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cochrane-simplification-train-2900

cochrane-simplification-train-2900

We identified one RCT and no CCTs; in this update no additional eligible studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.

The evidence is current to November 2019. We found one study (91 participants) comparing a continuous cisplatin infusion with a one-hour cisplatin bolus infusion in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the treatment cycle but it is not clear if the infusion duration was a total of five days. Only results from shortly after induction therapy were available. At the moment there is no evidence showing that the use of a different cisplatin infusion duration prevents hearing loss or adversely affects tumour response and adverse effects. No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. We need more high-quality research before definite conclusions can be made about the usefulness of different platinum infusion durations to prevent hearing loss in children with cancer. The quality of the evidence was low.

10.1002/14651858.CD010885.pub5

cochrane-simplification-train-2901

cochrane-simplification-train-2901

We identified 24 RCTs involving 3739 participants which were included in the review. IHCAs had a significant positive effect on knowledge (SMD 0.46; 95% confidence interval (CI) 0.22 to 0.69), social support (SMD 0.35; 95% CI 0.18 to 0.52) and clinical outcomes (SMD 0.18; 95% CI 0.01 to 0.35). Results suggest it is more likely than not that IHCAs have a positive effect on self-efficacy (a person's belief in their capacity to carry out a specific action) (SMD 0.24; 95% CI 0.00 to 0.48). IHCAs had a significant positive effect on continuous behavioural outcomes (SMD 0.20; 95% CI 0.01 to 0.40). Binary behavioural outcomes also showed a positive effect for IHCAs, although this result was not statistically significant (OR 1.66; 95% CI 0.71 to 3.87). It was not possible to determine the effects of IHCAs on emotional or economic outcomes. IHCAs appear to have largely positive effects on users, in that users tend to become more knowledgeable, feel better socially supported, and may have improved behavioural and clinical outcomes compared to non-users. There is a need for more high quality studies with large sample sizes to confirm these preliminary findings, to determine the best type and best way to deliver IHCAs, and to establish how IHCAs have their effects for different groups of people with chronic illness.

This review sought to find out how such computer programmes, known as Interactive Health Communication Applications (IHCAs), might affect people with chronic disease. The review authors found that IHCAs improved users' knowledge, social support, health behaviours and clinical outcomes. It is also more likely than not that IHCAs improve users' self-efficacy (a person's belief in their capacity to carry out a specific action). It was not possible to determine whether IHCAs had any effect on emotional and economic outcomes. The included studies involved different IHCAs, with different characteristics, for a wide range of chronic diseases. There was variability in several of the outcomes, and the results should therefore be treated with some caution. There is a need for more large, high quality studies to confirm these preliminary findings, to determine the best type and best way to deliver IHCAs, and to establish how IHCAs have their effects for different groups of people with chronic illness.

10.1002/14651858.CD004274.pub4

cochrane-simplification-train-2902

cochrane-simplification-train-2902

We included 14 RCTs of 5600 women randomised to receive high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. The studies were at low risk of bias in most areas. There is high-quality evidence that high-dose chemotherapy does not increase the likelihood of overall survival at any stage of follow-up (at three years: RR 1.02, 95% CI 0.95 to 1.10, 3 RCTs, 795 women, I² = 56%; at five years: RR 1.00, 95% CI 0.96 to 1.04, 9 RCTs, 3948 women, I² = 0%; at six years: RR 0.94, 95% CI 0.81 to 1.08, 1 RCT, 511 women; at eight years: RR1.17, 95% CI 0.95 to 1.43, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.99 to 1.42, 1 RCT, 382 women). There is high-quality evidence that high-dose chemotherapy improves the likelihood of event-free survival at three years (RR 1.19, 95% CI 1.06 to 1.34, 3 RCTs, 795 women, I² = 56%) but this effect was no longer apparent at longer duration of follow-up (at five years: RR 1.04, 95% CI 0.99 to 1.09, 9 RCTs, 3948 women, I² = 14%; at six years RR 1.04, 95% CI 0.87 to 1.24, 1 RCT, 511 women; at eight years: RR 1.27, 95% CI 0.99 to 1.64, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.95 to 1.45, 1 RCT, 382 women). Treatment-related deaths were much more frequent in the high-dose arm (RR 7.97, 95% CI 3.99 to 15.92, 14 RCTs, 5600 women, I² = 12%, high-quality evidence) and non-fatal morbidity was also more common and more severe in the high-dose group. There was little or no difference between the groups in the incidence of second cancers at four to nine years' median follow-up (RR 1.25, 95% CI 0.90 to 1.73, 7 RCTs, 3423 women, I² = 0%, high-quality evidence). Women in the high-dose group reported significantly worse quality-of-life scores immediately after treatment, but there were few statistically significant differences between the groups by one year. The primary studies were at low risk of bias in most areas, and the evidence was assessed using GRADE methods and rated as high quality for all comparisons. There is high-quality evidence of increased treatment-related mortality and little or no increase in survival by using high-dose chemotherapy with autograft for women with early poor prognosis breast cancer.

We included 14 randomised controlled trials (5600 women) which compared high-dose chemotherapy versus conventional chemotherapy in women with early breast cancer and with a high risk of recurrence. We defined these as women with breast cancer that has spread to multiple local lymph nodes without any evidence of spread beyond local lymph nodes. All studies reported their source of funding. Eight studies were funded by non-profit organisations, one by a public health insurance company, one by industry sources and four by a combination of non-profit organisations and industry sources. Four of the studies reported that authors had no potential conflict of interest, six reported that one or more of their authors had received some kind of support from pharmaceutical companies, and four did not mention whether any of their authors had any potential conflict of interest. Using high-dose chemotherapy has little or no effect on increasing survival. Although rates of event-free survival were higher in the high-dose arm over three-year follow-up, this effect was not apparent at longer follow-up. Treatment-related deaths were much more common in the high-dose group. Side-effects were also more common and more severe in the high-dose group. We did not find an effect on the number of women developing second cancers. The evidence was of high quality.

10.1002/14651858.CD003139.pub3

cochrane-simplification-train-2903

cochrane-simplification-train-2903

For this fourth update six new trials were included, bringing the total of included trials to 59. Foam alternatives to standard hospital foam mattresses reduce the incidence of pressure ulcers in people at risk (RR 0.40 95% CI 0.21 to 0.74). The relative merits of alternating- and constant low-pressure devices are unclear. One high-quality trial suggested that alternating-pressure mattresses may be more cost effective than alternating-pressure overlays in a UK context. Pressure-relieving overlays on the operating table reduce postoperative pressure ulcer incidence, although two trials indicated that foam overlays caused adverse skin changes. Meta-analysis of three trials suggest that Australian standard medical sheepskins prevent pressure ulcers (RR 0.56 95% CI 0.32 to 0.97). People at high risk of developing pressure ulcers should use higher-specification foam mattresses rather than standard hospital foam mattresses. The relative merits of higher-specification constant low-pressure and alternating-pressure support surfaces for preventing pressure ulcers are unclear, but alternating-pressure mattresses may be more cost effective than alternating-pressure overlays in a UK context. Medical grade sheepskins are associated with a decrease in pressure ulcer development. Organisations might consider the use of some forms of pressure relief for high risk patients in the operating theatre.

The review found that people lying on ordinary foam mattresses are more likely to get pressure ulcers than those lying on a higher-specification foam mattress. In addition the review also found that people who used sheepskin overlays on their mattress developed fewer pressure ulcers. While alternating-pressure mattresses may be more cost effective than alternating-pressure overlays, the evidence base regarding the merits of higher-specification constant low-pressure and alternating-pressure support surfaces for preventing pressure ulcers is unclear. Rigorous research comparing different support surfaces is needed.

10.1002/14651858.CD001735.pub5

cochrane-simplification-train-2904

cochrane-simplification-train-2904

For this update of the review, we identified one new trial, bringing the total to 17 trials (1034 participants) - all of which were generally at moderate or high risk of bias. In 12 trials participants also received compression bandaging. Eleven trials compared a graft with standard care in which no graft was used. Two of these trials (102 participants) compared a dressing with an autograft; three trials (80 participants) compared frozen allografts with dressings, and two trials (45 participants) compared fresh allografts with dressings. Two trials (345 participants) compared tissue-engineered skin (bilayer artificial skin) with a dressing. In two trials (97 participants) a single-layer dermal replacement was compared with standard care. Six trials compared alternative skin grafting techniques. The first trial (92 participants) compared autografts with frozen allograft, a second (51 participants) compared a pinch graft (autograft) with porcine dermis (xenograft), the third (110 participants) compared growth-arrested human keratinocytes and fibroblasts with placebo, the fourth (10 participants) compared an autograft delivered on porcine pads with an autograft delivered on porcine gelatin microbeads, the fifth trial (92 participants) compared a meshed graft with a cultured keratinocyte autograft, and the sixth trial (50 participants) compared a frozen keratinocyte allograft with a lyophilised (freeze-dried) keratinocyte allografts. Significantly more ulcers healed when treated with bilayer artificial skin than with dressings. There was insufficient evidence from the other trials to determine whether other types of skin grafting increased the healing of venous ulcers. Bilayer artificial skin, used in conjunction with compression bandaging, increases venous ulcer healing compared with a simple dressing plus compression. Further research is needed to assess whether other forms of skin grafts increase ulcer healing.

Approximately 1% of people in industrialised countries have a leg ulcer at some time, mainly caused by poor blood flow back from the legs towards the heart. Skin grafts, either using the patient's own skin, artificial skin or donor skin/cells, have been evaluated to see whether they improve the healing of ulcers. The review of trials found evidence that tissue-engineered skin composed of two layers increases the chance of healing. There was not enough evidence to recommend any other type of graft, and further research is required.

10.1002/14651858.CD001737.pub4

cochrane-simplification-train-2905

cochrane-simplification-train-2905

We found six trials recruiting a total of 549 infants. One trial showed that use of a percutaneous central venous catheter was associated with a smaller deficit between prescribed and actual nutrient intake during the trial period (mean difference (MD) -7.1%, 95% confidence interval (CI) -11.02 to -3.2). Infants in the percutaneous central venous catheter group needed significantly fewer catheters/cannulae (MD -4.3, 95% CI -5.24, -3.43). Meta-analysis of data from all trials revealed no evidence of an effect on the incidence of invasive infection (typical risk ratio (RR) 0.95, 95% CI 0.72 to 1.25; typical risk difference (RD) -0.01, 95% CI -0.08 to 0.06). Data from one small trial suggest that use of percutaneous central venous catheters to deliver parenteral nutrition increases nutrient input. The significance of this in relation to long-term growth and developmental outcomes is unclear. Three trials suggest that use of percutaneous central venous catheters decreases the number of catheters/cannulae needed to deliver nutrition. No evidence suggests that percutaneous central venous catheter use increases risks of adverse events, particularly invasive infection, although none of the included trials was large enough to rule out an effect on uncommon severe adverse events such as pericardial effusion.

We found six small randomised controlled trials (enrolling 549 infants in total) that addressed this question. The trials generally were of good methodological quality, although study findings may be biased by the inability to blind caregivers and investigators to the type of intervention provided. These trials provided only limited evidence on the effects of the interventions on nutrition. Analysis of data from three trials revealed that infants in the percutaneous central venous catheter group needed about four fewer catheters or cannulae during hospitalisation. Combined data from all trials showed no evidence of an effect on risk of bloodstream infection. Use of central venous catheters has been thought to increase the risk of bloodstream infection in newborn infants, but this review of randomised trials found no evidence that this was the case. More trials are needed to determine which method is better for improving nutrition and growth and development in newborn infants.

10.1002/14651858.CD004219.pub4

cochrane-simplification-train-2906

cochrane-simplification-train-2906

We included 39 studies involving 2441 participants with unilateral peripheral vestibular disorders in the review. Trials addressed the effectiveness of vestibular rehabilitation against control/sham interventions, medical interventions or other forms of vestibular rehabilitation. Non-blinding of outcome assessors and selective reporting were threats that may have biased the results in 25% of studies, but otherwise there was a low risk of selection or attrition bias. Individual and pooled analyses of the primary outcome, frequency of dizziness, showed a statistically significant effect in favour of vestibular rehabilitation over control or no intervention (odds ratio (OR) 2.67, 95% confidence interval (CI) 1.85 to 3.86; four studies, 565 participants). Secondary outcomes measures related to levels of activity or participation measured, for example, with the Dizziness Handicap Inventory, which also showed a strong trend towards significant differences between the groups (standardised mean difference (SMD) -0.83, 95% CI -1.02 to -0.64). The exception to this was when movement-based vestibular rehabilitation was compared to physical manoeuvres for benign paroxysmal positional vertigo (BPPV), where the latter was shown to be superior in cure rate in the short term (OR 0.19, 95% CI 0.07 to 0.49). There were no reported adverse effects. There is moderate to strong evidence that vestibular rehabilitation is a safe, effective management for unilateral peripheral vestibular dysfunction, based on a number of high-quality randomised controlled trials. There is moderate evidence that vestibular rehabilitation resolves symptoms and improves functioning in the medium term. However, there is evidence that for the specific diagnostic group of BPPV, physical (repositioning) manoeuvres are more effective in the short term than exercise-based vestibular rehabilitation; although a combination of the two is effective for longer-term functional recovery. There is insufficient evidence to discriminate between differing forms of vestibular rehabilitation.

We found 39 randomised controlled trials (involving 2441 participants) that investigated the use of vestibular rehabilitation in this group of disorders. All studies used a form of vestibular rehabilitation and involved adults who lived in the community with symptomatic, confirmed UPVD. The studies were varied in that they compared vestibular rehabilitation with other forms of management (for example, medication, usual care or passive manoeuvres), with control or placebo interventions or with other forms of vestibular rehabilitation. Another source of variation between studies was the use of different outcome measures (for example, reports of dizziness, improvements in balance, vision or walking, or ability to participate in daily life). Due to the variation between studies, only limited pooling (combining) of data was possible. The results of four studies could be combined, which demonstrated that vestibular rehabilitation was more effective than control or sham interventions in improving subjective reports of dizziness, and in improving participation in life roles. Two studies gave a combined result in favour of vestibular rehabilitation for improving walking. Other single studies all found in favour of vestibular rehabilitation for improvements in areas such as balance, vision and activities of daily living. The exception to these findings was for the specific group of people with BPPV, where comparisons of vestibular rehabilitation with specific physical repositioning manoeuvres showed that these manoeuvres were more effective in dizziness symptom reduction, particularly in the short term. However, other studies demonstrated that combining the manoeuvres with vestibular rehabilitation was effective in improving functional recovery in the longer term. There were no reports of adverse effects following any vestibular rehabilitation. In the studies with a follow-up assessment (3 to 12 months) positive effects were maintained. There was no evidence that one form of vestibular rehabilitation is superior to another. There is a growing and consistent body of evidence to support the use of vestibular rehabilitation for people with dizziness and functional loss as a result of UPVD. The studies were generally of moderate to high quality but were varied in their methods. This evidence is up to date to 18 January 2014.

