70 participants, low quality evidence) showed no difference between acupuncture and control in dry mouth symptoms (SMD -0.34, 95% CI -0.81 to 0.14, P value 0.17, I2 = 39%) with the confidence intervals including both a possible reduction or a possible increase in dry mouth symptoms. Acupuncture was associated with more adverse effects (tiny bruises and tiredness which were mild and temporary). There was a very small increase in unstimulated whole saliva (UWS) at the end of 4 to 6 weeks of treatment (three trials, 71 participants, low quality evidence) (MD 0.02 ml/minute, 95% CI 0 to 0.04, P value 0.04, I2 = 57%), and this benefit persisted at the 12-month follow-up evaluation (two trials, 54 participants, low quality evidence) (UWS, MD 0.06 ml/minute, 95% CI 0.01 to 0.11, P value 0.03, I2 = 10%). For the outcome of stimulated whole saliva (SWS, three trials, 71 participants, low quality evidence) there was a benefit favouring acupuncture (MD 0.19 ml/minute, 95% CI 0.07 to 0.31, P value 0.002, I2 = 1%) an effect which also persisted at the 12-month follow-up evaluation (SWS MD 0.28 ml/minute, 95% CI 0.09 to 0.47, P value 0.004, I2 = 0%) (two trials, 54 participants, low quality evidence). Two small studies, both at high risk of bias, compared the use of an electrostimulation device with a placebo device in participants with Sjögren's Syndrome (total 101 participants). A further study, also at high risk of bias, compared acupuncture-like electrostimulation of different sets of points in participants who had previously been treated with radiotherapy. None of these studies reported the outcome of dry mouth. There was no difference between electrostimulation and placebo in the outcomes of UWS or SWS at the end of the 4-week treatment period in the one study (very low that provided data for these outcomes. No adverse effects were reported. A single study at high risk of bias, compared the stimulatory effect of powered versus manual toothbrushing and found no difference for the outcomes of UWS or SWS. There is low quality evidence that acupuncture is no different from placebo acupuncture with regard to dry mouth symptoms, which is the most important outcome. This may be because there were insufficient participants included in the two trials to show a possible effect or it may be that there was some benefit due to 'placebo' acupuncture which could have biased the effect to the null. There is insufficient evidence to determine the effects of electrostimulation devices on dry mouth symptoms. It is well known that dry mouth symptoms may be problematic even when saliva production is increased, yet only two of the trials that evaluated acupuncture reported dry mouth symptoms, a worrying reporting bias. There is some low quality evidence that acupuncture results in a small increase in saliva production in patients with dry mouth following radiotherapy. There is insufficient evidence to determine the effects of electrostimulation devices on dry mouth symptoms or saliva production in patients with Sjögren's Syndrome. Reported adverse effects of acupuncture are mild and of short duration, and there were no reported adverse effects from electrostimulation.

The evidence on which this review is based was up-to-date as of 16 April 2013. Nine studies were included in this review. A total of 366 adult participants took part in these trials, with an average of 40 participants per trial, and an age range from 12 to 77 years. The causes of dry mouth were radiotherapy for oral cancers in four trials, Sjögren's syndrome in three trials, medication-related in one trial, and in the remaining trial participants had a range of causes of dry mouth. The included studies were divided into three groups, according the interventions evaluated. 1. Five small studies with a total 153 participants evaluated acupuncture. 2. Three studies evaluated electrostimulation devices. 3. One study evaluated a power toothbrush. The five studies evaluating the effects of acupuncture in people who had dry mouth were generally of poor quality. There was no evidence of a difference in dry mouth symptoms, but there was some evidence of a small increase in saliva production which persisted for a year after the end of the acupuncture treatment. There may not have been enough people included in the trials to show a difference in dry mouth, or it may have been that both the real acupuncture and the 'placebo' acupuncture had some beneficial effect. Acupuncture was associated with more adverse effects (tiny bruises and tiredness which were mild and temporary). The studies evaluating the effects of electrostimulation devices were poorly conducted and reported, and provided insufficient evidence to determine the effects of these devices on either dry mouth or saliva production. The single small study of a powered versus a manual toothbrush also found no difference for either dry mouth or saliva production. None of the included studies reported the outcomes of duration of effectiveness, quality of life, patient satisfaction, or oral health assessment. These studies were generally of poor quality (low and very low).

10.1002/14651858.CD009603.pub3

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cochrane-simplification-train-666

We included six studies; five (1863 participants) in painful diabetic neuropathy (PDN) and one (159 participants) in fibromyalgia. All were placebo-controlled and titrated to a target dose of 200 mg, 400 mg or 600 mg lacosamide daily, given as a divided dose. Study reporting quality was generally good, although the imputation method of last observation carried forward used in analyses of the primary outcomes is known to known to impart major bias where, as here, adverse event withdrawal rates were high. This, together with small numbers of patients and events for most outcomes at most doses meant that most results were of low quality, with moderate quality evidence available for some efficacy outcomes for 400 mg lacosamide. There were too few data for analysis of the 200 mg dose for painful diabetic neuropathy or any dose for fibromyalgia. In painful diabetic neuropathy, lacosamide 400 mg provided statistically increased rates of achievement of "moderate" and "substantial" benefit (at least 30% and at least 50% reduction from baseline in patient-reported pain respectively) and the patient global impression of change outcome of "much or very much improved". In each case the extra proportion benefiting above placebo was about 10%, yielding numbers needed to treat to benefit compared with placebo of 10 to 12. For lacosamide 600 mg there was no consistent benefit over placebo. There was no significant difference between any dose of lacosamide and placebo for participants experiencing any adverse event or a serious adverse event, but adverse event withdrawals showed a significant dose response. The number needed to treat to harm for adverse event withdrawal was 11 for lacosamide 400 mg and 4 for the 600 mg dose. Lacosamide has limited efficacy in the treatment of peripheral diabetic neuropathy. Higher doses did not give consistently better efficacy, but were associated with significantly more adverse event withdrawals. Where adverse event withdrawals are high with active treatment compared with placebo and when last observation carried forward imputation is used, as in some of these studies, significant overestimation of treatment efficacy can result. It is likely, therefore, that lacosamide is without any useful benefit in treating neuropathic pain; any positive interpretation of the evidence should be made with caution if at all.

This review included five studies in painful diabetic neuropathy (1863 participants) and one in fibromyalgia (159 participants). In people with painful diabetic neuropathy, lacosamide had only a modest effect, with a specific effect due to its use in 1 person in 10. This is a minor effect and may be an over-estimate due to use of the last observation carried forward method for analysis. There was insufficient information in fibromyalgia to draw any conclusions about the effect of lacosamide. There was no significant difference between lacosamide and placebo for participants with any, or a serious, adverse event, but there were significantly more adverse event withdrawals with lacosamide. Regulatory authorities have not licensed lacosamide for treating pain based on evidence presently available.

10.1002/14651858.CD009318.pub2

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cochrane-simplification-train-667

We included 14 RCTs that randomised 931 participants. Interventions assessed included: low-level laser therapy (LLLT) (4 studies); vibratory devices (5 studies); chewing adjuncts (3 studies); brain wave music or cognitive behavioural therapy (1 study) and post-treatment communication in the form of a text message (1 study). Twelve studies involved self-report assessment of pain on a continuous scale and two studies used questionnaires to assess the nature, intensity and location of pain. We combined data from two studies involving 118 participants, which provided low-quality evidence that LLLT reduced pain at 24 hours by 20.27 mm (95% CI -24.50 to -16.04, P < 0.001; I² = 0%). LLLT also appeared to reduce pain at six hours, three days and seven days. Results for the other comparisons assessed are inconclusive as the quality of the evidence was very low. Vibratory devices were assessed in five studies (272 participants), four of which were at high risk of bias and one unclear. Chewing adjuncts (chewing gum or a bite wafer) were evaluated in three studies (181 participants); two studies were at high risk of bias and one was unclear. Brain wave music and cognitive behavioural therapy were evaluated in one trial (36 participants) assessed at unclear risk of bias. Post-treatment text messaging (39 participants) was evaluated in one study assessed at high risk of bias. Adverse effects were not measured in any of the studies. Overall, the results are inconclusive. Although available evidence suggests laser irradiation may help reduce pain during orthodontic treatment in the short term, this evidence is of low quality and therefore we cannot rely on the findings. Evidence for other non-pharmacological interventions is either very low quality or entirely lacking. Further prospective research is required to address the lack of reliable evidence concerning the effectiveness of a range of non-pharmacological interventions to manage orthodontic pain. Future studies should use prolonged follow-up and should measure costs and possible harms.

We included 14 studies that involved a total of 931 teenagers and adults. The studies investigated the effects of using laser irradiation provided by the orthodontist, vibratory devices, changing chewing patterns (patients chewing gum or wafers), brain wave music, cognitive behavioural therapy, and text messages to support people after braces were fitted. The main outcome measured was the intensity of pain over the short term as reported by patients. We found insufficient evidence to assess the effectiveness of the interventions, although the available low-quality evidence suggested that laser irradiation may help to control short-term orthodontic pain. None of the studies considered side effects of the treatments. We identified relatively few studies, some of which used flawed methods or were not well reported. More research to look at the possible merits of non-drug methods of pain control would be helpful. Future studies should measure pain over longer time periods and should measure side effects and costs. The quality of the evidence on the effectiveness of non-drug ways to ease orthodontic pain was low to very low, so we are not able to rely on the findings.

10.1002/14651858.CD010263.pub2

cochrane-simplification-train-668

cochrane-simplification-train-668

Of 6947 identified citations, 19 RCTs fulfilled the eligibility criteria. These trials enrolled 9650 participants. Trial registries' searches identified nine registered but unpublished trials, two of which were labeled as 'ongoing trials'. In all included RCTs, the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, heparin appears to have no effect on mortality at 12 months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.93 to 1.03; risk difference (RD) 10 fewer per 1000; 95% CI 35 fewer to 15 more; moderate certainty of evidence) and mortality at 24 months (RR 0.99; 95% CI 0.96 to 1.01; RD 8 fewer per 1000; 95% CI 31 fewer to 8 more; moderate certainty of evidence). Heparin therapy reduces the risk of symptomatic VTE (RR 0.56; 95% CI 0.47 to 0.68; RD 30 fewer per 1000; 95% CI 36 fewer to 22 fewer; high certainty of evidence), while it increases in the risks of major bleeding (RR 1.30; 95% 0.94 to 1.79; RD 4 more per 1000; 95% CI 1 fewer to 11 more; moderate certainty of evidence) and minor bleeding (RR 1.70; 95% 1.13 to 2.55; RD 17 more per 1000; 95% CI 3 more to 37 more; high certainty of evidence). Results failed to confirm or to exclude a beneficial or detrimental effect of heparin on thrombocytopenia (RR 0.69; 95% CI 0.37 to 1.27; RD 33 fewer per 1000; 95% CI 66 fewer to 28 more; moderate certainty of evidence); quality of life (moderate certainty of evidence). Heparin appears to have no effect on mortality at 12 months and 24 months. It reduces symptomatic VTE and likely increases major and minor bleeding. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy should balance the benefits and downsides, and should integrate the patient's values and preferences. Editorial note:This is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

We searched the scientific literature for studies of anticoagulants in people with cancer. The evidence is current to 14 August 2017. We included 19 eligible trials. We selected 19 trials including 9650 participants with cancer. Most trials included participants with various types of cancer, especially small cell lung cancer, non-small cell lung cancer, and pancreatic cancer. All studies were conducted in the outpatient setting. The results suggest that the effect of injectable blood thinners on survival is uncertain, but if anything of small size. Also the results suggest that injectable blood thinners reduce the risk of blood clots by about half and possibly increase the risk of major bleeding and minor bleeding by 4 more per 1000 and 17 more per 1000, respectively. The effect on quality of life is uncertain. We judged the certainty of evidence to be high for symptomatic VTE and minor bleeding, and moderate for mortality, major bleeding and quality of life. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

10.1002/14651858.CD006652.pub5

cochrane-simplification-train-669

cochrane-simplification-train-669

Sixteen trials met the inclusion criteria, involving 1643 children of whom 865 received a simple behavioural intervention. Within each comparison, outcomes were mostly addressed by single trials, precluding meta-analysis. The only exception was bladder training versus enuresis alarm therapy which included two studies and demonstrated that alarm therapy was superior to bladder training. In single small trials, rewards, lifting and waking and bladder training were each associated with significantly fewer wet nights, higher full response rates and lower relapse rates compared to controls. Simple behavioural interventions appeared to be less effective when compared with other known effective interventions (such as enuresis alarm therapy and drug therapies with imipramine and amitriptyline). However, the effect was not sustained at follow-up after completion of treatment for the drug therapies. Based on one small trial, cognitive therapy also appeared to be more effective than rewards. When one simple behavioural therapy was compared with another, there did not appear to be one therapy that was more effective than another. Simple behavioural methods may be superior to no active treatment but appear to be inferior to enuresis alarm therapy and some drug therapy (such as imipramine and amitriptyline). Simple behavioural therapies could be tried as first line treatment before considering enuresis alarm therapy or drug therapy, which may be more demanding and have adverse effects, although evidence supporting their efficacy is lacking.