10.1002/14651858.CD005397.pub4

cochrane-simplification-train-2907

cochrane-simplification-train-2907

There were 24 included studies with 11959 participants in total. Many studies were of cross-over design and first-phase data were unavailable, or could not be extracted. Global impression of change (GIC) was the only outcome for which pooling of data was possible, involving only four studies. There was evidence of heterogeneity in the results, Chi2 test = 19.17 (df = 3, P < 0.001). The odds ratio (OR) for improvement in the piracetam group compared with placebo was 3.43 (95% confidence interval (CI) 2.32 to 5.07). Using a fixed-effect model, the OR for improvement with piracetam compared with placebo was 3.55 (95% CI 2.45 to 5.16). This estimate was derived from completers rather than from an intention-to-treat analysis as relevant data could not be extracted from the reports. In the limited data available, no significant differences were found between treatment and placebo groups for cognition (immediate memory, visuospatial, Mini Mental Status Examination (MMSE), delayed memory or speech) for dependency, or for depression. The large volume of unpublished and untraceable data not available to the review authors raises the possibility of publication bias. Published evidence does not support the use of piracetam in the treatment of people with dementia or cognitive impairment. Although effects were found on global impression of change, no benefit was shown by any of the more specific measures of cognitive function. The evidence indicates a need for further evaluation of piracetam.

Most of the trials of piracetam were undertaken many years ago and did not use methods which would be currently considered standard. Some of the studies suggested there may be some benefit from piracetam but overall the evidence is not consistent or positive enough to support its use for dementia or cognitive impairment.

10.1002/14651858.CD001011

cochrane-simplification-train-2908

cochrane-simplification-train-2908

We were unable to find any randomized controlled trials on antibiotic treatment approaches for community-acquired pneumonia in people with sickle cell disease. The updated review was unable to identify randomized controlled trials on efficacy and safety of the antibiotic treatment approaches for people with sickle cell disease suffering from community-acquired pneumonia. Randomized controlled trials are needed to establish the optimum antibiotic treatment for this condition. The trials regarding this issue should be structured and reported according to the CONSORT statement for improving the quality of reporting of efficacy and improved reports of harms in clinical research. Triallists should consider including the following outcomes in new trials: number of days to become afebrile; mortality; onset of pain crisis or complications of sickle cell disease following community-acquired pneumonia; diagnosis; hospitalization (admission rate and length of hospital stay); respiratory failure rate; and number of participants receiving a blood transfusion. There are no trials included in the review and we have not identified any relevant trials up to September 2016. We therefore do not plan to update this review until new trials are published.

We were not able to find any trials to include in this review. Trials addressing this issue should be structured and reported according to the CONSORT statement for improving the quality of reporting of efficacy and improved reports of harms in clinical research. Trial investigators should consider including the following outcomes in new trials: number of days to be free of fever, death, onset of pain crisis or complications of sickle cell disease following community-acquired pneumonia, diagnosis, hospitalization (admission rate and length of hospital stay), respiratory failure rate, and number of participants receiving a blood transfusion. Since no trials have been included in the review up until September 2016, we will still search for trials every two years, but will not publish an updated version of this review until any eligible trials are identified.

10.1002/14651858.CD005598.pub4

cochrane-simplification-train-2909

cochrane-simplification-train-2909

We included 33 studies of STPP involving 2173 randomised participants with common mental disorders. Studies were of diverse conditions in which problems with emotional regulation were purported to play a causative role albeit through a range of symptom presentations. These studies evaluated STPP for this review's primary outcomes (general, somatic, anxiety and depressive symptom reduction), as well as interpersonal problems and social adjustment. Except for somatic measures in the short-term, all outcome categories suggested significantly greater improvement in the treatment versus the control groups in the short-term and medium-term. Effect sizes increased in long-term follow-up, but some of these effects did not reach statistical significance. A relatively small number of studies (N < 20) contributed data for the outcome categories. There was also significant heterogeneity between studies in most categories, possibly due to observed differences between manualised versus non-manualised treatments, short versus longer treatments, studies with observer-rated versus self report outcomes, and studies employing different treatment models. There has been further study of STPP and it continues to show promise, with modest to large gains for a wide variety of people. However, given the limited data, loss of significance in some measures at long-term follow-up and heterogeneity between studies, these findings should be interpreted with caution. Furthermore, variability in treatment delivery and treatment quality may limit the reliability of estimates of effect for STPP. Larger studies of higher quality and with specific diagnoses are warranted.

We searched scientific databases to find all published and unpublished studies of STPP compared with wait-list control, treatment as usual or minimal treatment up to July 2012. We searched for studies in adults over 17 years of age with common mental disorders being treated in an outpatient setting. We excluded people with psychotic disorders. We included 33 studies involving 2173 people. When the results of the studies were combined and analysed, we found that there was a significantly greater improvement in the groups of people who received STPP versus the control groups, both in the short-term (less than three months after treatment) and medium-term (three to six months after treatment). These benefits generally appeared to increase in the long-term. However, some results did not remain statistically significant in the long-term and, in addition, the studies varied in terms of their design, meaning that these conclusions are tentative and need confirmation with further research. The finding that a short-term psychological therapy treatment may be broadly applicable and effective is of importance in the atmosphere of current global healthcare and economic restrictions. The studies were of variable quality.

10.1002/14651858.CD004687.pub4

cochrane-simplification-train-2910

cochrane-simplification-train-2910

This updated review includes two new randomized trials. In total, 10 randomized trials with 432 participants and four comparisons are included in this review. One trial had a low risk of bias. No differences were demonstrated in mortality, with risk ratio (RR) of 0.97 (95% confidence interval (CI) 0.20 to 4.59; P value 0.97; 268 participants, six trials, very low quality of evidence (grading of recommendations assessment, development and evaluation (GRADE)), and in pneumonia, with RR of 0.40 (95% CI 0.11 to 1.39; P value 0.15; 120 participants, three trials, very low quality of evidence (GRADE)). Statistically significant results included the following: The PEEP group had higher arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2) on day one postoperatively, with a mean difference of 22.98 (95% CI 4.40 to 41.55; P value 0.02; 80 participants, two trials, very low quality of evidence (GRADE)), and postoperative atelectasis (defined as an area of collapsed lung, quantified by computerized tomography scan) was less in the PEEP group (standard mean difference -1.2, 95% CI -1.78 to -0.79; P value 0.00001; 88 participants, two trials, very low quality of evidence (GRADE)). No adverse events were reported in the three trials that adequately measured these outcomes (barotrauma and cardiac complications). Using information size calculations, we estimated that a further 21,200 participants would have to be randomly assigned to allow a reliable conclusion about PEEP and mortality. Evidence is currently insufficient to permit conclusions about whether intraoperative PEEP alters risks of postoperative mortality and respiratory complications among undifferentiated surgical patients.

The evidence is current to October 2013. We found 10 randomized clinical trials involving 432 participants. The main limitation of our review was our inability to identify studies analysing intraoperative data. Six trials reported mortality. We pooled these data and found no differences between the group of patients who received PEEP and those who did not, but because of the small number of patients, and the fact that this outcome may be rare, these results did not allow us to make a conclusion about the effect of PEEP on mortality. Two results suggested some benefit of PEEP. First, oxygenation was better on the day after surgery in the PEEP group. Second, radiological imaging showed less atelectasis after surgery in the PEEP group. The studies that we found did not suggest that intraoperative PEEP causes harm. Because of the small number of studies, this finding is inconclusive. We performed calculations to predict how many more participants would be needed before reliable conclusions can be made about the effect on mortality of the application of PEEP. This number was 21,200. Evidence is currently insufficient to allow conclusions about how intraoperative PEEP affects postoperative mortality and respiratory complications. The quality of the evidence is very low because of poorly conducted studies, small numbers of participants and low event rates.

10.1002/14651858.CD007922.pub3

cochrane-simplification-train-2911

cochrane-simplification-train-2911

Three studies were eligible for inclusion in the review. Two small studies (randomising a total of 104 infants) evaluated the effect of prophylactic caffeine on short term outcomes. There were no meaningful differences between the caffeine and placebo groups in the number of infants with apnoea, bradycardia, hypoxaemic episodes, use of IPPV or side effects in either of the studies. Only two outcomes (use of IPPV and tachycardia) were common to the two studies and meta-analysis showed no substantive differences between the groups. One large trial of caffeine therapy (CAP 2006) in a heterogeneous group of infants at risk for and having apnoea of prematurity demonstrated an improved rate of survival without developmental disability at 18 to 21 months corrected age. The reports of the subgroup of infants treated with prophylactic caffeine did not demonstrate any significant differences in clinical outcomes except for a decrease in the risk of PDA ligation. The results of this review do not support the use of prophylactic caffeine for preterm infants at risk of apnoea. Any future studies need to examine the effects of prophylactic methylxanthines in preterm infants at higher risk of apnoea. This should include examination of important clinical outcomes such as need for IPPV, neonatal morbidity, length of hospital stay and long term development.

Two small studies and one large study were identified. The two small studies enrolled infants given caffeine as a preventative measure. Neither study demonstrated any decrease in apnoea or other short term complications. The one large study included a heterogeneous group of infants who received therapy for a variety of indications (prevention, treatment and avoidance of post-extubation apnoea of prematurity). In this overall population there was an improvement in clinical outcome at hospital discharge and developmental outcome at 18 to 21 months; however, these benefits could not be proven in the subpopulation who received prophylactic caffeine. A decrease in PDA was noted in this subpopulation.

10.1002/14651858.CD000432.pub2

cochrane-simplification-train-2912

cochrane-simplification-train-2912

We included eight cohort studies of which six were performed in primary care (total number of patients; n = 6622), one study was from an accident and emergency setting (n = 482), and one study was from a secondary care setting (n = 257). In the six primary care studies, the prevalence of spinal malignancy ranged from 0% to 0.66%. Overall, data from 20 index tests were extracted and presented, however only seven of these were evaluated by more than one study. Because of the limited number of studies and clinical heterogeneity, statistical pooling of diagnostic accuracy data was not performed. There was some evidence from individual studies that having a previous history of cancer meaningfully increases the probability of malignancy. Most "red flags" such as insidious onset, age > 50, and failure to improve after one month have high false positive rates. All of the tests were evaluated in isolation and no study presented data on a combination of positive tests to identify spinal malignancy. For most "red flags," there is insufficient evidence to provide recommendations regarding their diagnostic accuracy or usefulness for detecting spinal malignancy. The available evidence indicates that in patients with LBP, an indication of spinal malignancy should not be based on the results of one single "red flag" question. Further research to evaluate the performance of different combinations of tests is recommended.

Six family practice studies including over 6,600 back pain patients found 21 tumors (0.3%).  One study on back pain diagnosed in an emergency room and one on back pain in a spine clinic included 482 and 257 patients.  The family practice studies described 15 different questions and physical exam tests that have been used to screen for spinal tumors.  Most of the 15 were not accurate.  A previous history of cancer is a very useful indicator.  Other facts that may indicate cancer are age greater than 50, no prior history of back pain, and failure to improve after one month.  These are most likely useful when combined, or with other indicators such as a history of cancer.  By themselves, these three questions would result in over-testing of patients without cancer. The worst effects of low quality red flag screening are overtreatment and undertreatment.  If the tests are not accurate, patients without a tumor may get an x-ray, MRI, bone scan or CT scan that they don’t need—unnecessary exposure to x-rays, extra worry for the patient and extra cost.  At the other extreme (and much less common), it might be possible to miss a real tumor, and cause the patient to have extra time without the best treatment. Most of the studies were of low or moderate quality and did not use an MRI, the most accurate imaging test, to confirm the presence or absence of a tumor, so more research is needed to identify the best combination of questions and examination methods.

10.1002/14651858.CD008686.pub2

cochrane-simplification-train-2913

cochrane-simplification-train-2913

We included two studies (one RCT and one CBA study) in this review (n = 311). Both of these studies indicated that a training workshop increased the knowledge about HIV/AIDS of traditional healers. With regards to behaviour change, Peltzer 2006 detected a significant difference in traditional healers' reports of managing their patients; however, there was no evidence of a reduction of HIV/STI risk behaviours and referral practices, as assessed by self-report. The study by Poudyal 2003 did not assess this outcome. Two studies met the inclusion criteria for this review. Although these studies reported some positive outcomes, the few studies and methodological heterogeneity limits the conclusions that can be drawn about the effectiveness of HIV training programs aimed at traditional healers. More rigorous studies (i.e. those employing rigorous randomisation procedures, reliable outcome measures and larger sample sizes) are needed to provide better evidence of the impact of HIV training programs aimed at traditional healers.

This review found four studies that evaluated the effectiveness of HIV/AIDS training programs aimed at traditional healers; information about two of these studies is not yet available. Both of these studies found that workshops improved traditional healer knowledge about HIV/AIDS. However, an assessment of behaviour change in one study found that a training program improved traditional healer behaviour in terms of managing patients, but not in reducing risky behaviours and referral practices. Although the studies evaluated reported some positive outcomes, they were not of high quality. It is therefore difficult to be certain about the efficacy of interventions for educating traditional healers in the fundamentals of STI and HIV medicine.

10.1002/14651858.CD007190.pub2

cochrane-simplification-train-2914

cochrane-simplification-train-2914

Nineteen studies involving a total of 2,159 participants met criteria for inclusion. It was not possible to conduct a meta-analysis due to study heterogeneity with respect to populations, interventions, comparison groups, outcomes, and length of follow-up. Sample sizes ranged from 22 to 367. The populations studied ranged from general HIV-positive populations to studies focusing exclusively on children, women, Latinos, or adults with a history of alcohol dependence, to studies focusing almost exclusively on men. Study interventions included cognitive behavioral therapy, motivational interviewing, medication management strategies, and interventions indirectly targeting adherence, such as programs directed to reduce risky sexual behaviours. Ten studies demonstrated a beneficial effect of the intervention on adherence. We found that interventions targeting practical medication management skills, those administered to individuals vs groups, and those interventions delivered over 12 weeks or more were associated with improved adherence outcomes. We also found that interventions targeting marginalized populations such as women, Latinos, or patients with a past history of alcoholism were not successful at improving adherence. We were unable to determine whether effective adherence interventions were associated with improved virological or immunological outcomes. Most studies had several methodological shortcomings leaving them vulnerable to potential biases. We found evidence to support the effectiveness of patient support and education interventions intended to improve adherence to antiretroviral therapy. Interventions targeting practical medication management skills, those interventions administered to individuals vs groups, and those interventions delivered over 12 weeks or more were associated with improved adherence outcomes. There is a need for standardization and increased methodological rigour in the conduct of adherence trials.

This review identified 19 studies involving a total of 2,159 participants that evaluated an intervention intended to improve adherence. Ten of these studies demonstrated a beneficial effect of the intervention. We found that interventions targeting practical medication management skills, those administered to individuals vs groups, and those interventions delivered over 12 weeks or more were associated with improved adherence to antiretroviral therapy. We also found that interventions targeting marginalized populations such as women, Latinos, or patients with a past history of alcoholism were not successful at improving adherence. We did not find studies that evaluated the quality of the patient-provider relationship or the clinical setting. Most studies had several methodological shortcomings.

10.1002/14651858.CD001442.pub2

cochrane-simplification-train-2915

cochrane-simplification-train-2915

Forty-one studies (8928 patients) were included. The majority of included studies were rated as low risk of bias. Ten studies were rated at high risk of bias. Seven of these studies were single-blind and three studies were open-label. However, two open-label studies and four of the single-blind studies utilized investigator performed endoscopy as an endpoint, which may protect against bias. 5-ASA was significantly superior to placebo for maintenance of clinical or endoscopic remission. Forty-one per cent of 5-ASA patients relapsed compared to 58% of placebo patients (7 studies, 1298 patients; RR 0.69, 95% CI 0.62 to 0.77). There was a trend towards greater efficacy with higher doses of 5-ASA with a statistically significant benefit for the 1 to 1.9 g/day (RR 0.65; 95% CI 0.56 to 0.76) and the > 2 g/day subgroups (RR 0.73, 95% CI 0.60 to 0.89). SASP was significantly superior to 5-ASA for maintenance of remission. Forty-eight per cent of 5-ASA patients relapsed compared to 43% of SASP patients (12 studies, 1655 patients; RR 1.14, 95% CI 1.03 to 1.27). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome for the placebo and SASP-controlled studies was high. No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Twenty-nine per cent of once daily patients relapsed over 12 months compared to 31% of conventionally dosed patients (8 studies, 3127 patients; RR 0.91, 95% CI 0.82 to 1.01). Eleven per cent of patients in the once daily group failed to adhere to their medication regimen compared to 9% of patients in the conventional dosing group (6 studies, 1462 patients; RR 1.22, 95% CI 0.91 to 1.64). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Forty-four per cent of patients in the 5-ASA group relapsed compared to 41% of patients in the 5-ASA comparator group (6 studies, 707 patients; RR 1.08, 95% CI 0.91 to 1.28). A pooled analysis of two studies showed no statistically significant difference in efficacy between Balsalazide 6 g and 3 g/day. Twenty-three per cent of patients in the 6 g/day group relapsed compared to 33% of patients in the 3 g/day group (216 patients; RR 0.76; 95% CI 0.45 to 2.79). One study found Balsalazide 4 g to be superior to 2 g/day. Thirty-seven per cent of patients in the 4 g/day Balsalazide group relapsed compared to 55% of patients in the 2 g/day group (133 patients; RR 0.66; 95% CI 0.45 to 0.97). One study found a statistically significant difference between Salofalk granules 3 g and 1.5 g/day. Twenty-five per cent of patients in the Salofalk 3 g/day group relapsed compared to 39% of patients in the 1.5 g/day group (429 patients; RR 0.65; 95% CI 0.49 to 0.86). Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia, and nasopharyngitis. There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, 5-ASA and SASP, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulations and 5-ASA dose ranging studies. The trials that compared 5-ASA and SASP may have been biased in favour of SASP because most trials enrolled patients known to be tolerant to SASP which may have minimized SASP-related adverse events. 5-ASA was superior to placebo for maintenance therapy in ulcerative colitis. However, 5-ASA had a statistically significant therapeutic inferiority relative to SASP. Oral 5-ASA administered once daily is as effective and safe as conventional dosing for maintenance of remission in quiescent ulcerative colitis. There does not appear to be any difference in efficacy or safety between the various formulations of 5-ASA. Patients with extensive ulcerative colitis or with frequent relapses may benefit from a higher dose of maintenance therapy. High dose therapy appears to be as safe as low dose and is not associated with a higher incidence of adverse events.

This review includes 41 randomized trials with a total of 8928 participants. Oral 5-ASA was found to be more effective than placebo (fake drug) for maintaining remission. Although oral 5-ASA preparations are effective for maintaining remission in ulcerative colitis, they are no more effective than sulfasalazine (SASP) therapy. People who have become well can remain so by continuing to take either medication. There is no evidence that side effects are more frequent with one or the other medication. However, the side effects of 5-ASA may be notably less than those associated with SASP therapy. Common side effects associated with 5-ASA included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia (indigestion), and nasopharyngitis (inflammation of the nasal passages). Most of the trials comparing 5-ASA with SASP enrolled patients who were known to tolerate SASP. This may have reduced SASP-related side effects in these trials. Male infertility is associated with SASP and not with 5-ASA, so 5-ASA may be preferred for patients concerned about fertility. 5-ASA therapy is more expensive than SASP, so SASP may be the preferred option where cost is an important factor. Oral 5-ASA administered once daily is as effective and safe as conventional dosing (two or three times daily) for maintaining remission in ulcerative colitis. There does not appear to be any difference in efficacy or safety between the various formulations of 5-ASA. Patients with extensive ulcerative colitis or with frequent relapses may benefit from a higher dose of maintenance therapy. High dose therapy appears to be as safe as low dose and is not associated with a higher incidence of side effects.

10.1002/14651858.CD000544.pub4

cochrane-simplification-train-2916

cochrane-simplification-train-2916

Seven trials involving a total of 199 participants were included. A trial of adrenocorticotrophic hormone (43 participants) did not show any advantage compared with placebo for the treatment of ocular myasthenia gravis. Two double-blind trials compared prednisone with placebo for generalised myasthenia gravis. In the first (13 participants), the improvement was slightly greater in the prednisone group at six months. In the second (20 participants) which was a short-term trial, the improvement was significantly greater at two weeks. Two trials compared glucocorticosteroids with azathioprine (41 and 10 participants respectively). In one of these the rate of treatment failure was greater in the prednisone group. In a trial of glucocorticosteroids versus intravenous immunoglobulin (33 participants) no differences in treatment responses were encountered during a treatment period of 14 days. An open trial (39 participants) evaluating different corticosteroid doses revealed a shorter time to improvement in the high-dose group. None fulfilled the presently accepted standards of a high-quality trial. All these studies have risks of bias and have a weak statistical power. Limited evidence from randomised controlled trials suggests that corticosteroid treatment offers short-term benefit in myasthenia gravis compared with placebo. This supports the conclusions of observational studies and expert opinion. Limited evidence from randomised controlled trials does not show any difference in efficacy between corticosteroids and either azathioprine or intravenous immunoglobulin.

Seven randomised controlled trials which included in all 199 participants are published. None fulfilled the presently accepted standards of a high-quality trial. All these studies have risks of bias and have a weak statistical power. Limited evidence from randomised controlled trials suggests that corticosteroids offer short-term benefit compared with placebo (dummy treatment). This supports the conclusions of observational studies and expert opinion. Limited evidence from randomised controlled trials does not show any difference in efficacy between corticosteroids and either azathioprine or intravenous immunoglobulin. All trials had design flaws which limit the strength of the conclusions. Further randomised controlled trials are needed.

10.1002/14651858.CD002828.pub2

cochrane-simplification-train-2917

cochrane-simplification-train-2917

This review included 22 studies of good methodological quality that had enrolled 23,309 participants with COPD. The studies used similar designs, however, the duration varied from three months to four years. In 19 of the studies, 18 mcg tiotropium once daily via the Handihaler dry powder inhaler was evaluated, and in three studies, 5 or 10 mcg tiotropium once daily via the Respimat soft mist inhaler was evaluated. Compared to placebo, tiotropium treatment significantly improved the mean quality of life (mean difference (MD) -2.89; 95% confidence interval (CI) -3.35 to -2.44), increased the number of participants with a clinically significant improvement (odds ratio (OR) 1.52; 95% CI 1.38 to 1.68), and reduced the number of participants with a clinically significant deterioration (OR 0.65; 95% CI 0.59 to 0.72) in quality of life (measured by the St George's Respiratory Questionnaire (SGRQ)). Tiotropium treatment significantly reduced the number of participants suffering from exacerbations (OR 0.78; 95% CI 0.70 to 0.87). This corresponds to a need to treat 16 patients (95% CI 10 to 36) with tiotropium for a year in order to avoid one additional patient suffering exacerbations, based on the average placebo event rate of 44% from one-year studies. Tiotropium treatment led to fewer hospitalisations due to exacerbations (OR 0.85; 95% CI 0.72 to 1.00), but there was no statistically significant difference in all-cause hospitalisations (OR 1.00; 95% CI 0.88 to 1.13) or non-fatal serious adverse events (OR 1.03; 95% CI 0.97 to 1.10). Additionally, there was no statistically significant difference in all-cause mortality between the tiotropium and placebo groups (Peto OR 0.98; 95% CI 0.86 to 1.11). However, subgroup analysis found a significant difference between the studies using a dry powder inhaler and those with a soft mist inhaler (test for subgroup differences: P = 0.01). With the dry powder inhaler there were fewer deaths in the tiotropium group (Peto OR 0.92; 95% CI 0.80 to 1.05) than in the placebo group (yearly rate 2.8%), but with the soft mist inhaler there were significantly more deaths in the tiotropium group (Peto OR 1.47; 95% CI 1.04 to 2.08) than in the placebo group (yearly rate 1.8%). It is noted that the rates of patients discontinuing study treatment were uneven, with significantly fewer participants withdrawing from tiotropium treatment than from placebo treatment (OR 0.66; 95% CI 0.59 to 0.73). Participants on tiotropium had improved lung function at the end of the study compared with those on placebo (trough forced expiratory volume in one second (FEV1) MD 118.92 mL; 95% CI 113.07 to 124.77). This review shows that tiotropium treatment was associated with a significant improvement in patients' quality of life and it reduced the risk of exacerbations, with a number needed to treat to benefit (NNTB) of 16 to prevent one exacerbation. Tiotropium also reduced exacerbations leading to hospitalisation but no significant difference was found for hospitalisation of any cause or mortality. Thus, tiotropium appears to be a reasonable choice for the management of patients with stable COPD, as proposed in guidelines. The trials included in this review showed a difference in the risk of mortality when compared with placebo depending on the type of tiotropium delivery device used. However, these results have not been confirmed in a recent trial when 2.5 mcg or 5 mcg of tiotropium via Respimat was used in a direct comparison to the 18 mcg Handihaler.

We found 22 studies including 23,309 participants, comparing the long-term effectiveness and side effects of tiotropium and placebo. Compared with placebo, tiotropium treatment led to an improvement in quality of life, fewer people had an exacerbation (worsening of COPD symptoms), or exacerbations leading to hospital admissions. The number of people that needed to be treated for a year, for one person to avoid one additional exacerbation was 16 (95% confidence interval (CI) 10 to 36). We found no statistically significant difference between the tiotropium and placebo groups in terms of the number of hospital admissions for any cause, serious adverse events or deaths during the studies. However, when we divided the data depending on whether a dry powder inhaler or a soft mist inhaler was used in the studies, these two subgroups were significantly different. With the dry powder inhaler there were fewer deaths in the tiotropium group than in the placebo group, whereas with the soft mist inhaler there were significantly more deaths in the tiotropium group than in the placebo group. Also, there was a larger number of participants that stopped study medication early in the placebo group than in the tiotropium group. This review shows that treatment with tiotropium improves patients' quality of life, and reduces the risk of exacerbations, including exacerbations leading to hospitalisation. But tiotropium does not reduce hospitalisations for all causes or the number of deaths. Based on the evidence in this review, tiotropium appears to be a reasonable treatment choice for patients with stable COPD.

10.1002/14651858.CD009285.pub3

cochrane-simplification-train-2918

cochrane-simplification-train-2918

We included seven RCTs with a total of 571 participants in the review. Two of the seven trials involved 36 participants undergoing non-cardiac vascular surgery (infrarenal aortic surgery), and five involved 535 participants undergoing cardiac surgery, including valvular surgery, coronary artery bypass surgery, and cardiopulmonary bypass surgery. The intervention was started from 11 days to 25 minutes before surgery in six trials and during surgery in one trial. We considered all seven RCTs to carry a high risk of bias. The effects of ACEIs or ARBs on perioperative mortality and acute myocardial infarction were uncertain because the quality of the evidence was very low. The risk of death was 2.7% in the ACEIs or ARBs group and 1.6% in the placebo group (risk ratio (RR) 1.61; 95% confidence interval (CI) 0.44 to 5.85). The risk of acute myocardial infarction was 1.7% in the ACEIs or ARBs group and 3.0% in the placebo group (RR 0.55; 95% CI 0.14 to 2.26). ACEIs or ARBs may improve congestive heart failure (cardiac index) perioperatively (mean difference (MD) -0.60; 95% CI -0.70 to -0.50, very low-quality evidence). In terms of rate of complications, there was no difference in perioperative cerebrovascular complications (RR 0.48; 95% CI 0.18 to 1.28, very low-quality evidence) and hypotension (RR 1.95; 95% CI 0.86 to 4.41, very low-quality evidence). Cardiac surgery-related renal failure was not reported. ACEIs or ARBs were associated with shortened length of hospital stay (MD -0.54; 95% CI -0.93 to -0.16, P value = 0.005, very low-quality evidence). These findings should be interpreted cautiously due to likely confounding by the clinical backgrounds of the participants. ACEIs or ARBs may shorten the length of hospital stay, (MD -0.54; 95% CI -0.93 to -0.16, very low-quality evidence) Two studies reported adverse events, and there was no evidence of a difference between the ACEIs or ARBs and control groups. Overall, this review did not find evidence to support that perioperative ACEIs or ARBs can prevent mortality, morbidity, and complications (hypotension, perioperative cerebrovascular complications, and cardiac surgery-related renal failure). We found no evidence showing that the use of these drugs may reduce the rate of acute myocardial infarction. However, ACEIs or ARBs may increase cardiac output perioperatively. Due to the low and very low methodology quality, high risk of bias, and lack of power of the included studies, the true effect may be substantially different from the observed estimates. Perioperative (mainly elective cardiac surgery, according to included studies) initiation of ACEIs or ARBs therapy should be individualized.