The review found 16 trials which involved 1643 children. Most simple behavioural treatments were only studied in single small trials which makes the evidence less reliable. Simple treatments such as rewarding dry nights (e.g. with star charts), lifting and waking and bladder training appeared to be more effective than no treatment but they are not as effective when compared with other treatments known to work, such as enuresis alarm therapy and drug therapy. There does not appear to be one simple behavioural therapy that is more effective than another. On the other hand, simple treatments do not have any side effects or safety concerns. Therefore, simple methods could be tried as first line therapy before considering alarms or drugs for this common childhood condition.

10.1002/14651858.CD003637.pub3

cochrane-simplification-train-670

cochrane-simplification-train-670

Nineteen studies (907 participants) met the inclusion criteria for this review. We included 13 studies (770 participants) in meta-analyses (417 traumatic brain injury, 304 stroke, 49 other acquired brain injury) reducing to 660 participants once non-included intervention groups were removed from three and four group studies. We were unable to obtain data from the remaining six studies. Three studies (134 participants) compared cognitive rehabilitation with sensorimotor therapy. None reported our primary outcome; data from one study was available relating to secondary outcomes including concept formation and ADL. Six studies (333 participants) compared cognitive rehabilitation with no treatment or placebo. None reported our primary outcome; data from four studies demonstrated no statistically significant effect of cognitive rehabilitation on secondary outcomes. Ten studies (448 participants) compared two different cognitive rehabilitation approaches. Two studies (82 participants) reported the primary outcome; no statistically significant effect was found. Data from eight studies demonstrated no statistically significant effect on the secondary outcomes. We explored the effect of restorative interventions (10 studies, 468 participants) and compensative interventions (four studies, 128 participants) and found no statistically significant effect compared with other interventions. We identified insufficient high-quality evidence to reach any generalised conclusions about the effect of cognitive rehabilitation on executive function, or other secondary outcome measures. Further high-quality research comparing cognitive rehabilitation with no intervention, placebo or sensorimotor interventions is recommended.

We found 19 relevant studies involving 907 people. We were able to combine the results of 13 of these studies including 660 participants (395 traumatic brain injury, 234 stroke, 31 other acquired brain injury). Only two of the studies (82 people) reported the outcome in which we were most interested (a general measure of executive function). We found no evidence that cognitive rehabilitation interventions were helpful for people with executive dysfunction for any other outcomes. We recommend that more research is carried out to determine whether cognitive rehabilitation can improve executive function after stroke and brain injury.

10.1002/14651858.CD008391.pub2

cochrane-simplification-train-671

cochrane-simplification-train-671

Six studies met the inclusion criteria but were limited by small sample sizes, various treatment regimes used and outcomes assessed. The studies were overall of unclear quality. Data could only be pooled for the outcomes of treatment failure and hospitalisation. Other data could not be combined due to divergent outcome measurements. Meta-analysis revealed that children who received anticholinergics alone were significantly more likely to have treatment failure compared to those who received beta2-agonists from four trials on 171 children (odds ratio (OR) 2.27; 95% CI 1.08 to 4.75). Also, treatment failure on anticholinergics alone was more likely than when anticholinergics were combined with beta2-agonists from four trials on 173 children (OR 2.65; 95% CI 1.2 to 5.88). Data on clinical scores/symptoms that were measured on different scales were conflicting. Individual trials reported that lung function was superior in the combination group when compared with anticholinergic agents used alone. The use of anticholinergics was not found to be associated with significant side effects. In children over the age of two years with acute asthma exacerbations, inhaled anticholinergics as single agent bronchodilators were less efficacious than beta2-agonists. Inhaled anticholinergics were also less efficacious than inhaled anticholinergics combined with beta2-agonists. Inhaled anticholinergic drugs alone are not appropriate for use as a single agent in children with acute asthma exacerbations.

We found six small trials of unclear quality answering these two questions. We found data from four trials on 171 children comparing anticholinergics with beta2-agonists. Children on anticholinergics alone were significantly more likely to experience treatment failure than those on beta2-agonists (odds ratio (OR) 2.27; 95% CI 1.08 to 4.75). We also found data from four trials on 173 children comparing children on anticholinergics alone with children on anticholinergics plus beta2-agonists. In this case, treatment failure was more likely in children taking anticholinergics only than if they were combined with beta2-agonists (OR 2.65; 95% CI 1.2 to 5.88). We were only able to combine data for treatment failure and hospitalisation. In summary, we found that inhaled anticholinergics used on their own are less effective than inhaled beta2-agonists used alone or in combination with anticholinergics. Inhaled anticholinergics seem safe, with no significant side effects apparent.

10.1002/14651858.CD003797.pub2

cochrane-simplification-train-672

cochrane-simplification-train-672

The review included 10 RCTs (757 couples). The quality of the evidence was low or very low for all comparisons. The main limitations in the evidence were failure to describe study methods, serious imprecision and inconsistency. IUI versus TI (five RCTs) Two RCTs compared IUI with TI in natural cycles. There were no data on live birth or OHSS. We found no evidence of a difference in pregnancy rates (2 RCTs, 62 couples: odds ratio (OR) 4.57, 95% confidence interval (CI) 0.21 to 102, very low quality evidence; there were no events in one of the studies). Three RCTs compared IUI with TI both in cycles with OH. We found no evidence of a difference in live birth rates (1 RCT, 81 couples: OR 0.89, 95% CI 0.30 to 2.59; low quality evidence) or pregnancy rates (3 RCTs, 202 couples: OR 1.51, 95% CI 0.74 to 3.07; I2 = 11%, very low quality evidence). One RCT reported data on OHSS. None of the 62 women had OHSS. One RCT compared IUI in cycles with OH with TI in natural cycles. We found no evidence of a difference in live birth rates (1 RCT, 44 couples: OR 3.14, 95% CI 0.12 to 81.35; very low quality evidence). Data on OHSS were not available. IUI in cycles with OH versus IUI in natural cycles (five RCTs) We found no evidence of a difference in live birth rates (3 RCTs, 346 couples: OR 1.34, 95% CI 0.77 to 2.33; I2 = 0%, very low quality evidence) and pregnancy rates (4 RCTs, 399 couples: OR 1.68, 95% CI 1.00 to 2.82; I2 = 0%, very low quality evidence). There were no data on OHSS. IVF versus IUI in natural cycles or cycles with OH (two RCTs) We found no evidence of a difference in live birth rates between IVF versus IUI in natural cycles (1 RCT, 53 couples: OR 0.77, 95% CI 0.25 to 2.35; low quality evidence) or IVF versus IUI in cycles with OH (2 RCTs, 86 couples: OR 1.03, 95% CI 0.43 to 2.45; I2 = 0%, very low quality evidence). One RCT reported data on OHSS. None of the women had OHSS. Overall, we found no evidence of a difference between any of the groups in rates of live birth, pregnancy or adverse events (multiple pregnancy, miscarriage). However, most of the evidence was very low quality. There were no studies on IUI in natural cycles versus TI in stimulated cycles, IVF versus TI, ICSI versus TI, ICSI versus IUI (with OH) or ICSI versus IVF. We found insufficient evidence to determine whether there was any difference in safety and effectiveness between different treatments for male subfertility. More research is needed.

We searched medical databases for randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) investigating male subfertility. We found 10 randomised controlled trials, all comparing different treatments for couples with male subfertility, with a total of 757 couples. The studies evaluated the following treatment options: timed intercourse (TI; where sex occurred at a recommended time in the menstrual cycle) (with or without OH), IUI (with or without OH), IVF and ICSI. The evidence was current to April 2015. We were mainly interested in how many women had live births and OHSS. We found no evidence of a difference in live birth or pregnancy rates between treatments. We also found no evidence of a difference between any of the groups in rates of adverse effects (multiple pregnancy, miscarriage). Available data on OHSS was too limited for us to draw any conclusions. Most of the evidence was of low or very low quality. The main limitations were failure to describe study methods, small sample sizes and inconsistency in how trials were conducted. Evidence was available for only six of the 14 comparisons that we evaluated. More research is needed.

10.1002/14651858.CD000360.pub5

cochrane-simplification-train-673

cochrane-simplification-train-673

One trial, which included 112 infants, met the inclusion criteria for this review. Term newborn infants on mechanical ventilation with the need for continuous analgesia and sedation with fentanyl and midazolam were eligible for enrollment during the first 96 hours of ventilation. Study authors administered clonidine 1 μg/kg/h or placebo on day 4 after intubation. We found no differences between the two groups in all-cause death during hospitalization (risk ratio [RR] 0.69, 95% confidence interval [CI] 0.12 to 3.98). The quality of the evidence supporting these findings is low owing to imprecision of the estimates (one study; few events). The median (interquartile range) duration of mechanical ventilation was 7.1 days (5.7 to 9.1 days) in the clonidine group and 5.8 days (4.9 to 7.9 days) in the placebo group, respectively (P = 0.070). Among secondary outcomes, we found no differences in terms of duration of stay in the intensive care unit. Sedation scale values (COMFORT) and analgesia scores (Hartwig) during the first 72 hours of infusion of study medication were lower in the clonidine group than in the placebo group. At present, evidence is insufficient to show the efficacy and safety of clonidine for sedation and analgesia in term and preterm newborn infants receiving mechanical ventilation.

In medical literature searches completed to January 2017, we identified and included one trial with 112 newborns comparing clonidine with placebo. We did not identify funding by industry for the included trial. Clonidine did not reduce death, duration of mechanical ventilation, or duration of stay in the intensive care unit. Sedation and pain scale values were lower among newborns receiving clonidine. Owing to the small number of newborns included in the single included trial, we are uncertain as to whether clonidine is effective or safe in providing analgesia and sedation for mechanically ventilated neonates.

10.1002/14651858.CD012468.pub2

cochrane-simplification-train-674

cochrane-simplification-train-674

We identified four reviews reporting on 32 studies. Two reviews scored 7 on the AMSTAR criteria (moderate, score 5 to 7, quality) and two scored 9 (high, score 8 to 11, quality). The reported quality of the included studies was, by a variety of methods, low to moderate. Payment for working for a specified time period was generally ineffective, improving 3/11 outcomes from one study reported in one review. Payment for each service, episode or visit was generally effective, improving 7/10 outcomes from five studies reported in three reviews; payment for providing care for a patient or specific population was generally effective, improving 48/69 outcomes from 13 studies reported in two reviews; payment for providing a pre-specified level or providing a change in activity or quality of care was generally effective, improving 17/20 reported outcomes from 10 studies reported in two reviews; and mixed and other systems were of mixed effectiveness, improving 20/31 reported outcomes from seven studies reported in three reviews. When looking at the effect of financial incentives overall across categories of outcomes, they were of mixed effectiveness on consultation or visit rates (improving 10/17 outcomes from three studies in two reviews); generally effective in improving processes of care (improving 41/57 outcomes from 19 studies in three reviews); generally effective in improving referrals and admissions (improving 11/16 outcomes from 11 studies in four reviews); generally ineffective in improving compliance with guidelines outcomes (improving 5/17 outcomes from five studies in two reviews); and generally effective in improving prescribing costs outcomes (improving 28/34 outcomes from 10 studies in one review). Financial incentives may be effective in changing healthcare professional practice. The evidence has serious methodological limitations and is also very limited in its completeness and generalisability. We found no evidence from reviews that examined the effect of financial incentives on patient outcomes.

Since there are several reviews describing the effects of different types of financial incentives, it is important to bring this together in an overview to examine which are best at changing healthcare professionals' behaviours and what happens to patients. We therefore conducted an overview of systematic reviews that evaluated the impact of financial incentives on healthcare professional behaviour and patient outcomes. We searched a wide range of electronic databases from when they started up to December 2008. We included systematic reviews of studies evaluating the effectiveness of any type of financial incentive. We grouped financial incentives into five groups: payment for working for a specified time period; payment for each service, episode or visit; payment for providing care for a patient or specific population; payment for providing a pre-specified level or providing a change in activity or quality of care; and mixed or other systems. We summarised data using vote counting. We identified four reviews reporting on 32 studies. Two reviews were of moderate quality and two were of high quality. The studies that the reviews reported on were of low to moderate quality. Payment for working for a specified time period was generally ineffective. Payment for each service, episode or visit was generally effective, as were payment for providing care for a patient or specific population and payment for providing a pre-specified level or providing a change in activity or quality of care; mixed and other systems were of mixed effectiveness. When looking at the effect of financial incentives overall across different outcomes, they were of mixed effectiveness on consultation or visit rates; generally effective in improving processes of care, referrals and admissions, and prescribing costs; and generally ineffective in improving compliance with guidelines outcomes. On the basis of these findings, we concluded that financial incentives may be effective in changing healthcare professional practice. The evidence has serious methodological limitations and is also very limited in its completeness and generalisability. We found no evidence that financial incentives can improve patient outcomes.

10.1002/14651858.CD009255

cochrane-simplification-train-675

cochrane-simplification-train-675

Fifteen eligible trials were identified, but six were excluded. The following interventions were compared in the nine included studies: different non-surgical interventions (five trials); adjunctive treatments to non-surgical interventions (one trial); different surgical interventions (two trials); adjunctive treatments to surgical interventions (one trial). Follow-up ranged from 3 months to 4 years. No study was judged to be at low risk of bias. Statistically significant differences were observed in two small single trials judged to be at unclear or high risk of bias. After 4 months, adjunctive local antibiotics to manual debridement in patients who lost at least 50% of the bone around implants showed improved mean probing attachment levels (PAL) of 0.61 mm (95% confidence interval (CI) 0.40 to 0.82) and reduced probing pockets depths (PPD) of 0.59 mm (95% CI 0.39 to 0.79). After 4 years, patients with peri-implant infrabony defects > 3 mm treated with Bio-Oss and resorbable barriers gained 1.4 mm more PAL (95% CI 0.24 to 2.56) and 1.4 mm PPD (95% CI 0.81 to 1.99) than patients treated with a nanocrystalline hydroxyapatite. There is no reliable evidence suggesting which could be the most effective interventions for treating peri-implantitis. This is not to say that currently used interventions are not effective. A single small trial at unclear risk of bias showed the use of local antibiotics in addition to manual subgingival debridement was associated with a 0.6 mm additional improvement for PAL and PPD over a 4-month period in patients affected by severe forms of peri-implantitis. Another small single trial at high risk of bias showed that after 4 years, improved PAL and PPD of about 1.4 mm were obtained when using Bio-Oss with resorbable barriers compared to a nanocrystalline hydroxyapatite in peri-implant infrabony defects. There is no evidence from four trials that the more complex and expensive therapies were more beneficial than the control therapies which basically consisted of simple subgingival mechanical debridement. Follow-up longer than 1 year suggested recurrence of peri-implantitis in up to 100% of the treated cases for some of the tested interventions. As this can be a chronic disease, re-treatment may be necessary. Larger well-designed RCTs with follow-up longer than 1 year are needed.

Nine studies were included in the review and evaluated eight different treatment modalities. In one small study of short duration (4 months), it was shown that the use of locally applied antibiotics in addition to the deep manual cleaning of the diseased implants decreased the depth of the pockets around the implants by an additional 0.6 mm in patients affected by severe forms of peri-implantitis. In another small study of 4-year duration, it was shown that placing an animal-derived bone substitute with a resorbable barrier decreased the depth of the pockets by an additional 1.4 mm than synthetic bone. The majority of trials testing more complex and expensive therapies did not show any statistically or clinically significant advantages over the deep mechanical cleaning around the affected implants. In conclusion, at present, there is too little evidence to determine which is the most effective way to treat peri-implantitis. This is not to say that currently used interventions are not effective.

10.1002/14651858.CD004970.pub5

cochrane-simplification-train-676

cochrane-simplification-train-676

20 parallel-group trials were included. The reporting quality of trials was poor, only 25% and 5% of them reporting adequate method of randomisation and program allocation concealment, respectively. Incomplete data was adequately addressed in about half of the trials and this information was unclear for about 20% of the trials. Due to extensive heterogeneity across interventions, populations, and outcomes, the results were summarized only qualitatively. 12 of the 20 trials showed some evidence of effectiveness compared to a control or other intervention group, with persistence of effects ranging from 3 months to 3 years. Of the remaining 8 trials, one trial reported significant effects using one-tailed tests and 7 trials reported no significant effects of the multi-component interventions for reducing alcohol misuse. Assessment of the additional benefit of multiple versus single component interventions was possible in 7 trials with multiple arms. Only one of the 7 trials clearly showed a benefit of components delivered in more than one setting. There is some evidence that multi-component interventions for alcohol misuse prevention in young people can be effective. However, there is little evidence that interventions with multiple components are more effective than interventions with single components.

We conducted a Cochrane systematic review of 20 randomised controlled trials that examined the effectiveness of universal multi-component programs for the prevention of alcohol misuse in young people. Multi-component prevention programs are defined as those prevention efforts that deliver interventions in multiple settings, for example in both school and family settings, typically combining school curricula with a parenting intervention. A majority of the studies included in this review reported positive effects of multi-component programs for the prevention of alcohol misuse in young people, with effects persisting into the medium- and longer-term. But a notable proportion of trials reported no statistically significant effects. In seven studies we were able to assess the impact of single versus multiple components, and only 1 out of the 7 studies clearly showed a benefit of components delivered in more than one setting. In conclusion, there is some evidence that multi-component interventions for alcohol misuse prevention in young people can be effective. However, there is little evidence that interventions with multiple components are more effective than interventions with single components.

10.1002/14651858.CD009307

cochrane-simplification-train-677

cochrane-simplification-train-677

For this update to the original review, the search identified 65 potentially relevant articles. Twelve studies met the inclusion criteria (872 participants). Four trials studied the efficacy of electrical stimulation (313 participants), three trials studied exercises (199 participants), and five studies compared or combined some form of physical therapy with acupuncture (360 participants). For most outcomes we were unable to perform meta-analysis because the interventions and outcomes were not comparable. For the primary outcome of incomplete recovery after six months, electrostimulation produced no benefit over placebo (moderate quality evidence from one study with 86 participants). Low quality comparisons of electrostimulation with prednisolone (an active treatment) (149 participants), or the addition of electrostimulation to hot packs, massage and facial exercises (22 participants), reported no significant differences. Similarly a meta-analysis from two studies, one of three months and the other of six months duration (142 participants) found no statistically significant difference in synkinesis, a complication of Bell's palsy, between participants receiving electrostimulation and controls. A single low quality study (56 participants), which reported at three months, found worse functional recovery with electrostimulation (mean difference (MD) 12.00 points (scale of 0 to 100) 95% confidence interval (CI) 1.26 to 22.74). Two trials of facial exercises, both at high risk of bias, found no difference in incomplete recovery at six months when exercises were compared to waiting list controls or conventional therapy. There is evidence from a single small study (34 participants) of moderate quality that exercises are beneficial on measures of facial disability to people with chronic facial palsy when compared with controls (MD 20.40 points (scale of 0 to 100), 95% CI 8.76 to 32.04) and from another single low quality study with 145 people with acute cases treated for three months, in which significantly fewer participants developed facial motor synkinesis after exercise (risk ratio 0.24, 95% CI 0.08 to 0.69). The same study showed statistically significant reduction in time for complete recovery, mainly in more severe cases (47 participants, MD -2.10 weeks, 95% CI -3.15 to -1.05) but this was not a prespecified outcome in this meta analysis. Acupuncture studies did not provide useful data as all were short and at high risk of bias. None of the studies included adverse events as an outcome. There is no high quality evidence to support significant benefit or harm from any physical therapy for idiopathic facial paralysis. There is low quality evidence that tailored facial exercises can help to improve facial function, mainly for people with moderate paralysis and chronic cases. There is low quality evidence that facial exercise reduces sequelae in acute cases. The suggested effects of tailored facial exercises need to be confirmed with good quality randomised controlled trials.

For this updated review we found a total of 12 studies with 872 participants, most with high risk of bias. Four trials studied the efficacy of electrical stimulation (313 participants), three trials studied exercises (199 participants), and five studies combined some form of physical therapy and compared with acupuncture (360 participants). There is evidence from a single study of moderate quality that exercises are beneficial to people with chronic facial palsy when compared with controls and from another low quality study that it is possible that facial exercises could help to reduce synkinesis (a complication of Bell's palsy), and the time to recover. There is insufficient evidence to decide whether electrical stimulation works, to identify risks of these treatments or to assess whether the addition of acupuncture to facial exercises or other physical therapy could produce improvement. In conclusion, tailored facial exercises can help to improve facial function, mainly for people with moderate paralysis and chronic cases, and early facial exercise may reduce recovery time and long term paralysis in acute cases, but the evidence for this is of poor quality. More trials are needed to assess the effects of facial exercises and any risks.

10.1002/14651858.CD006283.pub3

cochrane-simplification-train-678

cochrane-simplification-train-678

Fifty-one published and unpublished trials (representing 55 group comparisons, 10,797 participants) met the inclusion criteria. In asthmatics with mild to moderate disease who were not on oral steroids, FP did not exhibit a dose-response effect in the lower dose comparisons in FEV1 (50mcg, 100mcg, 200mcg and 4-500mcg daily). There were no statistically significant differences between 4-500mcg and 800-1000mcg, and between 50-100 and 800-1000mcg of FP. When 200mcg was compared with 800-1000mcg daily FEV1 favoured the four/five fold increase. For PEF, a dose response was present with FP when low and moderate, and low and high doses of FP were compared. There was no evidence of a dose-response effect on symptoms or rescue beta-2 agonist use. The likelihood of hoarseness and oral candidiasis was significantly greater for the higher doses (800 to 1000 µg/day). People with oral steroid-dependent asthma treated with FP (2000 µg/day) were significantly more likely to reduce oral prednisolone than those on 1000 to 1500 µg/day (Peto odds Ratio 2.8, 95% CI 1.3 to 6.3). The highest dose also allowed a significant reduction in daily oral prednisolone dose compared to 1000 to 1500 µg/day (WMD 2.0 mg/day, 95% CI 0.1 to 4.0 mg/day). We have not found evidence of a pronounced dose response in FEV1 with increasing doses of fluticasone. The number of studies contributing to our primary outcomes was low. At dose ratios of 1:2, there are statistically significant differences in favour of the higher dose in morning peak flow across the low dose range. The clinical impact of these differences is open to interpretation. Patients with moderate disease achieve similar levels of asthma control on medium doses of fluticasone (400 to 500 µg/day) as they do on high doses (800 to 1000 µg/day). More work in severe asthma would help to confirm that doses of FP above 500 µg/day confer greater benefit in this subgroup than doses of around 200 µg/day. In oral corticosteroid-dependent asthmatics, reductions in prednisolone requirement may be gained with FP 2000 µg/day.