We searched the databases to 8 December 2014. We found seven randomized controlled trials (from 1992 to 2014) with 571 participants that met our inclusion criteria. Two of the seven trials involved 36 participants undergoing non-cardiac vascular surgery (infrarenal aortic surgery), and five involved 535 participants undergoing cardiac surgery, including valvular surgery, coronary artery bypass surgery, and cardiopulmonary bypass surgery. The interventions started from 11 days to 25 minutes before surgery in six trials and during surgery in one. All of the seven studies were conducted in Europe and the United States. One of the seven studies was funded by a drug company. Three trials involving 419 participants reported on deaths, but the results were imprecise with no evidence of a difference between the intervention and placebo groups (perioperative mortality). Two trials with 345 participants reported a similar number of participants in the two groups with changes in their electrocardiogram that indicated a heart attack (acute myocardial infarction). The output of the heart (cardiac index) appeared to be increased in one trial only. The two trials that reported the risk of low blood pressure as a potential complication of the intervention found no apparent difference; and the risk of stroke was similar with and without the intervention in three trials. The results from three studies showed that ACEIs or ARBs may reduce length of hospital stay, but these findings should be interpreted cautiously because of the possible influence of the clinical backgrounds of the participants studied. Two trials that assessed adverse events found no evidence of a difference between ACEIs or ARBs and placebo (no treatment). The quality of evidence for the outcomes was low or very low. The overall number of participants was small. Most participants were undergoing cardiac surgery, which meant the findings cannot be generalized to other types of surgery. We reran the search on February 3, 2017. We will deal with the three studies of interest when we update the review.

10.1002/14651858.CD009210.pub2

cochrane-simplification-train-2919

cochrane-simplification-train-2919

Thirteen studies met the eligibility criteria of the review, randomising 2157 adults. Education significantly reduced future hospital admissions (RR 0.50; 95% CI 0.27 to 0.91, high quality evidence); however, the estimated reduction in risk of re-presentation at ED following intervention was imprecise and did not reach statistical significance (RR 0.72; 95% CI 0.47 to 1.11, low quality evidence). Symptom control improved following education. The lack of statistically significant differences between asthma education and control groups in terms of peak flow, quality of life, study withdrawal and days lost were hard to interpret given the low number of studies contributing to these outcomes and statistical variation between the study results. Two studies from the USA measured costs: one study from the early 1990s measured cost and found no difference for total costs and costs related to physician visits and admissions to hospital. If data were restricted to emergency department treatment, education led to lower costs than control. A study from 2009 showed that associated costs of ED presentation and hospitalisation were lower following educational intervention. Our findings support educational interventions applied in the emergency department as a means of reducing subsequent asthma admissions to hospital. Whilst the direction of the effect on ED presentations was consistent with the reduction in risk of admission, the results were not definitive.. Outcomes were measured on average at 6 months after index ED presentation. The impact of educational intervention in this context on longer term outcomes relating to asthma morbidity is unclear. Priorities for additional research in this area include assessment of health-related quality of life, lung function assessment, exploration of the relationship between socio-economic status and asthma morbidity, and better description of the intervention assessed.

We reviewed evidence from randomised trials that assessed an educational intervention given after presentation in the emergency setting by adults over 17 years old. Thirteen trials involving 2157 people were included. The studies suggested that following the intervention there was a reduction in the frequency of future hospital admissions; however, the effect on visit to the emergency department was imprecise and the results of our analysis indicate that this was a chance result. Education may be an effective reinforcement strategy in reducing future hospital admission following emergency department attendance, but there was little evidence to suggest that it improved other indicators of chronic disease severity such as lung function and quality of life.

10.1002/14651858.CD003000.pub2

cochrane-simplification-train-2920

cochrane-simplification-train-2920

Six trials with 151 Japanese patients were included. All trials had high risk of bias. Four trials compared bezafibrate plus UDCA with no intervention plus UDCA (referenced as bezafibrate versus no intervention in the remaining text), and two trials compared bezafibrate with UDCA. No patient died and no patient developed liver-related complications in any of the included trials. Bezafibrate was without significant effects on the occurrence of adverse events compared with no intervention (5/32 (16%) versus 0/28 (0%)) (RR 5.40, 95% CI 0.69 to 42.32; 3 trials with 60 patients; I² = 0%) or with UDCA (2/32 (6%) versus 0/37 (0%)) (RR 6.19, 95% CI 0.31 to 122.05; 2 trials with 69 patients; I² = 0%). Bezafibrate significantly decreased the activity of serum alkaline phosphatases compared with no intervention (MD -186.04 U/L, 95% CI -249.03 to -123.04; 4 trials with 79 patients; I² = 34%) and when compared with UDCA (MD -162.90 U/L, 95% CI -199.68 to -126.12; 2 trials with 48 patients; I² = 0%). These results were supported by trial sequential analyses. Bezafibrate compared with no intervention significantly decreased plasma immunoglobulin M (MD -164.00 mg/dl, 95% CI -259.47 to -68.53; 3 trials with 50 patients; I² = 46%) and serum bilirubin concentration (MD -0.19 mg/dl, 95% CI -0.38 to -0.00; 2 trials with 34 patients; I² = 0%). However, the latter two results were not supported by trial sequential analyses. Bezafibrate compared with no intervention had no significant effect on the activity of serum gamma-glutamyltransferase (MD -1.22 U/L, 95% CI -11.97 to 9.52; 4 trials with 79 patients; I² = 42%) and serum alanine aminotransferase (MD -5.61 U/L, 95% CI -24.50 to 13.27; 2 trials with 35 patients; I² = 34%). Bezafibrate compared with UDCA had no significant effect on the activity of serum gamma-glutamyltransferase (MD 38.44 U/L, 95% CI -180.67 to 257.55; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -2.34 U/L, 95% CI -34.73 to 30.06; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -20.23 mg/dl, 95% CI -218.71 to 178.25; 2 trials with 41 patients; I² = 90%) in random-effects model meta-analyses, but bezafibrate significantly decreased the activity of serum gamma-glutamyltransferase (MD -58.18, 95% CI -76.49 to -39.88; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -13.94, 95% CI -18.78 to -9.09; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -99.90, 95% CI -130.72 to -69.07; 2 trials with 41 patients; I² = 90%) in fixed-effect model meta-analyses. One patient had bezafibrate withdrawn due to an adverse event compared to no intervention (RD 0.03, 95% CI -0.09 to 0.16; 2 trials with 60 patients; I² = 0%). This systematic review did not demonstrate any effect of bezafibrate versus no intervention on mortality, liver-related morbidity, adverse events, and pruritus in patients with primary biliary cirrhosis. Furthermore, we found no significant effects of bezafibrate on mortality, liver-related morbidity, or adverse events when compared with ursodeoxycholic acid, None of the trials assessed quality of life or fatigue. The data seem to indicate a possible positive intervention effect of bezafibrate on some liver biochemistry measures compared with the control group, but the observed effects could be due to systematic errors or random errors. We need more randomised clinical trials on the effects of bezafibrate on primary biliary cirrhosis with low risks of systematic errors and random errors.

There are studies suggesting that bezafibrate, alone or in combination with ursodeoxycholic acid, is effective in treatment of primary biliary cirrhosis. Mechanisms through which bezafibrate improves lipid serum concentration balance and prevents biliary cell damage still need to be fully understood. This review evaluates all data on the benefits and harms of bezafibrate for patients with primary biliary cirrhosis in randomised clinical trials. The findings of this review are based on six randomised clinical trials with 151 Japanese patients. Bezafibrate was compared with no intervention in four trials (with co-intervention of ursodeoxycholic acid in both the bezafibrate and control groups) and with ursodeoxycholic acid in two trials. The primary findings of the review are that bezafibrate has no statistically significant effects on mortality, liver-related morbidity, adverse events, and quality of life of patients with primary biliary cirrhosis. A possible positive intervention effect of bezafibrate versus no intervention on liver biochemistry measures can be real but could also be due to systematic errors or random errors. The benefits and harms of bezafibrate for patients with primary biliary cirrhosis need further assessment in randomised clinical trials comparing bezafibrate with placebo. Such trials ought to be conducted with impeccable methodology to reduce the risks of random errors and sufficiently large patient groups to reduce the risks of random errors.

10.1002/14651858.CD009145.pub2

cochrane-simplification-train-2921

cochrane-simplification-train-2921

We included 24 studies (9,997 participants). Eighteen studies evaluated amiodarone for primary prevention and six for secondary prevention. Only three studies used an ICD concomitantly with amiodarone for the comparison (all of them for secondary prevention). For primary prevention, amiodarone compared to placebo or no intervention (17 studies, 8383 participants) reduced SCD (RR 0.76; 95% CI 0.66 to 0.88), cardiac mortality (RR 0.86; 95% CI 0.77 to 0.96) and all-cause mortality (RR 0.88; 95% CI 0.78 to 1.00). The quality of the evidence was low. Compared to other antiarrhythmics (three studies, 540 participants), amiodarone reduced SCD (RR 0.44; 95% CI 0.19 to 1.00), cardiac mortality (RR 0.41; 95% CI 0.20 to 0.86) and all-cause mortality (RR 0.37; 95% CI 0.18 to 0.76). The quality of the evidence was moderate. For secondary prevention, amiodarone compared to placebo or no intervention (two studies, 440 participants) appeared to increase the risk of SCD (RR 4.32; 95% CI 0.87 to 21.49) and all-cause mortality (RR 3.05; 1.33 to 7.01). However, the quality of the evidence was very low. Compared to other antiarrhythmics (four studies, 839 participants) amiodarone appeared to increase the risk of SCD (RR 1.40; 95% CI 0.56 to 3.52; very low quality of evidence), but there was no effect in all-cause mortality (RR 1.03; 95% CI 0.75 to 1.42; low quality evidence). Amiodarone was associated with an increase in pulmonary and thyroid adverse events. There is low to moderate quality evidence that amiodarone reduces SCD, cardiac and all-cause mortality when compared to placebo or no intervention for primary prevention, and its effects are superior to other antiarrhythmics. It is uncertain if amiodarone reduces or increases SCD and mortality for secondary prevention because the quality of the evidence was very low.

We searched scientific databases for clinical trials comparing the effects of amiodarone versus other antiarrhythmics or placebo on SCD, mortality and any side effects. We included adult participants at high risk or who had previously presented with sudden cardiac arrest, a serious heart malfunction that causes the arrhythmia. The evidence is current to March 2015. We found 24 studies comprising 9,997 participants. In participants at high risk, the evidence showed that amiodarone may prevent SCD or mortality when compared to placebo, and it is probably better than other antiarrhythmics. On the other hand, in participants who have already suffered a prior cardiac arrest, it is uncertain whether amiodarone increases or reduces the risk of a new episode of cardiac arrest or death. Furthermore, amiodarone may lead to or worsen adverse effects in the thyroid or lungs, when compared with placebo or other antiarrhythmics. The overall quality of evidence of these studies was low.

10.1002/14651858.CD008093.pub2

cochrane-simplification-train-2922

cochrane-simplification-train-2922

Nine randomised controlled trials involving 395 patients were included. Six out of nine studies had a follow-up of less than one year, the longest study duration was 24 months. Only a third of the analysed studies revealed a low risk of bias. No information was available on quality of life, all-cause mortality and morbidity. Compared with conventional management, IGB did not show convincing evidence of a greater weight loss. On the other hand, complications of intragastric balloon placement occurred, however few of a serious nature. The relative risks for minor complications like gastric ulcers and erosions were significantly raised. Evidence from this review is limited for decision making, since there was large heterogeneity in IGB trials, regarding both methodological and clinical aspects. However, a co-adjuvant factor described by some authors in the loss and maintenance of weight has been the motivation and the encouragement to changing eating habits following a well-organized diet and a program of behavioural modification. The IGB alone and the technique of positioning appear to be safe. Despite the evidence for little additional benefit of the intragastric balloon in the loss of weight, its cost should be considered against a program of eating and behavioural modification.

Nine randomised controlled trials involving 395 patients were evaluated. Six out of nine studies had a follow-up of less than one year, the longest study duration was 24 months. The overall quality of trials was variable, only a third of the analysed studies showed a low risk of bias. No information was available on quality of life, all-cause mortality and morbidity. Compared with conventional management, IGB did not show convincing evidence of a greater weight loss. The relative risks for minor complications, for example gastric ulcers and erosions were significantly raised.

10.1002/14651858.CD004931.pub2

cochrane-simplification-train-2923

cochrane-simplification-train-2923

Seventeen trials with 1067 participants met the inclusion criteria. However, the required data from three included trials and some of the data from a fourth trial were not published and not made available. The included trials were highly heterogeneous in terms of subtype and severity of participants' dementia, and type, duration, and frequency of exercise. Only two trials included participants living at home. Our meta-analysis revealed that there was no clear evidence of benefit from exercise on cognitive functioning. The estimated standardized mean difference between exercise and control groups was 0.43 (95% CI -0.05 to 0.92, P value 0.08; 9 studies, 409 participants). There was very substantial heterogeneity in this analysis (I² value 80%), most of which we were unable to explain, and we rated the quality of this evidence as very low. We found a benefit of exercise programs on the ability of people with dementia to perform ADLs in six trials with 289 participants. The estimated standardized mean difference between exercise and control groups was 0.68 (95% CI 0.08 to 1.27, P value 0.02). However, again we observed considerable unexplained heterogeneity (I² value 77%) in this meta-analysis, and we rated the quality of this evidence as very low. This means that there is a need for caution in interpreting these findings. In further analyses, in one trial we found that the burden experienced by informal caregivers providing care in the home may be reduced when they supervise the participation of the family member with dementia in an exercise program. The mean difference between exercise and control groups was -15.30 (95% CI -24.73 to -5.87; 1 trial, 40 participants; P value 0.001). There was no apparent risk of bias in this study. In addition, there was no clear evidence of benefit from exercise on neuropsychiatric symptoms (MD -0.60, 95% CI -4.22 to 3.02; 1 trial, 110 participants; P value .0.75), or depression (SMD 0.14, 95% CI -0.07 to 0.36; 5 trials, 341 participants; P value 0.16). We could not examine the remaining outcomes, quality of life, mortality, and healthcare costs, as either the appropriate data were not reported, or we did not retrieve trials that examined these outcomes. There is promising evidence that exercise programs may improve the ability to perform ADLs in people with dementia, although some caution is advised in interpreting these findings. The review revealed no evidence of benefit from exercise on cognition, neuropsychiatric symptoms, or depression. There was little or no evidence regarding the remaining outcomes of interest (i.e., mortality, caregiver burden, caregiver quality of life, caregiver mortality, and use of healthcare services).

This review evaluated the results of 17 trials (search dates August 2012 and October 2013), including 1,067 participants, that tested whether exercise programs could improve cognition (which includes such things as memory, reasoning ability and spatial awareness), activities of daily living, behaviour and psychological symptoms (such as depression, anxiety and agitation) in older people with dementia. We also looked for effects on mortality, quality of life, caregivers' experience and use of healthcare services, and for any adverse effects of exercise. There was some evidence that exercise programs can improve the ability of people with dementia to perform daily activities, but there was a lot of variation among trial results that we were not able to explain. The studies showed no evidence of benefit from exercise on cognition, psychological symptoms, and depression. There was little or no evidence regarding the other outcomes listed above. There was no evidence that exercise was harmful for the participants. We judged the overall quality of evidence behind most of the results to be very low. Additional well-designed trials would allow us to enhance the quality of the review by investigating the best type of exercise program for people with different types and severity of dementia and by addressing all of the outcomes.

10.1002/14651858.CD006489.pub4

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cochrane-simplification-train-2924

No new trials were included from the 2012 search. The review still includes two trials of short duration comparing sulpiride with placebo (total n = 113). No study reported our primary outcome of interest of 'global state: clinically significant response', nor our secondary outcomes of interest of 'quality of life', 'severe adverse effects', and 'safety assessments'. As regards mental state, there were no clear differences between groups for either positive or negative symptoms; measured positive symptoms using the Manchester scale were skewed and therefore not included in meta-analysis (n = 18, 1 RCT, very low quality evidence). Measured negative symptoms using the Manchester scale also demonstrated no clear difference (n = 18, 1 RCT, MD -3.0 CI -1.66 to 1.06, very low quality evidence). Few people left these studies by three months (n = 113, 2 RCTs, RR 1.00 CI 0.25 to 4.00). One subscore finding demonstrated a significant improvement in social behaviour using the Current Behaviour Schedule (CBS) when receiving placebo (n = 18, 1 RCT, MD -2.90 CI -5.60 to -0.20). There were no data for many important outcomes such as global outcomes, service use or adverse effects. Sulpiride may be an effective antipsychotic drug but evidence of its superiority over placebo from randomised trials is very limited. Practice will have to use evidence from sources other than trials until better evidence is generated.

The aim of this review was to evaluate the effects of sulpiride for schizophrenia compared to placebo (‘dummy’ treatment). Two short-term (12 weeks) studies with a total of 113 people are included. Information was limited and poorly reported. The inclusion of two small studies with small sample sizes meant that resulting data were not overly robust or meaningful. Overall no clear difference was noted between those receiving sulpiride and those receiving placebo for mental state or for leaving the study early. There was no information on other important outcomes, including: general functioning, service use, hospital admission, employment, family burden, satisfaction with care and side effects. The use of sulpiride seems to be based on clinical experience rather than strong evidence. Its widespread use in developing countries might have more to do with its lower cost than its effectiveness. Longer, well-planned, better conducted and reported randomised control trials would contribute to our knowledge about the effectiveness and potential side effects of this drug. This plain language summary has been written by a consumer Benjamin Gray: Service User and Service User Expert: Rethink Mental Illness. Email: [email protected]

10.1002/14651858.CD007811.pub2

cochrane-simplification-train-2925

cochrane-simplification-train-2925

We included five RCTs involving a total of 1231 participants with NMIBC in this review. Due to poor reporting, the risk of bias in the included studies was often unclear. We assessed the studies under two main comparisons: intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs), and intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT). Intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs): We observed no clear difference between BCG plus IFN-α and BCG alone for recurrence (average risk ratio (RR) 0.76, 95% confidence interval (CI) 0.44 to 1.32; 4 RCTs; 925 participants; very low-quality evidence) or progression (average RR 0.26, 95% CI 0.04 to 1.87; 2 RCTs; 219 participants; low-quality evidence). The included RCTs did not report on the other primary outcome of this review, discontinuation of therapy due to adverse events. Regarding secondary outcomes, we observed no clear difference for disease-specific mortality (RR 0.38, 95% CI 0.05 to 3.05; 1 RCT; 99 participants; very low-quality evidence). Two RCTs reporting contradictory findings for adverse events could not be pooled due to variation in definitions. There were no data from the included RCTs on time-to-death or disease-specific quality of life. Intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT): We observed shorter time-to-recurrence for participants in the BCG alternating with IFN-α group compared with the BCG alone group (hazard ratio (HR) 2.86, 95% CI 1.98 to 4.13; 1 RCT; 205 participants; low-quality evidence), but no clear differences in time-to-progression (HR 2.39, 95% CI 0.92 to 6.21; 1 RCT; 205 participants; low-quality evidence) and discontinuation of therapy due to adverse events (RR 2.97, 95% CI 0.31 to 28.09; 1 RCT; 205 participants; low-quality evidence). Regarding secondary outcomes, there were no clear differences between the BCG alternating with IFN-α and BCG alone groups for disease-specific mortality (HR 2.74, 95% CI 0.73 to 10.28; 1 RCT; 205 participants; low-quality evidence), time-to-death (overall survival) (HR 1.00, 95% CI 0.68 to 1.47; 1 RCT; 205 participants; low-quality evidence), or systemic or local adverse events (RR 1.65, 95% CI 0.41 to 6.73; 1 RCT; 205 participants; low-quality evidence). There were no data on disease-specific quality of life. We found low- to very low-quality evidence suggesting no clear differences in recurrence or progression with BCG plus IFN-α compared with BCG alone for people with NMIBC; there was no information to determine the effect on discontinuation of therapy due to adverse events. Low-quality evidence suggests BCG alternating with IFN-α compared with BCG alone may increase time-to-recurrence, however low-quality evidence also suggests no clear differences for time-to-progression or discontinuation of therapy due to adverse events. Additional high-quality, adequately powered trials using standardised instillation regimens and doses of both BCG and IFN-α, reporting outcomes in subgroups stratified by patient and tumour characteristics, and on long-term outcomes related not only to recurrence but also to progression, discontinuation due to adverse events, and mortality may help to clarify the ideal treatment strategy and provide a more definitive result.

The evidence is current to 25 August 2016. We included five studies with a total of 1231 participants with non-muscle-invasive bladder cancer. Four studies compared BCG given together with IFN-α versus BCG alone. One study compared BCG alternating with IFN-α versus BCG alone. The follow-up period in the studies ranged from two months to nearly 20 years. BCG combined with IFN-α (four studies):We found very low-quality evidence showing no clear difference in recurrence (four studies involving 925 participants) or progression (two studies involving 219 participants) between participants who received BCG combined with IFN-α and those who received BCG alone. None of the studies reported on the important outcome of stopping treatment due to adverse events. There was also very low-quality evidence showing no clear difference between groups for cancer-specific mortality (one study, 99 participants). There were mixed findings for adverse events (two studies, 120 and 670 participants, respectively). BCG alternating with IFN-α (one study):We found low-quality evidence showing a higher probability of recurrence when BCG was alternated with IFN-α compared with BCG alone (study involving 205 participants). We also found low-quality evidence that showed no clear difference in the probability of progression, risk of stopping treatment due to adverse events, and cancer-specific mortality between those participants receiving BCG alternating with IFN-α and those receiving BCG alone (one study involving 205 participants). There was also no clear difference between groups for overall survival or adverse events (one study involving 205 participants). None of the five studies reported on quality of life of the participants. As the included studies were often poorly conducted or reported, we rated the quality of the evidence as low overall. Further research is likely to have an important impact on our confidence in the accuracy of results.

10.1002/14651858.CD012112.pub2

cochrane-simplification-train-2926

cochrane-simplification-train-2926

We identified 3745 citations after de-duplication of search results and excluded 3619 records during title and abstract reviews. We assessed 126 full-text papers for inclusion in the review, of which four publications (on three RCTs) providing data from 1100 people met eligibility criteria for this review. All three RCTs had methodological limitations due to high attrition rates. Overall, moderate-quality evidence indicates that bupropion XL is an efficacious intervention for prevention of recurrence of depressive episodes in people with a history of SAD (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.44 to 0.72; 3 RCTs, 1100 participants). However, bupropion XL leads to greater risk of headaches (moderate-quality evidence), insomnia and nausea (both low-quality evidence) when compared with placebo. Numbers needed to treat for additional beneficial outcomes (NNTBs) vary by baseline risks. For a population with a yearly recurrence rate of 30%, the NNTB is 8 (95% CI 6 to 12). For populations with yearly recurrence rates of 50% and 60%, NNTBs are 5 (95% CI 4 to 7) and 4 (95% CI 3 to 6), respectively. We could find no studies on other SGAs and no studies comparing SGAs with other interventions of interest, such as light therapy, psychological therapies, melatonin or agomelatine. Available evidence indicates that bupropion XL is an effective intervention for prevention of recurrence of SAD. Nevertheless, even in a high-risk population, three out of four people will not benefit from preventive treatment with bupropion XL and will be at risk for harm. Clinicians need to discuss with patients advantages and disadvantages of preventive SGA treatment, and might want to consider offering other potentially efficacious interventions, which might confer a lower risk of adverse events. Given the lack of comparative evidence, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences. Future researchers need to assess the effectiveness and risk of harms of SGAs other than bupropion for prevention of SAD. Investigators also need to compare benefits and harms of pharmacological and non-pharmacological interventions.

In populations with a high risk of developing a new depressive episode in the next winter, results show that antidepressants can prevent winter depression in about one in four people. In populations with a lower risk of recurrence, antidepressants can prevent a new depressive episode in one of eight people. The other seven people suffer from winter depression despite treatment or would not have suffered from winter depression anyway. People using antidepressants are at slightly higher risk of experiencing headaches, nausea or insomnia when compared with people not taking antidepressants. Doctors need to discuss with patients the advantages and disadvantages of antidepressants and other potentially preventive treatments for winter depression, such as light treatment, psychological therapies or lifestyle interventions. As no available studies have compared these treatments, the decision for or against preventive treatment of SAD and the treatment selected should be strongly based on patient preferences. Review authors recommend that future studies should directly compare antidepressants against other treatments, such as light therapy, psychological therapies or other drugs to determine the best treatment for preventing winter depression.

10.1002/14651858.CD011268.pub3

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cochrane-simplification-train-2927

Four controlled trials of 3,4-diaminopyridine compared with placebo in a total of 54 participants with Lambert-Eaton myasthenic syndrome were eligible: three cross-over trials and one parallel group. Two were added at this update. One of these trials also assessed pyridostigmine in conjunction with 3,4-diaminopyridine. A further cross-over trial compared intravenous immunoglobulin (IVIg) to placebo in nine participants. Four trials of 3,4-diaminopyridine reported significant improvement in the primary outcome, muscle strength score, or myometric limb measurement for between hours and a week following treatment, and significant improvement in resting compound muscle action potential (CMAP) amplitude following 3,4-diaminopyridine, compared with placebo. A meta-analysis of the primary endpoint showed Quantitative Myasthenia Gravis (QMG) muscle score assessed between three and eight days was likely to improve by a mean of 2.44 points (95% confidence interval 3.6 to 1.22). Meta-analysis of the secondary endpoint CMAP amplitude also showed a mean improvement of 1.36 mV (95% confidence interval 0.99 to 1.72) over the same period. The risk of bias was determined to be low, and quality of evidence moderate to high. A single cross-over trial reported significant improvement in myometric limb strength and non-significant improvement in mean resting CMAP amplitude with IVIg compared to placebo. Clinical improvement lasted for up to eight weeks. Limited but moderate to high quality evidence from randomised controlled trials showed that over days 3,4-diaminopyridine, or for up to 8 weeks IVIg, improved muscle strength scores and CMAP amplitudes in participants with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this effect. Other possible treatments have not been tested in randomised controlled trials.

Four small randomised controlled trials involving 54 participants in total showed that 3,4-diaminopyridine improves muscle strength. This was determined by measuring the compound muscle action potential (CMAP) which is a test that records the amount of electrical activity generated in a muscle when it is stimulated by its nerve. Although the number of trials is relatively small, the quality of evidence from these trials is moderate to high, which supports the findings of this review. The changes are measured over days only. A single trial involving nine participants showed that intravenous immunoglobulin also improved muscle strength up to 8 weeks from treatment. Other possible treatments such as plasma exchange, steroids and immunosuppressive agents have not been tested in randomised controlled trials. Further trials of these treatments are needed.