This review examined the effectiveness of FP when given at different doses for treating asthma in children and adults. High doses (800 to 1000 microgram per day) led to small improvements in measures of airway opening compared to low doses (50 to 100 microgram per day) in people with mild to moderate asthma. High dose FP did not lead to clear improvements in symptoms over the lower dose and increased the risk of a hoarse voice and fungal mouth infections. In people with severe asthma, very high doses FP (2000 microgram per day) appeared to allow more people on oral steroids to stop or reduce their dose of oral steroid tablets compared to lower doses of FP (1000 to 1500 microgram per day).

10.1002/14651858.CD003534.pub3

cochrane-simplification-train-679

cochrane-simplification-train-679

We included 21 trials (19 adult, two paediatric) totaling 1676 participants (1628 adults, 48 children) in this updated review. Pooled data from 16 eligible trials reporting weaning duration indicated that automated closed loop systems reduced the geometric mean duration of weaning by 30% (95% confidence interval (CI) 13% to 45%), however heterogeneity was substantial (I2 = 87%, P < 0.00001). Reduced weaning duration was found with mixed or medical ICU populations (42%, 95% CI 10% to 63%) and Smartcare/PS™ (28%, 95% CI 7% to 49%) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (10%, 95% CI 3% to 16%) and ICU LOS (8%, 95% CI 0% to 15%). There was no strong evidence of an effect on mortality rates, hospital LOS, reintubation rates, self-extubation and use of non-invasive ventilation following extubation. Prolonged mechanical ventilation > 21 days and tracheostomy were reduced in favour of automated systems (relative risk (RR) 0.51, 95% CI 0.27 to 0.95 and RR 0.67, 95% CI 0.50 to 0.90 respectively). Overall the quality of the evidence was high with the majority of trials rated as low risk. Automated closed loop systems may result in reduced duration of weaning, ventilation and ICU stay. Reductions are more likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PS™ and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population.

We identified 21 studies that provided information on a total of 1676 people including 1628 adults and 48 children. The evidence was current to 30th September 2013. Studies were conducted in people with medical reasons such as pneumonia and other infections for needing admission to ICU, people admitted following trauma, and people admitted after heart or other forms of surgery. As well, various commercially available computerized weaning systems were studied. We found that computerized weaning systems resulted in a reduced weaning duration as well as reduced overall time on the ventilator and stay in an ICU. The average time required for a person to be weaned off the ventilator was reduced by 30%. The overall time on the ventilator was reduced by 10% and the length of stay in ICU by 8%. Not all studies demonstrated these reductions. Studies conducted only in people admitted to ICU following surgery did not demonstrate reductions in weaning, overall time on a ventilator or ICU stay. Because of differences in the methods and results of some studies included in this review, further large scale research is warranted. There is also a need for more studies that examine the effect of computerized weaning systems in children.

10.1002/14651858.CD009235.pub3

cochrane-simplification-train-680

cochrane-simplification-train-680

Twenty-six randomised trials involving 3388 participants were included. Overall the quality of trials, as reported, was poor. None of the studies investigated incidence of hypothyroidism, changes in weight, health-related quality of life, ophthalmopathy progression or economic outcomes. Four trials examined the effect of duration of therapy on relapse rates, and when using the titration regimen 12 months was superior to six months, but there was no benefit in extending treatment beyond 18 months. Twelve trials examined the effect of block-replace versus titration block-regimens. The relapse rates were similar in both groups at 51% in the block-replace group and 54% in the titration block-group (OR 0.86, 95% confidence interval (CI) 0.68 to1.08) though adverse effects (rashes (10% versus 6%) and withdrawing due to side effects (16% versus 9%)) were significantly higher in the block-replace group. Three studies considered the addition of thyroxine with continued low dose antithyroid therapy after initial therapy with antithyroid drugs. There was significant heterogeneity between the studies and the difference between the two groups was not significant (OR 0.58, 95% CI 0.05 to 6.21). Four studies considered the addition of thyroxine alone after initial therapy with antithyroid drugs. There was no significant difference in the relapse rates between the groups after 12 months follow-up (OR 1.15, 95% CI 0.79 to 1.67). Two studies considered the addition of immunosuppressive agents. The results which were in favour of the interventions would need to be validated in other populations. The evidence suggests that the optimal duration of antithyroid drug therapy for the titration regimen is 12 to 18 months. The titration (low dose) regimen had fewer adverse effects than the block-replace (high dose) regimen and was no less effective. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism. Immunosuppressive therapies need further evaluation.

Twenty-six RCTs involving 3388 participants were identified. The majority of participants in all the studies were female (83% in the studies reporting sex distribution). The mean age was 40 years. The duration of follow up was between two to five years in eleven trials. In high dose ('block-replace') versus low dose ('titration') studies the duration of therapy was six months in two studies, 18 months in four studies and 12 months in the remaining trials. The main outcome was the relapse rate of hyperthyroidism over one year after completion of drug treatment and this was the primary outcome in all the studies assessed. There were no deaths reported in any of the studies. None of the studies detailed incidence of hypothyroidism, changes in weight during the course of therapy, health-related quality of life, ophthalmopathy progression or economic outcomes. The evidence (based on four studies) suggests that the optimal duration of antithyroid drug therapy for the low dose regimen is 12 to 18 months. The low dose regimen had fewer adverse effects than the high dose regimen and was no less effective in trials (based on 12 trials) of equal duration. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism. Studies using immunosuppressive agents need further validation of safety and efficacy in controlled trials among different populations. Data regarding side effects and number of participants withdrawn from therapy due to side effects were available in seven studies. The number of participants reporting rashes was significantly higher in the high versus low dose group (10% versus 6%). The number of participants withdrawing due to side effects were also significantly higher in the high versus low dose group (16% versus 9%).

10.1002/14651858.CD003420.pub4

cochrane-simplification-train-681

cochrane-simplification-train-681

We included 11 randomised controlled trials involving 2796 people. The quality of these studies was moderate to low, with most of the studies at unclear risk of bias in terms of random sequence generation and allocation concealment, and high risk of bias for blinded outcome assessment and selective outcome reporting. Five trials involving 581 people compared consumer-providers to professionals in similar roles within mental health services (case management roles (4 trials), facilitating group therapy (1 trial)). There were no significant differences in client quality of life (mean difference (MD) -0.30, 95% confidence interval (CI) -0.80 to 0.20); depression (data not pooled), general mental health symptoms (standardised mean difference (SMD) -0.24, 95% CI -0.52 to 0.05); client satisfaction with treatment (SMD -0.22, 95% CI -0.69 to 0.25), client or professional ratings of client-manager relationship; use of mental health services, hospital admissions and length of stay; or attrition (risk ratio 0.80, 95% CI 0.58 to 1.09) between mental health teams involving consumer-providers or professional staff in similar roles. There was a small reduction in crisis and emergency service use for clients receiving care involving consumer-providers (SMD -0.34 (95%CI -0.60 to -0.07). Past or present consumers who provided mental health services did so differently than professionals; they spent more time face-to-face with clients, and less time in the office, on the telephone, with clients' friends and family, or at provider agencies. Six trials involving 2215 people compared mental health services with or without the addition of consumer-providers. There were no significant differences in psychosocial outcomes (quality of life, empowerment, function, social relations), client satisfaction with service provision (SMD 0.76, 95% CI -0.59 to 2.10) and with staff (SMD 0.18, 95% CI -0.43 to 0.79), attendance rates (SMD 0.52 (95% CI -0.07 to 1.11), hospital admissions and length of stay, or attrition (risk ratio 1.29, 95% CI 0.72 to 2.31) between groups with consumer-providers as an adjunct to professional-led care and those receiving usual care from health professionals alone. One study found a small difference favouring the intervention group for both client and staff ratings of clients' needs having been met, although detection bias may have affected the latter. None of the six studies in this comparison reported client mental health outcomes. No studies in either comparison group reported data on adverse outcomes for clients, or the financial costs of service provision. Involving consumer-providers in mental health teams results in psychosocial, mental health symptom and service use outcomes for clients that were no better or worse than those achieved by professionals employed in similar roles, particularly for case management services. There is low quality evidence that involving consumer-providers in mental health teams results in a small reduction in clients' use of crisis or emergency services. The nature of the consumer-providers' involvement differs compared to professionals, as do the resources required to support their involvement. The overall quality of the evidence is moderate to low. There is no evidence of harm associated with involving consumer-providers in mental health teams. Future randomised controlled trials of consumer-providers in mental health services should minimise bias through the use of adequate randomisation and concealment of allocation, blinding of outcome assessment where possible, the comprehensive reporting of outcome data, and the avoidance of contamination between treatment groups. Researchers should adhere to SPIRIT and CONSORT reporting standards for clinical trials. Future trials should further evaluate standardised measures of clients' mental health, adverse outcomes for clients, the potential benefits and harms to the consumer-providers themselves (including need to return to treatment), and the financial costs of the intervention. They should utilise consistent, validated measurement tools and include a clear description of the consumer-provider role (eg specific tasks, responsibilities and expected deliverables of the role) and relevant training for the role so that it can be readily implemented. The weight of evidence being strongly based in the United States, future research should be located in diverse settings including in low- and middle-income countries.

We conducted a systematic review, comprehensively searching databases and other materials to identify randomised controlled trials which involved past or present consumers of mental health services employed as providers of mental healthcare services for adult clients. To be included, studies had to make one of two comparisons: 1) consumer-providers versus professionals employed to do the same role within a mental health service, or 2) mental health services with and without consumer-providers as an adjunct to the service. We found 11 randomised controlled trials involving approximately 2796 people. The quality of the evidence is moderate to low; it was unclear in many cases whether steps were taken to minimise bias, both in the way that participants were allocated to groups, and in how the outcomes were assessed and reported. Five of the 11 trials involving 581 people compared consumer-providers to professionals who occupied similar roles within mental health services (case management roles (4 trials), and facilitating group therapy (1 trial)). There were no significant differences between the two groups, in terms of client (care recipient) quality of life, mental health symptoms, satisfaction, use of mental health services, or on the numbers of people withdrawing from the study. People receiving care from past or present users of mental health services used crisis and emergency services slightly less than those receiving care from professional staff. Past or present consumers who provided mental health services did so differently than professionals; they spent more time face-to-face with clients, and less time in the office, on the telephone, with clients' friends and family, or at provider agencies. Six of the 11 trials, involving 2215 people, compared mental health services with or without the addition of consumer-providers. There were no significant differences in quality of life, empowerment, function and social relations, in client satisfaction, attendance rates, hospital use, or in the numbers of people withdrawing from the study, between groups with consumer-providers as an adjunct to professional care and those receiving usual care by health professionals alone. None of these six studies reported on clients' mental health symptoms. None of the studies reported on adverse outcomes (harms) for clients, or on the costs of providing the services. Overall, we concluded that employing past or present consumers of mental health services as providers of mental health services achieves psychosocial, mental health symptom and service use outcomes that are no better or worse than those achieved by professional staff in providing care. There is no evidence that the involvement of consumer-providers is harmful. More high-quality and well-reported randomised trials are needed, particularly to evaluate mental health outcomes, adverse outcomes for clients, the potential benefits and harms to the consumer-providers themselves (including a need to return to treatment), and whether it is cost-effective to employ them. Future researchers should include a clear description of the consumer-provider role and relevant training for the role so that it can be readily implemented, and should investigate consumer-providers in settings outside the United States.

10.1002/14651858.CD004807.pub2

cochrane-simplification-train-682

cochrane-simplification-train-682

Thirteen studies on 1505 infants were included. Infants given opioids showed reduced premature infant pain profile (PIPP) scores compared to the control group (weighted mean difference -1.71; 95% confidence interval -3.18 to -0.24). Differences in execution and reporting of trials mean that this meta-analysis should be interpreted with caution. Heterogeneity was significantly high in all analyses of pain, even when lower quality studies were excluded and analysis limited to very preterm newborns. Meta-analyses of mortality, duration of mechanical ventilation, and long and short-term neurodevelopmental outcomes showed no statistically significant differences. Very preterm infants given morphine took significantly longer to reach full enteral feeding than those in control groups (weighted mean difference 2.10 days; 95% confidence interval 0.35 to 3.85). One study compared morphine with a sedative: the treatments showed similar pain scores, but morphine had fewer adverse effects. There is insufficient evidence to recommend routine use of opioids in mechanically ventilated newborns. Opioids should be used selectively, when indicated by clinical judgment and evaluation of pain indicators. If sedation is required, morphine is safer than midazolam. Further research is needed.

This review found no evidence for routine use of opioids for newborns on breathing machines. Although relief of pain was variable, opioids were no better or worse for babies (in terms of death, strokes, future development, duration of ventilation or hospital stay) than other drugs or placebo. Further research is needed.

10.1002/14651858.CD004212.pub3

cochrane-simplification-train-683

cochrane-simplification-train-683

We included nine trials involving 1371 participants. Overall, results were mixed. Regarding five trials in clinical populations, three assessed smoking cessation behaviours, all featuring arterial scanning procedures to assess cardiovascular risk, and reported a statistically significant effect favouring the intervention, producing a pooled odds ratio (OR) of 2.81 (95% confidence interval (CI) 1.23 to 6.41, P = 0.01). One of these trials also measured physical activity and reported no statistically significant difference between the groups. A further trial measured skin examination behaviour following a skin photography procedure for assessing moles, and reported a statistically significant increase in favour of the intervention, with an OR of 4.86 (95% CI 1.95 to 12.10, P = 0.0007). The final clinical population trial measured a range of dietary intake and medication usage behaviours and featured an arterial scanning procedure assessing cardiovascular risk, and reported no statistically significant effects. Among the four trials in non-clinical populations, all featuring ultraviolet (UV) photography to highlight UV-related skin damage, a statistically significant result favouring the intervention was found in one trial for reducing tanning booth use, producing a mean difference (MD) of -1.10 (95% CI -1.90 to -0.30, P = .007) and one trial reported an outcome on which the control condition was favoured, with an MD of 0.45 (95% CI 0.04 to 0.86, P = 0.03) on intentional hours spent in the sun. In two further trials, no statistically significant behavioral effects were reported regarding time spent in the sun or sun protection behaviours. There was no evidence of significant adverse effects in the included trials, although this was not well reported. Due to the limited nature of the available evidence and the mixed results that were found, no strong statements can be made about the effectiveness of communicating medical imaging results to change health behaviour. Only three trials in clinical populations were similar enough in term of setting, intervention and outcome to allow meta-analysis. We suggest, however, that targeted interventions using medical imaging technologies may be effective in certain contexts, or as applied to certain behaviours, but that this should be considered on an intervention by intervention basis, and not assumed as a general principle.

We included nine trials involving 1371 participants in the review. In general, no strong evidence was found to support the effectiveness of this approach, but it was shown to be effective in some contexts. In smoking cessation interventions the effect of showing and explaining artery scanning images (to assess the risk of cardiovascular disease) was found to be more effective than not communicating images. In other outcomes, the effects were mixed. There was no evidence of significant harmful effects of this approach, although this was not well reported. A main limitation of the review is the small number of studies in this area and the great differences between them in terms of the precise nature of the interventions and the populations being studied. This makes drawing broad conclusions difficult.

10.1002/14651858.CD007434.pub2

cochrane-simplification-train-684

cochrane-simplification-train-684

Five studies (833 participants) were included; one was a very small pilot study of 7 participants. All studies compared oral ω-3FA supplements against placebo. Four studies enrolled participants with arteriovenous grafts (AVGs), and the other had participants with arteriovenous fistulas (AVFs). The risk of bias for both efficacy and safety outcomes was unclear for all studies, due mainly to incomplete reporting for allocation concealment and incompleteness of study follow-up. In AVF patients, ω-3FA supplementation probably makes little or no difference to the 12-month risk of patency loss (1 study, 536 participants: RR 1.01, 95% CI 0.84 to 1.21; moderate certainty evidence), risk of death (1 study, 567 participants: RD 0.00, 95% CI -0.03 to 0.02; moderate certainty evidence) and risk of hospitalisation (1 study, 567 participants: RD 0.00, 95% CI -0.08 to 0.08; low certainty evidence). There was no information on cardiovascular events and major bleeding. In AVG patients, it is very uncertain whether ω-3FA supplementation reduces the risk of patency loss within 6 months (2 studies, 41 participants: RR 0.91, 95% CI 0.36 to 2.28; very low certainty evidence) or 12 months (2 studies, 220 participants: RR 0.59, 95% CI 0.27 to 1.31; very low certainty evidence). ω-3FA supplementation may make little or no difference to the risk of death within 6 to 12 months in AVG patients (4 studies, 261 participants: RD 0.01, 95% CI -0.05 to 0.07; low certainty evidence). It is very uncertain if ω-3FA supplementation increases the risk of hospitalisation (3 studies, 65 participants: RD 0.08, 95% CI -0.11 to 0.28; very low certainty evidence), changes the risk of cardiovascular events (4 studies, 261 participants: RD -0.02, 95% CI -0.11 to 0.07; very low certainty evidence), or increases the risk of major bleeding (3 studies, 65 participants: RD 0.08, 95% CI -0.11 to 0.28; very low certainty evidence) within 6 to 12 months in AVG patients. There may be an increase in the risk of mild gastrointestinal adverse reactions (3 studies, 65 participants: RD 0.25, 95% CI 0.07 to 0.43; low certainty evidence) such as a sensation of bloatedness, gas or a fishy aftertaste. In CKD patients with an AVF, there is moderate certainty that ω-3FA supplementation makes little or no difference to preventing patency loss; and in patients with an AVG, it is very uncertain that ω-3FA supplementation prevents patency loss within 12 months.

We found five randomised controlled trials (RCTs) that studied a total of 833 participants; one was a very small pilot study of seven participants. Four studies involved patients with AVGs; there was only one study of AVFs. The outcomes were measured over a period of six or 12 months. There were reservations about the overall quality of all the studies, making us moderately to highly uncertain about the evidence. In AVF patients, we are moderately certain that fish oil supplements do not prevent blockage nor do they cause additional harm but the evidence only comes from one study. In AVG patients, we are very uncertain of the evidence for preventing blockage or causing serious harm, but there may be an increased risk of mild digestive side-effects such as a sensation of bloatedness, gas or a fishy aftertaste. There is limited high quality data on the benefits of omega-3 fish oil supplementation for preventing HD blockage in kidney failure patients. We did not find strong evidence that omega-3 fish oil supplements could prevent blockage of HD vascular access or that it increases the risk of serious and non-serious side-effects. All the evidence for preventing blockages come from just one or two studies, so more and better quality studies are needed.

10.1002/14651858.CD011353.pub2

cochrane-simplification-train-685

cochrane-simplification-train-685

We identified seven RCTs involving 403 participants. All the trials were at unclear risk of bias. Trials compared the use of phototherapy with standard care only (six trials) or sham phototherapy (one trial). Only one of the trials included a third arm in which another type of phototherapy was applied. Overall, there was insufficient evidence to determine the relative effects of phototherapy for healing pressure ulcers. Time to complete healing was reported in three studies. Two studies showed the ultraviolet (UV) treated group had a shorter mean time to complete healing than the control group (mean difference -2.13 weeks (95% CI -3.53 to -0.72, P value 0.003)). One study reported that the laser group had a longer mean time to complete healing than the control group (mean difference 5.77 weeks; 95% CI -0.25 to 11.79). However, this result should be interpreted with caution, as these were small studies and the findings may have been due to chance. Three studies reported proportions of ulcers healed with a variety of results. One study reported a different outcome measure, and the other two studies had different treatment durations. These variations did not allow us to pool the studies and draw any conclusions as to whether phototherapy is effective or not. Adverse effects were reported in only two studies that compared phototherapy with control; the risk ratio for adverse events was imprecise. One study reported risk ratio (RR) 0.72 (95%CI 0.18 to 2.80). However, another study reported RR 0.89 (95% CI: 0.71 to 1.12) based on the number of events in each group, rather than the number of people with events. Among five studies reporting the rate of change in ulcer area, three studies found no statistically significant difference between the two groups. Pooling was not undertaken because of differences in outcome measures reported. The results were based on data from trials with unclear risk of bias for which generation of the randomisation sequence, concealment allocation and blinding of outcome assessors were unclear. No studies reported on quality of life, length of hospital stay, pain or cost. We are very uncertain as to the effects of phototherapy in treating pressure ulcers. The quality of evidence is very low due to the unclear risk of bias and small number of trials available for analysis. The possibility of benefit or harm of this treatment cannot be ruled out. Further research is recommended.

The review authors searched the medical literature up to 7 January 2014, and identified seven relevant medical trials, with a total of 403 participants. Six trials compared the use of phototherapy with standard care only; one trial compared it with standard care plus sham phototherapy. Only one trial included a third treatment group that investigated another type of phototherapy. Two trials reported the time taken for pressure ulcers to heal completely, and these showed an improvement in healing time for people in the phototherapy group who received treatment with ultraviolet light. However, this result should be interpreted with caution, as these were small, poor quality trials, at unclear risk of bias (i.e. with potentially misleading results), and the findings may have been due to chance. The other trials reported either conflicting results or various measures/time points among trials, which meant that we could not conclude whether or not phototherapy is effective for treating pressure ulcers. Two trials reported incidence of harmful (adverse) effects and noted no significant differences between the phototherapy and standard treatment groups. Four trials provided funding information, two from industry funding, the others from an institutional grant. No studies reported on quality of life, length of hospital stay, pain or cost. This review identified only a few, small studies provided with insufficient evidence to support the use of phototherapy as a routine treatment for pressure ulcers. More trials will need to be conducted before it can be established whether this treatment works and is safe.

10.1002/14651858.CD009224.pub2

cochrane-simplification-train-686

cochrane-simplification-train-686

We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Of these, two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies in this comparison, mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation. The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence). Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence). Moderate to low quality evidence showed neither intravenous magnesium and oral magnesium therapy has an effect on reducing painful crisis, length of hospital stay and changing quality of life in treating sickle cell disease. Therefore, no definitive conclusions can be made regarding its clinical benefit. Further randomized controlled studies, perhaps multicentre, are necessary to establish whether intravenous and oral magnesium therapies have any effect on improving the health of people with sickle cell disease.

The review included five studies with a total of 386 people with sickle cell disease aged between four and 53 years. Two studies (306 people) compared intravenous magnesium to a placebo (in this case saline (salty water)) in people admitted to hospital as an emergency because of pain and lasted until they were discharged (less than four weeks). Two of the three longer-term studies compared oral magnesium pidolate with placebo and the third study compared hydroxyurea and magnesium pidolate to each other and to placebo but we have only included the results of the comparison of magnesium pidolate to placebo). Not all the studies reported on our outcomes and we could not analyse data from most of the studies. We did find that in the people admitted to hospital as emergency cases, intravenous magnesium did not reduce pain levels, could not shorten the length of time spent in hospital and did not improve their quality of life compared to placebo. However, more people given magnesium experienced warmth where the needle was inserted than those people who were given placebo. Oral magnesium pidolate, given over a longer period, did not reduce the severity of painful episodes and had no measurable effect on properties of sickled red cells (e.g. magnesium levels in the blood). Oral magnesium appeared to be safe and well-tolerated with only mild side effects (diarrhoea and headache). Further research is needed to compare the short-term and long-term benefits of magnesium treatment and its side effects. The quality of evidence for intravenous magnesium and oral magnesium in treating sickle cell disease was moderate for pain when using short-term intravenous magnesium and for levels of magnesium in the blood when taking longer-term oral magnesium supplements. The quality of evidence was low for all other outcomes we measured. All of the included studies of oral or intravenous magnesium for treating sickle cell disease had some aspects that could undermine the reliability of their results. Therefore, we have some uncertainty of these findings and further research may provide evidence that could change our conclusions.