10.1002/14651858.CD003279.pub3

cochrane-simplification-train-2928

cochrane-simplification-train-2928

We identified 104 trials including 111,653 participants that met the inclusion criteria. Participants were mostly adult smokers from the general population, but some studies included teenagers, pregnant women, and people with long-term or mental health conditions. Most trials (58.7%) were at high risk of bias, while 30.8% were at unclear risk, and only 11.5% were at low risk of bias for all domains assessed. Most studies (100/104) assessed proactive telephone counselling, as opposed to reactive forms. Among trials including smokers who contacted helplines (32,484 participants), quit rates were higher for smokers receiving multiple sessions of proactive counselling (risk ratio (RR) 1.38, 95% confidence interval (CI) 1.19 to 1.61; 14 trials, 32,484 participants; I2 = 72%) compared with a control condition providing self-help materials or brief counselling in a single call. Due to the substantial unexplained heterogeneity between studies, we downgraded the certainty of the evidence to moderate. In studies that recruited smokers who did not call a helpline, the provision of telephone counselling increased quit rates (RR 1.25, 95% CI 1.15 to 1.35; 65 trials, 41,233 participants; I2 = 52%). Due to the substantial unexplained heterogeneity between studies, we downgraded the certainty of the evidence to moderate. In subgroup analysis, we found no evidence that the effect of telephone counselling depended upon whether or not other interventions were provided (P = 0.21), no evidence that more intensive support was more effective than less intensive (P = 0.43), or that the effect of telephone support depended upon whether or not people were actively trying to quit smoking (P = 0.32). However, in meta-regression, telephone counselling was associated with greater effectiveness when provided as an adjunct to self-help written support (P < 0.01), or to a brief intervention from a health professional (P = 0.02); telephone counselling was less effective when provided as an adjunct to more intensive counselling. Further, telephone support was more effective for people who were motivated to try to quit smoking (P = 0.02). The findings from three additional trials of smokers who had not proactively called a helpline but were offered telephone counselling, found quit rates were higher in those offered three to five telephone calls compared to those offered just one call (RR 1.27, 95% CI 1.12 to 1.44; 2602 participants; I2 = 0%). There is moderate-certainty evidence that proactive telephone counselling aids smokers who seek help from quitlines, and moderate-certainty evidence that proactive telephone counselling increases quit rates in smokers in other settings. There is currently insufficient evidence to assess potential variations in effect from differences in the number of contacts, type or timing of telephone counselling, or when telephone counselling is provided as an adjunct to other smoking cessation therapies. Evidence was inconclusive on the effect of reactive telephone counselling, due to a limited number studies, which reflects the difficulty of studying this intervention.

We found 104 studies (including 111,653 participants) testing the effect of any type of telephone counselling. The participants were mostly adult smokers from the general population, but some studies also looked at teenagers, pregnant women, and people with long-term or mental health conditions. Some studies included participants who had called helplines that provide smoking counselling (quitlines). Other studies included people who had not called quitlines, but received calls from counsellors or other healthcare providers. Some studies provided telephone counselling alone, but many others provided telephone counselling along with minimal support such as self-help leaflets, or more active support such as face-to-face counselling, or with stop-smoking medication. The number of calls offered ranged from a single call to 12 calls. Some studies only recruited people trying to stop smoking, while others offered support even to those not actively trying to stop. Studies needed to compare groups whose participants had similar characteristics at the start of the study, to investigate whether the participants had stopped smoking for at least six months, and ideally would test whether people had quit with blood or urine tests. We judged few studies to be well designed and conducted. Most had at least one issue that could have affected the results. In people who had called helplines, providing additional telephone counselling increased their chances of stopping smoking from 7% to 10%. In people who had not called a helpline, but received telephone calls from counsellors or other healthcare providers, their chances of stopping smoking increased from 11% to 14%. In studies which directly compared more versus fewer calls, people who were offered more calls (three to five) tended to be more likely to quit than those who received only one call. Telephone counselling appears to increase the chances of stopping smoking, whether or not people are motivated to quit or are receiving other stop-smoking support. The overall certainty of the evidence was moderate, meaning that further research is likely to have an important impact on our conclusions.

10.1002/14651858.CD002850.pub4

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cochrane-simplification-train-2929

We included seven adult studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cutoff levels used (15 to 35 ppb), the way in which FeNO was used to adjust therapy, and duration of study (4 to 12 months). Of 1700 randomised participants, 1546 completed the trials. The mean ages of the participants ranged from 28 to 54 years old. The inclusion criteria for the participants in each study varied, but all had a diagnosis of asthma and required asthma medications. In the meta-analysis, there was a significant difference in the primary outcome of asthma exacerbations between the groups, favouring the FeNO group. The number of people having one or more asthma exacerbations was significantly lower in the FeNO group compared to the control group (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.43 to 0.84). The number needed to treat to benefit (NNTB) over 52 weeks was 12 (95% CI 8 to 32). Those in the FeNO group were also significantly more likely to have a lower exacerbation rate than the controls (rate ratio 0.59, 95% CI 0.45 to 0.77). However, we did not find a difference between the groups for exacerbations requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48). There was also no significant difference between groups for any of the secondary outcomes (FEV1, FeNO levels, symptoms scores, or inhaled corticosteroid doses at final visit). We considered three included studies that had inadequate blinding to have a high risk of bias. However, when these studies were excluded from the meta-analysis, the difference between the groups for the primary outcomes (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'exacerbations') to very low (for the outcome 'inhaled corticosteroid dose at final visit') based on the lack of blinding and statistical heterogeneity. Six of the seven studies were industry supported, but the company had no role in the study design or data analyses. With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in adults with asthma showed that tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms, end-of-study FeNO levels, or inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. As the main benefit shown in the studies in this review was a reduction in asthma exacerbations, the intervention may be most useful in adults who have frequent exacerbations. Further RCTs encompassing different asthma severity, ethnic groups in less affluent settings, and taking into account different FeNO cutoffs are required.

We included all randomised controlled trials that compared adjustment of asthma medications by usual clinical care (control group) versus using exhaled nitric oxide. The participants included in the trials had asthma diagnosed as per relevant asthma guidelines. The evidence is current to June 2016, when the searches were last completed. We found seven studies in the searches. Of 1700 randomised participants, 1546 completed the trials. The studies varied in a few aspects including duration, cutoff levels used for altering medications based on fractional exhaled nitric oxide (FeNO), and the way each study defined exacerbations. The included studies ranged from 4 months to 12 months in duration. The FeNO cutoff values the studies used also varied. The levels used for decreasing medications ranged from 10 ppb to 25 ppb. Likewise, the levels used for increasing medications ranged from 15 ppb to 35 ppb in the included studies. The majority of the studies were industry supported. The mean ages of the participants ranged from 28 to 54 years old. In this review involving 1700 adults with asthma, we found that guiding the dose of asthma medications based on exhaled nitric oxide (compared to a control group) was beneficial in reducing the number of exacerbations (flare-ups) during the study period. However, we did not find a difference between groups for other asthma outcomes that impact on day-to-day clinical symptoms, hospitalisations, or inhaled steroid dose. Thus, using exhaled nitric oxide levels to adjust asthma therapy may reduce the risk of adults having an asthma flare-up but did not impact on day-to-day symptoms. The quality of evidence ranged from moderate when comparing the two groups for the exacerbation outcomes, to very low when comparing the groups for inhaled corticosteroid dose at final visit.

10.1002/14651858.CD011440.pub2

cochrane-simplification-train-2930

cochrane-simplification-train-2930

We included 61 studies with a total population of 6264 subfertile men, aged between 18 and 65 years, part of a couple who had been referred to a fertility clinic and some of whom were undergoing assisted reproductive techniques (ART). Investigators compared and combined 18 different oral antioxidants. The evidence was of 'low' to 'very low' quality: the main limitation was that out of the 44 included studies in the meta-analysis only 12 studies reported on live birth or clinical pregnancy. The evidence is current up to February 2018. Live birth: antioxidants may lead to increased live birth rates (OR 1.79, 95% CI 1.20 to 2.67, P = 0.005, 7 RCTs, 750 men, I2 = 40%, low-quality evidence). Results suggest that if in the studies contributing to the analysis of live birth rate, the baseline chance of live birth following placebo or no treatment is assumed to be 12%, the chance following the use of antioxidants is estimated to be between 14% and 26%. However, this result was based on only 124 live births from 750 couples in seven relatively small studies. When studies at high risk of bias were removed from the analysis, there was no evidence of increased live birth (Peto OR 1.38, 95% CI 0.89 to 2.16; participants = 540 men, 5 RCTs, P = 0.15, I2 = 0%). Clinical pregnancy rate: antioxidants may lead to increased clinical pregnancy rates (OR 2.97, 95% CI 1.91 to 4.63, P < 0.0001, 11 RCTs, 786 men, I2 = 0%, low-quality evidence) compared to placebo or no treatment. This suggests that if in the studies contributing to the analysis of clinical pregnancy, the baseline chance of clinical pregnancy following placebo or no treatment is assumed to be 7%, the chance following the use of antioxidants is estimated to be between 12% and 26%. This result was based on 105 clinical pregnancies from 786 couples in 11 small studies. Adverse events Miscarriage: only three studies reported on this outcome and the event rate was very low. There was no difference in miscarriage rate between the antioxidant and placebo or no treatment group (OR 1.74, 95% CI 0.40 to 7.60, P = 0.46, 3 RCTs, 247 men, I2 = 0%, very low-quality evidence). The findings suggest that in a population of subfertile men with an expected miscarriage rate of 2%, the chance following the use of an antioxidant would result in the risk of a miscarriage between 1% and 13%. Gastrointestinal: antioxidants may lead to an increase in mild gastrointestinal upsets when compared to placebo or no treatment (OR 2.51, 95% CI 1.25 to 5.03, P = 0.010, 11 RCTs, 948 men, I2 = 50%, very low-quality evidence). This suggests that if the chance of gastrointestinal upsets following placebo or no treatment is assumed to be 2%, the chance following the use of antioxidants is estimated to be between 2% and 9%. However, this result was based on a low event rate of 35 out of 948 men in 10 small or medium-sized studies, and the quality of the evidence was rated very low and was high in heterogeneity. We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as insufficient studies compared the same interventions. In this review, there is low-quality evidence from seven small randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low-quality evidence suggests that clinical pregnancy rates may also increase. Overall, there is no evidence of increased risk of miscarriage, however antioxidants may give more mild gastrointestinal upsets but the evidence is of very low quality. Subfertilte couples should be advised that overall, the current evidence is inconclusive based on serious risk of bias due to poor reporting of methods of randomisation, failure to report on the clinical outcomes live birth rate and clinical pregnancy, often unclear or even high attrition, and also imprecision due to often low event rates and small overall sample sizes. Further large well-designed randomised placebo-controlled trials reporting on pregnancy and live births are still required to clarify the exact role of antioxidants.

Cochrane authors conducted a review including 61 randomised controlled trials comparing 18 different antioxidants with placebo, no treatment or another antioxidant in a total population of 6264 subfertile men. The age range of the participants was 18 to 65 years; they were part of a couple who had been referred to a fertility clinic and some were undergoing fertility treatment. The evidence is current to February 2018. Antioxidants may be associated with an increased live birth and clinical pregnancy rate. Based on the studied population for live birth, we would expect that out of 100 subfertile men not taking antioxidants, 12 couples would have a baby, compared with between 14 and 26 couples per 100 who would have a baby if taking antioxidants. If studies with high risk were removed from the analysis, there was no evidence of increased live birth. In the people who were studied for clinical pregnancy, we would expect that out of 100 subfertile men not taking antioxidants, seven couples would have a clinical pregnancy, compared with between 12 and 26 couples per 100 who would have a clinical pregnancy if taking antioxidants. Adverse events were poorly reported. However based on three studies, we could conclude that miscarriage did not occur more often if taking antioxidants. The use of antioxidants could give more gastrointestinal upsets, meaning that we expect that out of 100 subfertile men not taking antioxidants, two would have gastrointestinal upsets compared to between two and nine men if taking antioxidants. Antioxidant supplementation taken by subfertile males of a couple attending a fertility clinic may increase the chance of a live birth, however the overall quality of evidence was low from only seven small randomised controlled trials. Low-quality evidence also suggests that clinical pregnancy rates may increase. Overall, there is no evidence of increased risk of miscarriage, however evidence of very low quality suggest that antioxidants may give more mild gastrointestinal upsets. Subfertile couples should be advised that overall the current evidence is inconclusive due to the poor reporting of methods, failure to report on the clinical outcomes live birth rate and clinical pregnancy, and furthermore imprecision due to often low event rates, high number of dropouts and small study group sizes. Further large well-designed randomised placebo-controlled trials reporting on pregnancy and live births are still required to clarify the exact role of antioxidants.

10.1002/14651858.CD007411.pub4

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cochrane-simplification-train-2931

We included five trials with a total of 1920 women. Two placebo-controlled trials of women with PMDD showed less severe premenstrual symptoms after three months with drospirenone 3 mg plus ethinyl estradiol 20 μg than with placebo (MD -7.92; 95% CI -11.16 to -4.67). The drospirenone group had greater mean decreases in impairment of productivity (MD -0.31; 95% CI -0.55 to -0.08), social activities (MD -0.29; 95% CI -0.54 to -0.04), and relationships (MD -0.30; 95% CI -0.54 to -0.06). Side effects more common with the use of the drospirenone COC contraceptive were nausea, intermenstrual bleeding, and breast pain. The respective odds ratios were 3.15 (95% CI 1.90 to 5.22), 4.92 (95% CI 3.03 to 7.96), and 2.67 (95% CI 1.50 to 4.78). Total adverse events related to the study drug were more likely for the drospirenone COC group (OR 2.36; 95% CI 1.62 to 3.44). Three trials studied the effect of drospirenone 3 mg plus ethinyl estradiol 30 μg on less severe symptoms. A placebo-controlled six-month trial had insufficient data for primary outcome analysis. Another six-month study used levonorgestrel 150 µg plus ethinyl estradiol 30 µg for the comparison group but did not provide enough data on premenstrual symptoms. In a two-year trial, the drospirenone COC group had similar premenstrual symptoms to the comparison group given desogestrel 150 µg plus ethinyl estradiol 30 µg (OR 0.87; 95% CI 0.63 to 1.22). The groups were also similar for adverse events related to treatment (OR 1.02; 95% CI 0.78 to 1.33). Drospirenone 3 mg plus ethinyl estradiol 20 μg may help treat premenstrual symptoms in women with severe symptoms, that is, premenstrual dysphoric disorder. The placebo also had a large effect. We do not know whether the combined oral contraceptive works after three cycles, helps women with less severe symptoms, or is better than other oral contraceptives. Larger and longer trials of higher quality are needed to address these issues. Trials should follow CONSORT guidelines.