10.1002/14651858.CD011358.pub3

cochrane-simplification-train-687

cochrane-simplification-train-687

We identified two studies with a total of 79 participants. One study, with 41 participants, compared cyclobenzaprine with clonazepam and with placebo. Participants taking cyclobenzaprine had some improvement of pain intensity compared to those on clonazepam, mean difference (MD) -0.25 (95% CI, -0.41 to -0.09; P value 0.002) and placebo, MD -0.25 (95% CI, 0.41 to -0.09; P value 0.002). The other study, with 38 participants, compared cyclobenzaprine with lidocaine infiltration. Thirty days after treatment there were statistically non-significant differences between comparison groups, favoring lidocaine infiltration, for the mean for global pain, MD 0.90 (95% CI -0.35 to 2.15, P value 0.16), and for the mean for pain at digital compression, MD 0.60 (95% CI -0.55 to 1.75, P value 0.30). There were no life-threatening adverse events associated with the medications. There was insufficient evidence to support the use of cyclobenzaprine in the treatment of MP. We identified only two small studies in which a total of 35 participants were given cyclobenzaprine, and it was not possible to estimate risks for benefits or harms. Further high quality RCTs of cyclobenzaprine for treating MP need to be conducted before firm conclusions on its effectiveness and safety can be made. Experts in this area should elect cut-off points for participants to identify whether a patient has achieved a clinically relevant reduction of pain (primary outcome), so that their results can be combined easily into future versions of this review.

The purpose of this review was to assess how effective cyclobenzaprine is at reducing pain and improving sleep in patients with MP. We searched extensively through scientific publications and found two trials, with a total of 79 participants. These tested cyclobenzaprine against another drug called clonazepam, and fake medication (placebo), or against injections of a local anesthetic called lidocaine. A total of 35 of the 79 participants in the two trials were given cyclobenzaprine. Cyclobenzaprine was slightly better than clonazepam and placebo at reducing jaw pain, but was no better at improving sleep quality. The results from the other trial were not scientifically reliable because of the small number of participants involved, but lidocaine injections seemed to reduce pain slightly better than cyclobenzaprine pills. Despite this result, it is likely that, because it is uncomfortable to receive any form of injection, people who suffer from MP will prefer to be treated with cyclobenzaprine pills. There were no life-threatening adverse events associated with any of the medications studied. Further studies are needed to show whether cyclobenzaprine really works for treating MP, but at the moment doctors cannot say whether it is really useful.

10.1002/14651858.CD006830.pub3

cochrane-simplification-train-688

cochrane-simplification-train-688

Two randomised controlled trials have examined the effect of the aminosteroid tirilazad mesylate on death and disability following head injury. To date, only the results of one of these trials are available for analysis. The risk of death in patients treated with tirilazad was almost identical to those given placebo RR = 1.05 (95% confidence interval 0.86 to 1.29). The risk of death and severe disability in patients treated with tirilazad was again almost identical to those given placebo RR = 1.07 (95% confidence interval 0.93 to 1.23). There is no evidence to support the routine use of aminosteroids in the management of traumatic head injury. On the basis of the existing evidence from randomised trials of aminosteroids in head injury, it is not possible to refute the possibility of moderate but potentially clinically important benefits or harms. A further randomised controlled trial of tirilazad mesylate with 1156 participants has been completed, the results of which should become available in the near future.

The review author searched the medical literature to find out if aminosteroids help people with traumatic brain injury when given within seven days of the injury. The author looked for randomised controlled trials in which one group of patients received a treatment (aminosteroids) while a similar group received non-active treatment (placebo) in addition to standard care. To reduce possible bias, each patient is randomly assigned to a group. The author found two such studies, which used the aminosteroid tirilazad mesylate, but the results of one of the studies were not available at the time of review. The completed study involved 1131 patients. The results of this study showed no benefit from the aminosteroid. The aminosteroid group did not have more side effects than the placebo group but aminosteroids are fairly new drugs that may have unknown less common side effects. More research is needed on the use of aminosteroids to treat traumatic brain injury but currently there is no evidence to recommend their use.

10.1002/14651858.CD001527

cochrane-simplification-train-689

cochrane-simplification-train-689

Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.

The researchers identified three studies that included a total of 165 patients. One study (67 patients) compared oral methotrexate (12.5 mg/week) to placebo (e.g. a sugar pill or fake medicine), one study (26 patients) compared oral methotrexate (15 mg/week) and sulfasalazine (3 g/day) to sulfasalazine alone, and one study (72 patients in total; of which, 34 had ulcerative colitis ) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) or 5-aminosalicylic acid (3 g/day). Two studies were judged to be of very low quality and the placebo-controlled study was judged to be of high quality. There was no difference between the methotrexate and placebo treatment groups for the number of people who maintained remission at nine months. This suggests that, when used at this low dose (12.5 mg/week) methotrexate does not maintain remission in patients with inactive ulcerative colitis. However, this result is uncertain due to the small number of people who were assessed There was no difference between the combination therapy (methotrexate plus sulfasalazine) and sulfasalazine treatment groups for the number of people who maintained remission at 12 months. This result is uncertain due to poor study design and the low number of participants. The other, small study showed no differences between methotrexate and the other treatments (6-mercaptopurine and 5-aminosalicylic acid) in the proportion of participants who were able to maintain remission. These results are uncertain due to poor study design and the low number of participants. The side effects reported in the studies included leucopenia (a decrease in the number of white blood cells), migraine, rash, nausea and dyspepsia (indigestion), mild alopecia (hair loss), mild increase in levels of an enzyme found in the liver (aspartate aminotransferase), a collection of pus in the abdominal tissue (peritoneal abscess), abnormally low levels of the protein albumin in the blood (hypoalbuminemia), and pneumonia. At present, the results from medical trials do not support the use of low dose oral methotrexate (12.5 mg to 15 mg/week) for maintenance of remission in people with inactive ulcerative colitis. It is not known whether a higher dose of oral methotrexate, or giving methotrexate by a different route (e.g. by injection), would be effective for maintenance of remission in people with inactive ulcerative colitis. In future, researchers should consider organizing a study with a larger number of participants who receive a higher dose of methotrexate (15 to 25 mg/week). Future studies should also investigate methotrexate given by injection. The results of such studies may resolve the uncertainty surrounding the use of methotrexate as maintenance therapy in people with inactive ulcerative colitis.

10.1002/14651858.CD007560.pub3

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cochrane-simplification-train-690

From 2667 references, we identified two randomized studies, in six reports, that included 431 participants. All participants were clinically staged to have at least T3 and/or node positive thoracic esophageal carcinoma, 93% of which was squamous cell histology. The risk of methodological bias of the included studies was low to moderate. High-quality evidence found the addition of esophagectomy had little or no difference on overall survival (HR 0.99, 95% CI 0.79 to 1.24; P = 0.92; I² = 0%; two trials). Neither study reported PFS, therefore, freedom from loco-regional relapse was used as a proxy. Moderate-quality evidence suggested that the addition of esophagectomy probably improved freedom from locoregional relapse (HR 0.55, 95% CI 0.39 to 0.76; P = 0.0004; I² = 0%; two trials), but low-quality evidence suggested it may increase the risk of treatment-related mortality (RR 5.11, 95% CI 1.74 to 15.02; P = 0.003; I² = 2%; two trials). The other pre-specified outcomes (quality of life, treatment-related toxicity, and use of salvage procedures for dysphagia) were reported by only one study, which found very low-quality evidence that use of esophagectomy was associated with reduced short-term QoL (MD 0.93, 95% CI 0.24 to 1.62), and low-quality evidence that it reduced use of salvage procedures for dysphagia (HR 0.52, 95% CI 0.36 to 0.75). Neither study compared treatment-related morbidity between treatment groups. Based on the available evidence, the addition of esophagectomy to chemoradiotherapy in locally advanced esophageal squamous cell carcinoma, provides little or no difference on overall survival, and may be associated with higher treatment-related mortality. The addition of esophagectomy probably delays locoregional relapse, however, this end point was not well defined in the included studies. It is undetermined whether these results can be applied to the treatment of adenocarcinomas, tumors involving the distal esophagus and gastro-esophageal junction, and to people with poor response to chemoradiation.

We included two randomized studies, in six published reports, with 431 participants with locally advanced esophageal cancer. We searched biomedical databases, clinical trial registries, conference proceedings, and reference lists up to 7 February 2017 for studies. The quality of evidence ranged from very low to high, depending on the outcome being assessed, because the trials were small and at unclear or high risk of bias (a systematic error or deviation from the truth that affects the results, favouring one treatment over another). We found evidence that adding surgery reduced the risk of the cancer recurring at the primary site, but did not improve overall survival. Moreover, there were more treatment-related deaths in the group of participants who underwent surgery.

10.1002/14651858.CD010511.pub2

cochrane-simplification-train-691

cochrane-simplification-train-691

We identified 21 trials and included three, reporting results from 131 participants lasting between three months and one year. Two trials compared supplements to additional nutritional advice and one to no intervention. Two of the included trials recruited only children. In one trial the risk of bias was low across all domains, in a second trial the risk of bias was largely unclear and in the third mainly low. Blinding of participants was unclear in two of the trials. Also, in one trial the clinical condition of groups appeared to be unevenly balanced at baseline and in another trial there were concerns surrounding allocation concealment. There were no significant differences between people receiving supplements or dietary advice alone for change in weight, height, body mass index, z score or other indices of nutrition or growth. Changes in weight (kg) at three, six and 12 months respectively were: mean difference (MD) 0.32 (95% confidence interval (CI) -0.09 to 0.72); MD 0.47 (95% CI -0.07 to 1.02 ); and MD 0.16 (-0.68 to 1.00). Total calorie intake was greater in people taking supplements at 12 months, MD 265.70 (95% CI 42.94 to 488.46). There were no significant differences between the groups for anthropometric measures of body composition, lung function, gastro-intestinal adverse effects or activity levels. Moderate quality evidence exists for the outcomes of changes in weight and height and low quality evidence exists for the outcomes of change in total calories, total fat and total protein intake as results are applicable only to children between the ages of 2 and 15 years and many post-treatment diet diaries were not returned. Evidence for the rate of adverse events in the treatment groups was extremely limited and judged to be of very low quality Oral calorie supplements do not confer any additional benefit in the nutritional management of moderately malnourished children with cystic fibrosis over and above the use of dietary advice and monitoring alone. While nutritional supplements may be used, they should not be regarded as essential. Further randomised controlled trials are needed to establish the role of short-term oral protein energy supplements in people with cystic fibrosis and acute weight loss and also for the long-term nutritional management of adults with cystic fibrosis or advanced lung disease, or both.

This review includes three randomised controlled trials with a total of 131 participants and two of them only included children. Two of the trials compared supplements to dietary advice and one compared supplements to no advice. The trials lasted between three months and one year. Key results There were no major differences between people receiving supplements or just dietary advice for any nutritional or growth measurements. This was also true for measures of body composition, lung function, adverse effects on the digestive system or people's levels of activity. Advice and monitoring appear to be enough to manage the diet of moderately malnourished children. Future trials should look into the use of calorie supplements for acute weight loss or long-term care for adults with cystic fibrosis. Quality of the evidence One of the trials appeared to be well run and the risk of bias was low for all the aspects of trial design that we assessed; so we do not think any bias will influence the results in a negative way. In the other two trials, we were not sure if the people taking part could guess which treatment group they were in. In one of these two trials, we further thought it was likely that the person recruiting them to the trial knew which group the participant would be in. In the second of these trials, the people in the group receiving supplements appeared to be generally in better clinical condition at the start of the trial than those who didn't receive any supplements or advice. These factors affect our confidence in the results from these trials. We judged the quality of the evidence for the changes in weight and height to be moderate, but judged the quality of the evidence for the changes in total calories, total fat and total protein intake as low since results are applicable only to children aged between 2 and 15 years; also many post-treatment diet diaries were not returned to the investigators. Evidence for the rate of adverse events in the treatment groups was extremely limited and judged to be of very low quality.

10.1002/14651858.CD000406.pub5

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cochrane-simplification-train-692

We included 29 primary studies (18 from the original review and 11 from this update), corresponding to 34 data sets, published between 2000 and 2018 in the meta-analyses, with a mean prevalence of proven or probable IA of 16.3 (median prevalence 11.1% , range 2.5% to 57.1%). Most patients had received chemotherapy for haematological malignancy or had undergone hematopoietic stem cell transplantation. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The summary estimates of sensitivity and specificity were 79.2% (95% confidence interval (CI) 71.0 to 85.5) and 79.6% (95% CI 69.9 to 86.6) for a single positive test result, and 59.6% (95% CI 40.7 to 76.0) and 95.1% (95% CI 87.0 to 98.2) for two consecutive positive test results. PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as the diagnostic criterion for IA in a population of 100 people with a disease prevalence of 16.3% (overall mean prevalence), three people with IA would be missed (sensitivity 79.2%, 20.8% false negatives), and 17 people would be unnecessarily treated or referred for further tests (specificity of 79.6%, 21.4% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that nine IA people would be missed (sensitivity 59.6%, 40.4% false negatives) and four people would be unnecessarily treated or referred for further tests (specificity of 95.1%, 4.9% false positives). Like galactomannan, PCR has good NPV for excluding disease, but the low prevalence of disease limits the ability to rule in a diagnosis. As these biomarkers detect different markers of disease, combining them is likely to prove more useful.

We conducted our most recent search for studies in March 2018 and combined with an earlier search selected 29 clinical studies reporting the evaluation of PCR tests prospectively in cohorts of people at high risk of IA. None of the companies involved in the diagnosis of invasive fungal diseases funded any of the studies included in the review. Most studies were at low risk of bias and low concern regarding applicability. However, differences in the reference standard may have contributed to differences we found in the distribution of cases as being classified as IA or not. Several PCR techniques were used in the studies. Pooling the data from the studies showed that sensitivity and specificity of PCR for the diagnosis of IA varied (from 59% to 79.2% and from 79% to 95.2%, respectively) depending on the interpretative criteria used to define a test as positive. When used as a diagnostic criterion for IA in a population of 100 people with a disease prevalence of 16.3% (overall mean prevalence), a single PCR positive test would have missed three people with the disease, and falsely classified 17 people as having the disease, who would be treated unnecessarily or referred for further tests. A requirement of two positive tests as a diagnostic criterion in a population with the same disease prevalence would miss nine people with the disease and falsely classify four people as having the disease. These numbers should be interpreted with caution because the reference standard is based on the degree of certainty of diagnosis and is rarely proven so cannot provide consistent assessment of cases as being IA or not. Overall, PCR shows moderate diagnostic accuracy when used as a screening test for IA in high-risk patient groups. Importantly, when the rate of sensitivity is low, the sensitivity of the tests means that a negative result allows the diagnosis to be excluded with confidence except when the patient is receiving certain antifungal drugs. With the low prevalence of the disease, a high negative predictive value such that a negative test allows the diagnosis to be excluded.

10.1002/14651858.CD009551.pub4

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cochrane-simplification-train-693

Two trials met the inclusion criteria. Faix 1988 randomised 42 premature infants with radiological diagnosis of NEC. Infants were randomised to receive either intravenous ampicillin and gentamicin or ampicillin, gentamicin and clindamycin. Hansen 1980 randomised 20 infants with NEC to receive intravenous ampicillin and gentamicin with or without enteral gentamicin. In the study by Faix 1988, there were no statistical differences in mortality (RR 1.10; 95% CI 0.32 to 3.83) or bowel perforation (RR 2.20; 95% CI 0.45 to 10.74) between the two groups although there was a trend towards higher rate of strictures in the group that received clindamycin (RR 7.20; 95% CI 0.97 to 53.36). The Hansen 1980 study showed no statistically significant difference in death, bowel perforation or development of strictures. There was insufficient evidence to recommend a particular antibiotic regimen for the treatment of NEC. There were concerns about adverse effects following the usage of clindamycin, related to the development of strictures. To address this issue a large randomised controlled trial needs to be performed.

The authors of this study reviewed the medical literature to ascertain the best antibiotic combination for the treatment of this condition. Four eligible studies were identified and only two of these studies were found to be suitable for analysis. Both these studies were performed before 1988. The two studies included 62 infants with NEC and compared one antibiotic regimen to another. There was no difference between the two groups. The authors concluded that there was insufficient evidence to recommend a particular antibiotic regimen for NEC.

10.1002/14651858.CD007448.pub2

cochrane-simplification-train-694

cochrane-simplification-train-694

We included 10 trials involving 1967 patients undergoing 2157 operations. The quality of trials was generally poor. Follow up varied from hospital discharge to five years. Carotid patch angioplasty was associated with a reduction in the risk of ipsilateral stroke during the perioperative period (odds ratio (OR) 0.31, 95% confidence interval (CI) 0.15 to 0.63, P = 0.001) and long-term follow up (OR 0.32, 95%CI 0.16 to 0.63, P = 0.001). It was also associated with a reduced risk of perioperative arterial occlusion (OR 0.18, 95% CI 0.08 to 0.41, P < 0.0001), and decreased restenosis during long-term follow up in eight trials (OR 0.24, 95% CI 0.17 to 0.34, P < 0.00001). These results are more certain than those of the previous review since the number of operations and events have increased. However, the sample sizes are still relatively small, data were not available from all trials, and there was significant loss to follow up. Very few arterial complications, including haemorrhage, infection, cranial nerve palsies and pseudo-aneurysm formation were recorded with either patch or primary closure. No significant correlation was found between use of patch angioplasty and the risk of either perioperative or long-term all-cause death rates. Limited evidence suggests that carotid patch angioplasty may reduce the risk of perioperative arterial occlusion and restenosis. It would appear to reduce the risk of ipsilateral stroke and there is a non significant trend towards a reduction in perioperative any stroke rate and all-cause case fatality.

Evidence from this review of 10 trials involving 1967 patients undergoing 2157 operations now suggests a benefit from using routine patch angioplasty during carotid endarterectomy. About 20% of strokes result from narrowing of the carotid artery (the main artery supplying blood to the brain). Carotid endarterectomy is an operation that involves opening the carotid artery to remove this narrowing and, therefore, reduce the risk of stroke. However, there is a 2% to 10% risk of the operation itself causing a stroke. Some surgeons advocate the incorporation of a patch made out of either synthetic material or the patient's own vein, into the arterial closure. This may help to reduce the risk of the artery being narrowed during suture placement and may, therefore, reduce the risk of recurrent blockage and consequent stroke or death or both. However, use of a patch may increase surgical difficulty and operation length. Furthermore, thin-walled vein patches may rupture with potentially fatal consequences and synthetic materials are vulnerable to infection.

10.1002/14651858.CD000160.pub3

cochrane-simplification-train-695

cochrane-simplification-train-695

As a result of searches undertaken in 2014, we found one new study and in 2016 more data for already included studies. Five relevant studies with 1132 participants (585 are relevant to this review) are now included. All are hospital-based trials and, despite over 60 years of chlorpromazine use, have durations of less than six months and all are at least at moderate risk of bias. We found only data on low-dose (≤ 400 mg/day) versus medium-dose chlorpromazine (401 mg/day to 800 mg/day) and low-dose versus high-dose chlorpromazine (> 800 mg/day). When low-dose chlorpromazine (≤ 400 mg/day) was compared to medium-dose chlorpromazine (401 mg/day to 800 mg/day), there was no clear benefit of one dose over the other for both global and mental state outcomes (low-quality and very low-quality evidence). There was also no clear evidence for people in one dosage group being more likely to leave the study early, over the other dosage group (moderate-quality evidence). Similar numbers of participants from each group experienced agitation and restlessness (very low-quality evidence). However, significantly more people in the medium-dose group (401 mg/day to 800 mg/day) experienced extrapyramidal symptoms in the short term (2 RCTS, n = 108, RR 0.47, 95% CI 0.30 to 0.74, moderate-quality evidence). No data for death were available. When low-dose chlorpromazine (≤ 400 mg/day) was compared to high-dose chlorpromazine (> 800 mg/day), data from one study with 416 patients were available. Clear evidence of a benefit of the high dose was found with regards to global state. The low-dose group had significantly fewer people improving (RR 1.13, 95% CI 1.01 to 1.25, moderate-quality evidence). There was also a marked difference between the number of people leaving the study from each group for any reason, with significantly more people leaving from the high-dose group (RR 0.60, 95% CI 0.40 to 0.89, moderate-quality evidence). More people in the low-dose group had to leave the study due to deterioration in behaviour (RR 2.70, 95% CI 1.34 to 5.44, low-quality evidence). There was clear evidence of a greater risk of people experiencing extrapyramidal symptoms in general in the high-dose group (RR 0.43, 95% CI 0.32 to 0.59, moderate-quality evidence). One death was reported in the high-dose group yet no effect was shown between the two dosage groups (RR 0.33, 95% CI 0.01 to 8.14, moderate-quality evidence). No data for mental state were available. The dosage of chlorpromazine has changed drastically over the past 50 years with lower doses now being the preferred of choice. However, this change was gradual and arose not due to trial-based evidence, but due to clinical experience and consensus. Chlorpromazine is one of the most widely used antipsychotic drugs yet appropriate use of lower levels has come about after many years of trial and error with much higher doses. In the absence of high-grade evaluative studies, clinicians have had no alternative but to learn from experience. However, such an approach can lack scientific rigor and does not allow for proper dissemination of information that would assist clinicians find the optimum treatment dosage for their patients. In the future, data for recently released medication should be available from high-quality trials and studies to provide optimum treatment to patients in the shortest amount of time.

An updated search for relevant randomised controlled trials was run in October 2014, and again, in December 2016 and found one new study. Five studies have now been found that meet the review inclusion criteria. The included studies are all randomised, and investigate the effects of giving different doses of chlorpromazine to people with schizophrenia. The total number of participants was 585. Chlorpromazine showed different effects at varying doses. Based on weak evidence, the effects on people’s mental health at low dosage and medium dosage are much the same. However, there are more side effects at medium dose. There is more improvement in people’s mental health at high dose compared to low dose. However, side effects are much more numerous and debilitating at high dose. In the past fifty years, low dose has been the favoured amount to use with patients. This change has come about gradually and is based on everyday experience and consensus rather than hard scientific evidence. Chlorpromazine is low-cost and widely available. Despite its many side effects, chlorpromazine is likely to remain a benchmark or ‘gold standard’ drug and one of the most widely used treatments for schizophrenia worldwide. All trials in the review are hospital- based and all but one date from 20 years ago. There are a limited number of studies of limited quality and these are poorly reported and short term. Further research and trials on chlorpromazine dose are justified. Ben Gray, Senior Peer Researcher, McPin Foundation. http://mcpin.org/

10.1002/14651858.CD007778.pub2

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cochrane-simplification-train-696

A total of 12 randomised trials were identified, totaling 843 patients. The size of the randomised clinical trials ranged from 30 to 155 patients. Both preoperative (neoadjuvant) and postoperative (adjuvant), systemic and locoregional (+/- embolisation), chemo- and immunotherapy interventions were tested. Treatment regimens and patients selected were not comparable, so no pooling was done. Only one regimen using preoperative transcatheter arterial chemoembolisation with doxorubicin was similar in two trials. Four of the twelve trials reported survival benefit at five years when given adjuvant or neoadjuvant therapy. Disease-free survival was reported in nine trials, and the estimated hazard ratios show that disease-free survival was significant in two trials at five years. These two trials had not shown a survival advantage, but the recurrence was significantly lower in patients given adjuvant or neoadjuvant therapy. The highest toxicity rate was in a trial using oral 1-hexylcarbamoyl 5-fluorouracil which resulted in 12 out of 38 patients being withdrawn from the trial because of adverse events. There is no clear evidence for efficacy of any of the adjuvant and neo-adjuvant protocols reviewed, but there is some evidence to suggest that adjuvant therapy may be beneficial offering prolonged disease-free survival. In order to detect a realistic treatment advantage, larger trials with lower risk of systematic error will have to be conducted.