We did a computer search for trials that compared a birth control pill containing drospirenone and estrogen to a placebo ('dummy') or another birth control pill in treating premenstrual symptoms. We wrote to researchers to find other trials. We looked at whether the pills reduced symptoms and if side effects were reported. Women recorded their symptoms over time. We found five trials with 1920 women. Two trials compared a dummy pill to a drospirenone pill with low estrogen. All the women had PMDD, the severe form of PMS, before the trial. After three months, women on the drospirenone pill with low estrogen had less severe premenstrual symptoms than the group taking the dummy pill. Women in the drospirenone group said they could do more and had more social activities and friends. Women on the drospirenone pill had more nausea, bleeding between periods, and breast pain. These side effects are common with birth control pills. Three trials studied a drospirenone pill with more estrogen for treating less severe symptoms. These women did not all have PMDD. One compared the drospirenone pill to a dummy pill but did not have enough data for our review. Two compared the study pill to another birth control pill. The two-year study showed the groups were similar for premenstrual symptoms and side effects. The six-month study did not give enough data on the symptoms. A drospirenone pill with low estrogen seems to help premenstrual symptoms in women with severe symptoms (PMDD). The drospirenone pill worked a little better than the dummy pill, which also affected symptoms. We do not know if the birth control pill works longer than three cycles, helps women with less severe symptoms, or is better than other birth control pills. Longer and better studies with more women are needed to address these issues. Trials reports should be clearer about how the study was done.

10.1002/14651858.CD006586.pub4

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cochrane-simplification-train-2932

Ten trials met the inclusion criteria. Telehealthcare was assessed as part of a complex intervention, including nurse case management and other interventions. Telehealthcare was associated with a clinically significant increase in quality of life in two trials with 253 participants (mean difference -6.57 (95% confidence interval (CI) -13.62 to 0.48); minimum clinically significant difference is a change of -4.0), but the confidence interval was wide. Telehealthcare showed a significant reduction in the number of patients with one or more emergency department attendances over 12 months; odds ratio (OR) 0.27 (95% CI 0.11 to 0.66) in three trials with 449 participants, and the OR of having one or more admissions to hospital over 12 months was 0.46 (95% CI 0.33 to 0.65) in six trials with 604 participants. There was no significant difference in the OR for deaths over 12 months for the telehealthcare group as compared to the usual care group in three trials with 503 participants; OR 1.05 (95% CI 0.63 to 1.75). Telehealthcare in COPD appears to have a possible impact on the quality of life of patients and the number of times patients attend the emergency department and the hospital. However, further research is needed to clarify precisely its role since the trials included telehealthcare as part of more complex packages.

This study shows that people treated this way do manage to stay out of hospital longer than people treated by conventional systems of care. There are also some data showing that although these systems are expensive to start off with, if they are successful at keeping people out of hospital, then the cost saving from this means that they are cheaper in the long run.

10.1002/14651858.CD007718.pub2

cochrane-simplification-train-2933

cochrane-simplification-train-2933

Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 500 mg NNT 3.5 (2.7 to 4.8); 600 to 650 mg NNT 4.6 (3.9 to 5.5); 975 to 1000 mg NNT 3.6 (3.4 to 4.0). There was no dose response. Sensitivity analysis showed no significant effect of trial size or quality on this outcome. About half of participants needed additional analgesia over four to six hours, compared with about 70% with placebo. Five people would need to be treated with 1000 mg paracetamol, the most commonly used dose, to prevent one needing rescue medication over four to six hours, who would have needed it with placebo. Adverse event reporting was inconsistent and often incomplete. Reported adverse events were mainly mild and transient, and occurred at similar rates with 1000 mg paracetamol and placebo. No serious adverse events were reported. Withdrawals due to adverse events were uncommon and occurred in both paracetamol and placebo treatment arms. A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.

This review assessed data from fifty-one studies and found that paracetamol provided effective pain relief for about half of participants experiencing moderate to severe pain after an operation, including dental surgery for a period of about four hours. There were no clear differences between doses of paracetamol typically used. These single dose studies did not associate paracetamol with any serious side effects.

10.1002/14651858.CD004602.pub2

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cochrane-simplification-train-2934

Four studies were eligible for inclusion (281 participants): Two studies compared relaxation with electroacupuncture or superficial needling, one study compared relaxation with paced respiration or placebo control (α-wave electroencephalographic biofeedback) and one study compared relaxation with no treatment. No evidence was found of a difference between relaxation and acupuncture or superficial needle insertion in the number of hot flushes per 24 hours (mean difference (MD) 0.05, 95% confidence interval (CI) -1.33 to 1.43, two studies, 72 participants, I2 = 0%; very low-quality evidence). Nor did any evidence suggest a difference between the two interventions in hot flush severity, measured using the Kupperman Index (MD -1.32, 95% CI -5.06 to 2.43, two studies, 72 participants, I2 = 0%; very low-quality evidence). The other two studies found no clear evidence of a difference in hot flush frequency between relaxation and paced respiration, placebo or no treatment. The data for these comparisons were unsuitable for analysis. None of these studies reported night sweats, sleep disturbances associated with night sweats or adverse effects as an outcome. The main limitations of identified evidence were lack of data, imprecision and failure to report study methods in adequate detail. Evidence is insufficient to show the effectiveness of relaxation techniques as treatment for menopausal vasomotor symptoms, or to determine whether this treatment is more effective than no treatment, placebo, acupuncture, superficial needle insertion or paced respiration.

We found four randomised controlled studies, with 281 participants. Relaxation was compared with electroacupuncture, superficial needling, paced respiration, placebo and no treatment. The age range of participants was 30 to 77 years. These trials were conducted in Sweden, the UK and the USA. No study was funded by an agency with commercial interest in the results of the study. The evidence is current to February 2014. Evidence is insufficient to show the effectiveness of relaxation techniques as treatment for menopausal vasomotor symptoms, or to determine whether this treatment is more effective than no treatment, placebo, acupuncture, superficial needle insertion or paced respiration. No evidence indicates that relaxation reduces the number of hot flushes per 24 hours or their severity. None of the studies reported night sweats, sleep disturbances associated with night sweats or adverse effects as an outcome. The quality of the evidence was very low. The main limitations of identified evidence included lack of data, imprecision and failure to report study methods in adequate detail.

10.1002/14651858.CD008582.pub2

cochrane-simplification-train-2935

cochrane-simplification-train-2935

Our searches identified 1840 records, from which we included 40 completed reviews (19 Cochrane; 21 non-Cochrane), covering 18 individual interventions and dose and setting of interventions. The 40 reviews contain 503 studies (18,078 participants). We extracted pooled data from 31 reviews related to 127 comparisons. We judged the quality of evidence to be high for 1/127 comparisons (transcranial direct current stimulation (tDCS) demonstrating no benefit for outcomes of activities of daily living (ADLs)); moderate for 49/127 comparisons (covering seven individual interventions) and low or very low for 77/127 comparisons. Moderate-quality evidence showed a beneficial effect of constraint-induced movement therapy (CIMT), mental practice, mirror therapy, interventions for sensory impairment, virtual reality and a relatively high dose of repetitive task practice, suggesting that these may be effective interventions; moderate-quality evidence also indicated that unilateral arm training may be more effective than bilateral arm training. Information was insufficient to reveal the relative effectiveness of different interventions. Moderate-quality evidence from subgroup analyses comparing greater and lesser doses of mental practice, repetitive task training and virtual reality demonstrates a beneficial effect for the group given the greater dose, although not for the group given the smaller dose; however tests for subgroup differences do not suggest a statistically significant difference between these groups. Future research related to dose is essential. Specific recommendations for future research are derived from current evidence. These recommendations include but are not limited to adequately powered, high-quality RCTs to confirm the benefit of CIMT, mental practice, mirror therapy, virtual reality and a relatively high dose of repetitive task practice; high-quality RCTs to explore the effects of repetitive transcranial magnetic stimulation (rTMS), tDCS, hands-on therapy, music therapy, pharmacological interventions and interventions for sensory impairment; and up-to-date reviews related to biofeedback, Bobath therapy, electrical stimulation, reach-to-grasp exercise, repetitive task training, strength training and stretching and positioning. Large numbers of overlapping reviews related to interventions to improve upper limb function following stroke have been identified, and this overview serves to signpost clinicians and policy makers toward relevant systematic reviews to support clinical decisions, providing one accessible, comprehensive document, which should support clinicians and policy makers in clinical decision making for stroke rehabilitation. Currently, no high-quality evidence can be found for any interventions that are currently used as part of routine practice, and evidence is insufficient to enable comparison of the relative effectiveness of interventions. Effective collaboration is urgently needed to support large, robust RCTs of interventions currently used routinely within clinical practice. Evidence related to dose of interventions is particularly needed, as this information has widespread clinical and research implications.

We judged the quality of evidence to be high in relation to one intervention: a type of brain stimulation called transcranial direct current stimulation (tDCS), which is not currently used within routine practice. This high-quality evidence shows that tDCS does not improve people's ability to perform activities of daily living. We judged the quality of evidence to be moderate for 48 comparisons (covering seven individual interventions) and low or very low for 76 comparisons. Reasons for downgrading the quality of evidence to moderate, low or very low include small numbers of studies and participants, poor methodological quality or reporting of studies included within reviews, substantial heterogeneity (variation) between study results and poor review quality or reporting of methods. We conclude that high-quality evidence related to the effectiveness of interventions to improve upper limb function is urgently needed, in particular for those interventions for which moderate-quality evidence currently suggests a beneficial effect.

10.1002/14651858.CD010820.pub2

cochrane-simplification-train-2936

cochrane-simplification-train-2936

We did not identify any trial comparing one TPO mimetic versus another. We analysed six eligible trials involving 746 adult patients. All trials were reported as randomised and double-blind trials including male and female patients. Two trials compared TPO mimetics (romiplostim or eltrombopag) with placebo, one trial evaluated eltrombopag in addition to the hypomethylating agent azacitidine, two trials analysed romiplostim additionally to a hypomethylating agent (azacitidine or decitabine) and one trial evaluated romiplostim in addition to the immunomodulatory drug lenalidomide. There are more data on romiplostim (four included, completed, full-text trials) than on eltrombopag (two trials included: one full-text publication, one abstract publication). Due to small sample sizes and imbalances in baseline characteristics in three trials and premature termination of two studies, we judged the potential risk of bias of all included trials as high. Due to heterogenous reporting, we were not able to pool data for OS. Instead of that, we analysed mortality during study. There is little or no evidence for a difference in mortality during study for thrombopoietin mimetics compared to placebo (RR 0.97, 95% confidence interval (CI) 0.73 to 1.27, N = 6 trials, 746 patients, low-quality evidence). It is unclear whether the use of TPO mimetics induces an acceleration of transformation to AML (RR 1.02, 95% CI 0.59 to 1.77, N = 5 trials, 372 patients, very low-quality evidence).Thrombopoietin mimetics probably improve the incidence of all bleeding events (RR 0.92, 95% CI 0.86 to 0.99, N = 5 trials, 390 patients, moderate-quality evidence). This means that in the study population, 713 out of 1000 in the placebo arm will have a bleeding event, compared to 656 of 1000 (95% CI 613 to 699) in the TPO mimetics arm. There is little or no evidence for a difference that TPO mimetics significantly diminish the rate of transfusion requirement (RR 0.83, 95% CI 0.66 to 1.05, N = 4 trials, 358 patients, low-quality evidence). No studies were found that looked at quality of life or duration of thrombocytopenia. There is no evidence that patients given TPO mimetics suffer more all adverse events (RR 1.01, 95% CI 0.96 to 1.07, N = 5 trials, 390 patients, moderate-quality evidence). There is uncertainty whether the number of serious adverse events decrease under therapy with TPO mimetics (RR 0.89, 95% CI 0.54 to 1.46, N = 4 trials, 356 patients, very low-quality evidence). We identified one ongoing study and one study marked as completed (March 2015), but without publication of results for MDS patients (only results reported for AML and MDS patients together). Both studies evaluate MDS patients receiving eltrombopag in comparison to placebo. No trial evaluated one TPO mimetic versus another. Six trials including adult patients analysed one TPO mimetic versus placebo, sometimes combined with standard therapy in both arms. Given the uncertainty of the quality of evidence, meta-analyses show that there is little or no evidence for a difference in mortality during study and premature progress to AML. However, these assumptions have to be further explored. Treatment with TPO mimetics resulted in a lower number of MDS patients suffering from bleeding events.There is no evidence for a difference between study groups regarding transfusion requirement. Enlarged sample sizes and a longer follow-up of future trials should improve the estimate of safety and efficacy of TPO mimetics, moreover health-related quality of life should be evaluated. As two ongoing studies currently investigate eltrombopag (one already completed, but without published results), we are awaiting results for this drug.

We searched medical databases such as Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, conference proceedings and study registries (January 2000 to August 2017). No trial evaluated one TPO mimetic (romiplostim or eltrombopag) versus another. We found eight eligible trials (six included, two ongoing, one of which is completed but without final results for MDS patients) and we included 746 adult patients in our review. The trials were randomised, double-blinded and used either romiplostim or eltrombopag versus placebo. In four trials hypomethylating agents or immunomodulatory drugs were administered in combination to romiplostim or eltrombopag. Only adults were included. A meta-analysis of overall survival data was not possible, since data were too heterogeneous to pool. Instead of that, we analysed mortality data. There was no evidence for a difference between TPO mimetics and placebo in terms of mortality during study, transformation to AML, transfusion requirement, adverse events and serious adverse events. Thrombopoietin mimetics probably decrease the number of patients having bleeding events. In the study population, 713 out of 1000 in the placebo arm had a bleeding event, compared to 656 of 1000 (95% confidence interval (CI) 613 to 699) in the TPO mimetics arm. No trial evaluated health-related quality. The quality of evidence for the outcomes incidence of bleeding events and all adverse events is moderate due to high risk of bias (small sample sizes and imbalances in baseline characteristics in three trials, premature closure of two trials, selective reporting in one trial, industrial sponsorship). The quality of evidence for the outcomes mortality during study and transfusion requirements is low, due to imprecision through small number of events and high risk of bias. It is very low for the outcomes transformation to AML and serious adverse events, because of very small number of events, high risk of bias and heterogeneity between trials. Although this systematic review reveals a potential patient-relevant benefit regarding decreasing bleeding events for evaluated adult patients, future trials should focus on outcomes referring to safety, efficacy and quality of life aspects of TPO mimetics to test their everyday usage. The assumption of premature progress to AML could not be clearly verified. Because of the low number of included trials and small sample sizes, uncertainties of the findings in this review exist and demand further investigation with more trials and participants and longer follow-up periods.