This review sets on to determine the efficacy and adverse events of different neoadjuvant therapies (drug given before) versus adjuvant therapies (drug given after) compared to surgery alone, or surgery and placebo or supportive therapy when given to improve relapse and survival rates for operable hepatocellular carcinoma. A total of 12 randomised trials were identified, totaling 843 patients. The size of the randomised clinical trials ranged from 30 to 155 patients. Nine of the twelve trials reported no survival benefit from adjuvant therapy. Two trials reported a significant difference for survival and four studies for disease-free survival for the treatment group, but the results of one of the trials on both its groups were very poor when compared to other trials. Two of the trials that did not report any absolute survival advantage reported statistically significant differences in disease-free survival. The highest toxicity rate was in a trial using oral 1-hexylcarbamoyl 5- fluorouracil which resulted in 12 out of 38 patients being withdrawn from the trial because of adverse events. In conclusion, this review found insufficient evidence to show that adjuvant and neo-adjuvant therapy increase survival from hepatocellular carcinoma, but there is limited evidence to suggest that neoadjuvant or adjuvant therapy may be useful for disease-free survival.

10.1002/14651858.CD001199.pub2

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cochrane-simplification-train-697

We included two RCTs, that randomised 514 pregnant women (347 women analysed) at a mean gestational age of 22 weeks. Both trials were conducted in the outpatient department of the same two hospitals in the USA between 1993 and 2001, and had a follow-up of 14 days. One of the trials was sponsored by a drug company. We considered both trials to be at a high risk of bias. One trial compared ceftriaxone (125 mg, intramuscular) with cefixime (400 mg, oral); the other trial had three arms, and assessed ceftriaxone (250 mg, intramuscular) versus either amoxicillin (3 g, oral) plus probenecid (1 g, oral) or spectinomycin (2 g, intramuscular). We did not include the spectinomycin data because this medication is no longer produced. We were unable to conduct meta-analysis because the trials compared different medications. We found inconclusive evidence that there were clear differences in the cure of gonococcal infections (genital, extragenital, or both) between intramuscular ceftriaxone versus oral amoxicillin plus oral probenecid (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.98 to 1.16; one RCT; 168 women; very low-quality evidence) or intramuscular ceftriaxone versus oral cefixime (RR 0.99, 95% CI 0.91 to 1.08; one RCT; 95 women; very low-quality evidence). Neither of the trials reported on two of this review's primary maternal outcomes: incidence of obstetric complications (miscarriage, premature rupture of membranes, preterm delivery, or fetal death), or disseminated gonococcal infection, or on the incidence of neonatorum ophthalmia in the neonates. One trial reported one case of vomiting in the oral amoxacillin plus probenecid group. Trials reported pain at the injection sites, but did not quantify it. Hyperberbilurrubinemia was more frequent in neonates whose mothers were exposed to ceftriaxone. There were no clear differences between groups for neonatal malformation. This Cochrane Review found high levels of cure of gonococcal infections in pregnancy with the given antibiotic regimens. However, the evidence in this review is inconclusive as it does not support one particular regimen over another. This conclusion was based on very low-quality evidence (downgraded for poor trial design, imprecision) from two trials (involving 514 women), which we assessed to be at a high risk of bias for a number of domains. The harm profiles of the antibiotic regimes featured in this review remain unknown. High-quality RCTs are needed, with sufficient power to assess the clinical effectiveness and potential harms of antibiotics in pregnant women with gonorrhoea. These should be planned according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT),conducted following CONSORT recommendations, and based on Patient-Centered Outcomes Research Institute (PCORI) outcomes.

We searched for evidence in April 2017 and found two randomised controlled trials, conducted in outpatient departments of the same two hospitals in the USA, between 1993 and 2001. One trial was sponsored by a drug company. The trials randomised a total of 514 pregnant women (347 women analysed), at an average gestational age of 22 weeks. Both trials had a follow-up of 14 days. We were unable to pool the results because the trials used different comparisons. One trial compared ceftriaxone (125 mg, intramuscular) with cefixime (400 mg, oral), and the other trial assessed a higher dose of ceftriaxone (250 mg, intramuscular) versus either amoxicillin (3 g, oral) plus probenecid (1 g, oral) or spectinomycin (2 g, intramuscular). We did not include data from the spectinomycin group because this medication is no longer produced. We found no clear difference in the rate of cure of gonococcal infection (both genital and unrelated to the genital organs) for the different treatment groups, which was in the order of 89% to 96% (very low-quality evidence). Trials did not report on the incidence of obstetric complications, disseminated gonococcal infection in the mother, or ophthalmia neonatorum in the baby. They provided little information on side effects of the antibiotic regimens. One trial reported one case of vomiting in the oral amoxacillin plus probenecid group. Trials reported pain at the injection sites, but did not report numbers or severity. Hyperberbilurrubinemia (where the baby has too much bilirubin in the blood) was more frequent in newborns whose mothers were exposed to ceftriaxone. There was no clear difference between groups for neonatal malformation. We found high levels of cure of gonococcal infection in pregnancy with the given antibiotic regimens, but here was not enough evidence to support one particular regimen over another. Despite high levels of cure, our confidence in the results of this review is very low because both included trials were small, did not blind women to which treatment they received, and had a high number of withdrawals (28% and 41%), meaning they were at high risk of bias. Therefore, there is a need for high-quality trials to be conducted to assess the clinical effectiveness and potential harms of antibiotics for treating gonorrhoea in pregnancy women.

10.1002/14651858.CD011167.pub2

cochrane-simplification-train-698

cochrane-simplification-train-698

Eight RCTs involving 358,750 participants were included. These trials investigated two available and three pre-licensure vaccines. Two RCTs assessing efficacy of the commercially available inactivated Nakayama vaccine were identified. A two-dose schedule of the licensed vaccine provided significant protection of 95% (95% CI 10% to 100%) for one year only, while two doses of an unpurified precursor vaccine protected children by 81% (95% CI 45% to 94%) in year one and by 59% (95% CI 2% to 83%) in year two. Serious adverse events were not observed. Mild and moderate episodes of injection site soreness, fever, headache, and nausea were reported in less than 6% of children receiving inactivated vaccine compared to 0.6% of unvaccinated controls. One cluster-RCT compared the live-attenuated SA14-14-2 vaccine (widely used in China) with no intervention measuring adverse events. Fever was reported in 2.7% of vaccinees compared to 3.1% of controls, while 0.1% of both groups suffered diarrhoea or seizures. Four small pre-licensure RCTs assessing a genetically engineered vaccine and two cell culture-derived inactivated vaccines revealed high immunogenicity and relative safety. Only one of the three currently used vaccines has been assessed for efficacy in a RCT. Other RCTs have assessed their safety, however, and they appear to cause only occasional mild or moderate adverse events. Further trials of effectiveness and safety are needed for the currently used vaccines, especially concerning dose levels and schedules. Trials investigating several new vaccines are planned or in progress.

In this review of randomized controlled trials, a commercially available inactivated vaccine given in two doses was shown to provide disease protection for at least one year after vaccination, but with some adverse events. Disease protection by two vaccines, widely used in China but presently commercially unavailable, has not been investigated in randomized controlled trials. Further research is needed on all currently used as well as newly developed vaccines.

10.1002/14651858.CD004263.pub2

cochrane-simplification-train-699

cochrane-simplification-train-699

Twenty-two randomised trials were included in the review (N = 695). Studies were highly variable in their country of origin, sample size, participant age, intervention delivery type, and outcome measures. Risk of bias was variable across categories. There were very few studies for which there was adequate blinding of participants and personnel, and some were also judged at high risk of bias in blinding of outcome assessors. There was also evidence of some bias in sequence generation and allocation concealment. Not all studies reported data that fell within the pre-defined primary outcome categories for the review, instead many studies reported measures which were intervention-specific (e.g. emotion recognition). The wide range of measures used within each outcome category and the mixed results from these measures introduced further complexity when interpreting results. Studies were grouped into four main categories according to intervention target/primary outcome measure. These were: emotion recognition studies, joint attention and social communication studies, imitation studies, and studies teaching ToM itself. Within the first two of these categories, a sub-set of studies were deemed suitable for meta-analysis for a limited number of key outcomes. There was very low quality evidence of a positive effect on measures of communication based on individual results from three studies. There was low quality evidence from 11 studies reporting mixed results of interventions on measures of social interaction, very low quality evidence from four studies reporting mixed results on measures of general communication, and very low quality evidence from four studies reporting mixed results on measures of ToM ability. The meta-analysis results we were able to generate showed that interventions targeting emotion recognition across age groups and working with people within the average range of intellectual ability had a positive effect on the target skill, measured by a test using photographs of faces (mean increase of 0.75 points, 95% confidence interval (CI) 0.22 to 1.29 points, Z = 2.75, P < 0.006, four studies, N = 105). Therapist-led joint attention interventions can promote production of more joint attention behaviours within adult-child interaction (mean increase of 0.55 points, 95% CI 0.11 to 0.99 points, Z = 2.45, P value = 0.01, two studies, N = 88). Further analysis undermines this conclusion somewhat by demonstrating that there was no clear evidence that intervention can have an effect on joint attention initiations as measured using a standardised assessment tool (mean increase of 0.23 points, 95% CI -0.48 to 0.94 points, Z = 0.63, P value = 0.53, three studies, N = 92). No adverse effects were apparent. While there is some evidence that ToM, or a precursor skill, can be taught to people with ASD, there is little evidence of maintenance of that skill, generalisation to other settings, or developmental effects on related skills. Furthermore, inconsistency in findings and measurement means that evidence has been graded of 'very low' or 'low' quality and we cannot be confident that suggestions of positive effects will be sustained as high-quality evidence accumulates. Further longitudinal designs and larger samples are needed to help elucidate both the efficacy of ToM-linked interventions and the explanatory value of the ToM model itself. It is possible that the continuing refinement of the ToM model will lead to better interventions which have a greater impact on development than those investigated to date.

We found 22 research studies involving 695 participants, which reported on the efficacy of interventions related to theory of mind. The evidence is current to 7th August 2013. Despite all studies using a high-quality basic methodology (the randomised controlled trial), there was concern over poor study design and reporting in some aspects. While there is some evidence that theory of mind, or related skills, can be taught to people with ASD, there is currently poor quality  evidence that these skills can be maintained, generalised to other settings, or that teaching theory of mind has an impact on developmentally-linked abilities. For example, it was rare for a taught skill to generalise to a new context, such as sharing attention with a new adult who was not the therapist during the intervention. New skills were not necessarily maintained over time. This evidence could imply that the theory of mind model has little relevance for educational and clinical practice in ASD. Further research using longitudinal methods, better outcome measures, and higher standards of reporting is needed to throw light on the issues. This is particularly important as the specific details of the theory of mind model continue to evolve.

10.1002/14651858.CD008785.pub2