10.1002/14651858.CD009883.pub2

cochrane-simplification-train-2937

cochrane-simplification-train-2937

We identified six trials for inclusion. Five studies on 206 participants contributed data, while one study was available in abstract form only and was not fully incorporated into this review. For the primary outcome of endotracheal intubation there were two studies that contributed data: two intubations were needed in 45 participants on NPPV and no intubations in 41 control patients (risk ratio 4.48; 95% CI 0.23 to 89.13). There were no deaths in either of these studies. Length of hospital stay was reported in two studies, though meta-analysis was not possible. Hospitalisation was reported in one small study, in which there were three admissions out of 17 on NPPV and 10 admissions out of 16 in control patients (RR 0.28, 95% CI 0.09, 0.84). This review of studies has highlighted the paucity of data that exist to support the use of NPPV in patients in status asthmaticus. As such this course of treatment remains controversial despite its continued use in current clinical practice. Larger, prospective randomised controlled trials of rigorous methodological design are needed to determine the role of NPPV in patients with asthma.

We undertook this review to determine the effectiveness of NPPV in patients with severe acute asthma. Six randomised controlled trials were included in the review. Compared to usual medical care alone, NPPV reduced hospitalisations, increased the number of patients discharged from the emergency department, and improved respiratory rate and lung function measurements. The application of NPPV in patients with asthma, despite some promising preliminary results, still remains controversial. Further studies are needed to determine the role of NPPV in the management of severe acute asthma and especially in status asthmaticus.

10.1002/14651858.CD004360.pub4

cochrane-simplification-train-2938

cochrane-simplification-train-2938

We have included 18 studies (involving 1498 women) in this review. However, only nine of the included studies (with 750 women) reported 24 comparisons of analgesia with other analgesia or placebo and had data that could be included in our meta-analyses. The majority of studies investigated pharmacological analgesics and these were grouped into classes for this review. Non-steroidal anti-inflammatory drugs (NSAIDs) were significantly better than placebo at relieving pain from uterine involution as assessed by their summed pain intensity differences (SPID) (mean difference (MD) 4.34; 95% confidence interval (CI) 2.87 to 5.82; three studies, 204 women) and summed pain relief scores (MD 5.94; 95% CI 3.83 to 8.01; three studies, 204 women). NSAIDS were compared with opioids in one small study of 23 women reporting SPID and summed pain relief and found no difference. A larger study of 127 women found NSAIDs to be significantly better than opioids at reducing pain intensity six hours following study intervention (MD -0.70; 95% CI -1.04 to -0.35). Opioids were compared with placebo in three studies that could be included in meta-analyses; one small study of 23 women reporting SPID and summed pain relief and found no difference. One study of 95 women found no difference in pain intensity six hours following the study intervention. A third study of 108 women found significantly more women in the placebo group reported no pain relief than women in the opioid group (risk ratio 0.10; 95% CI 0.04 to 0.23). Aspirin was significantly better than paracetamol when pain intensity score was assessed six hours after study intervention (MD 0.85; 95% CI 0.29 to 1.41; one study 48 women) at relieving pain from uterine involution. Paracetamol was not better than placebo when pain intensity was assessed six hours after the study intervention in one study of 48 women. Non-steroidal anti-inflammatory drugs (NSAID) including aspirin were better than placebo at relieving pain from uterine cramping/involution following vaginal birth. NSAIDs were better than paracetamol and paracetamol was not better than placebo, though numbers of participants for these comparisons were small. Data for opioids compared with NSAIDs and opioids compared with placebo were conflicting, with some measures showing similar effect and others indicating NSAIDs were better than opioids and opioids were not better than placebo. There were insufficient data to make conclusions regarding the effectiveness of opioids at relieving pain from uterine cramping/involution. The median year of publication of included studies was 1981; therefore more research is needed to assess the effectiveness of current pharmacological and non-pharmacological analgesia at relieving pain from uterine cramping/involution following vaginal birth.

Types of analgesia used to relieve the pain include paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) included aspirin and naproxen, opioids including codeine and non-pharmacological methods such as transcutaneous electrical nerve stimulation (TENS). The results from 18 randomised controlled trials involving 1498 women, of which nine (750 women) had data that could be included in the review meta-analyses, indicated that aspirin and other NSAIDs including naproxen were more effective at relieving uterine cramping pain than paracetamol or a placebo. NSAIDs included naproxen, aspirin, ketorolac and flurbiprofen. Only naproxen is still used in women who are breastfeeding. Aspirin is not recommended for use by breastfeeding women as there is concern that it will be passed to the baby in the breast milk. Codeine was not always more effective than a placebo or NSAIDs in the included studies and can sedate breastfed babies. Women offered codeine for pain relief should be informed about the potential for adverse effects for their babies. Codeine should only be prescribed for breastfeeding women with after birth pain if there is no alternative and their breastfed infants should be closely monitored for sedation and signs of codeine toxicity. Information about the safety of the NSAIDs for breastfeeding women and their babies was limited. The majority of analyses in this review included only one study with small numbers of participants. The average year of the included studies is 1981 and therefore further research is recommended comparing NSAIDs currently available and known to be safe for women who are breastfeeding and their babies.

10.1002/14651858.CD004908.pub2

cochrane-simplification-train-2939

cochrane-simplification-train-2939

The updated search resulted in no new trials meeting the inclusion criteria of this review, thus leaving it to the seven already included randomised trials (six evaluating ursodeoxycholic acid versus placebo or no intervention, and one evaluating tauro-ursodeoxycholic acid versus no intervention) enrolling a total of 335 participants. The administration of bile acids began one day or more after liver transplantation. All patients received the standard triple-drug immunosuppressive regimen (steroids, azathioprine, and cyclosporine or tacrolimus) to suppress the allograft rejection response after liver transplantation. Bile acids compared with placebo or no intervention did not significantly change all-cause mortality (RR 0.85, 95% CI 0.53 to 1.36), mortality related to allograft rejection (RR 0.30, 95% CI 0.01 to 7.12), retransplantation (RR 0.76, 95% CI 0.20 to 2.86), acute cellular rejection, or number of patients with steroid-resistant rejection. Bile acids significantly reduced the number of patients who had chronic rejection in a fixed-effect model but not in a random-effects model meta-analysis. Bile acids were safe and well tolerated by liver-transplanted patients. However, this observation is based on data analysis from three trials with only 187 patients. We did not find evidence to support or refute bile acids for liver-transplanted patients. Further randomised trials are necessary before bile acids can be recommended to liver-transplanted patients.

Results of the seven randomised clinical trials included in the review in which patients received standard immunosuppressive treatment (steroids, azathioprine, and cyclosporine or tacrolimus) with or without bile acids after liver transplantation, did not show any significant effects of bile acids on all-cause mortality, mortality related to rejection, acute cellular rejection, steroid resistant rejection, or need for retransplantation. One analysis suggested that bile acids might beneficially influence number of patients with chronic rejection, but was contradicted by the analyses. The evidence that the use of ursodeoxycholic acid might have beneficial effects on chronic rejection and length of hospitalisation is weak as it is produced from trials with high risk of bias and insufficient number of included patients. That bile acids seemed well tolerated, with no reports of serious adverse events, is good knowledge, but much more research is needed before their use is acquitted. None of the randomised clinical trials assessed the effects of bile acids on quality of life or cost-effectiveness.

10.1002/14651858.CD005442.pub2

cochrane-simplification-train-2940

cochrane-simplification-train-2940

This review update includes a total of 12 trials (944) women (type 1 diabetes: 660 women; type 2 diabetes: 113 women; type 1 or type 2 (unspecified): 171 women. The trials took place in Europe, the USA and Canada. Three of the 12 included studies are at low risk of bias, eight studies are at moderate risk of bias, and one study is at high risk of bias. Four trials reported that they were provided with the continuous glucose monitors free of charge or at a reduced cost by the manufacturer. Continuous glucose monitoring (CGM) versus intermittent glucose monitoring, (four studies, 609 women) CGM may reduce hypertensive disorders of pregnancy (pre-eclampsia and pregnancy-induced hypertension) (risk ratio (RR) 0.58, 95% confidence interval (CI) 0.39 to 0.85; 2 studies, 384 women; low-quality evidence), although it should be noted that only two of the four relevant studies reported data for this composite outcome. Conversely, this did not translate into a clear reduction for pre-eclampsia (RR 0.65, 95% CI 0.39 to 1.08; 4 studies, 609 women, moderate-quality evidence). There was also no clear reduction in caesarean section (average RR 0.94, 95% CI 0.75 to 1.18; 3 studies, 427 women; I2 = 41%; moderate-quality evidence) or large-for-gestational age (average RR 0.84, 95% CI 0.57 to 1.26; 3 studies, 421 women; I2 = 70%; low-quality evidence) with CGM. There was not enough evidence to assess perinatal mortality (RR 0.82, 95% CI 0.05 to 12.61, 71 infants, 1 study; low-quality evidence), or mortality or morbidity composite (RR 0.80, 95% CI 0.61 to 1.06; 1 study, 200 women) as the evidence was based on single studies of low quality. CGM appears to reduce neonatal hypoglycaemia (RR 0.66, 95% CI 0.48 to 0.93; 3 studies, 428 infants). Neurosensory disability was not reported. Other methods of glucose monitoring For the following five comparisons, self-monitoring versus a different type of self-monitoring (two studies, 43 women); self-monitoring at home versus hospitalisation (one study, 100 women), pre-prandial versus post-prandial glucose monitoring (one study, 61 women), automated telemedicine monitoring versus conventional system (three studies, 84 women), and constant CGM versus intermittent CGM (one study, 25 women), it is uncertain whether any of the interventions has any impact on any of our GRADE outcomes (hypertensive disorders of pregnancy, caesarean section, large-for-gestational age) because the quality of the evidence was found to be very low. This was due to evidence largely being derived from single trials, with design limitations and limitations with imprecision (wide CIs, small sample sizes, and few events). There was not enough evidence to assess perinatal mortality and neonatal mortality and morbidity composite. Other important outcomes, such as neurosensory disability, were not reported in any of these comparisons. Two new studies (406 women) have been incorporated to one of the comparisons for this update. Although the evidence suggests that CGM in comparison to intermittent glucose monitoring may reduce hypertensive disorders of pregnancy, this did not translate into a clear reduction for pre-eclampsia, and so this result should be viewed with caution. There was no evidence of a difference for other primary outcomes for this comparison. The evidence base for the effectiveness of other monitoring techniques analysed in the other five comparisons is weak and based on mainly single studies with very low-quality evidence. Additional evidence from large well-designed randomised trials is required to inform choices of other glucose monitoring techniques and to confirm the effectiveness of CGM.

This is an update of a review first published in 2014, updated in 2017. We searched for evidence from randomised controlled studies in November 2018. We identified 12 studies involving 944 women (type 1 diabetes: 660 women; type 2 diabetes: 113 women; in two trials (171 women) there was a mix of type 1 and type 2 diabetes. The trials were from Europe, USA and Canada. There were six comparisons. These were: continuous versus intermittent monitoring of blood glucose (four studies, 609 women); two different ways of self-monitoring (two studies, 43 women); self-monitoring at home versus hospitalisation to control blood glucose levels (one study, 100 women); blood glucose monitoring before a meal (pre-prandial) versus blood glucose monitoring after a meal (post-prandial) (one study, 61 women); automated telemedicine monitoring versus conventional care (three studies, 84 women); and constant continuous monitoring versus intermittent continuous monitoring (one study, 25 women), Continuous versus intermittent monitoring may reduce overall high blood pressure problems during pregnancy (two studies, 384 women, low-quality evidence). However, it should be noted that only two of four relevant studies reported data for this outcome. There was more evidence on high blood pressure and protein in their urine (pre-eclampsia), which showed no clear difference (four studies, 609 women). We also found no difference in the number of women having a caesarean section (three studies, 427 women; moderate-quality evidence). There was not enough evidence to assess infant deaths or the combined outcome of infant deaths and ill-health as these outcomes were based on single studies. Four studies received some support from commercial partners. The other comparisons of different ways of monitoring blood glucose levels were based on very small studies or single studies with very low-quality evidence that did not show any clear differences in outcomes. Although the evidence from randomised controlled studies suggests that continuous monitoring of blood glucose levels may be more effective in reducing high blood pressure problems during pregnancy, only two studies reported on this. There was no clear reduction for pre-eclampsia based on evidence from four studies. For other methods of glucose monitoring, the review showed that there is not enough evidence to say with any certainty which monitoring method for blood glucose is best. More research is needed to find out which other monitoring method is best at reducing the risk of complications for pregnant women with pre-existing diabetes and to confirm the effectiveness of continuous glucose monitoring.

10.1002/14651858.CD009613.pub4

cochrane-simplification-train-2941

cochrane-simplification-train-2941

Four trials involving 1873 participants, heterogeneous with respect to aetiology of ED, were included. Study design was two cross-over and two parallel group trials. Only the latter provided adequate data for meta-analyses. PGE1 was effective during follow-up in the "at least one successful intercourse" outcome (Peto Odds Ratio, OR 7.22, 95% CI. 5.68-9.18) . One cross-over study reported "at least one successful intercourse" in 63.6% of participants with at least one dose of PGE1 (P < 0.01 for each active dose versus placebo). In the other cross-over study, only one of three treatment groups conducted a self-evaluation (55.5%: "good" or "excellent" response). Adverse effects were most frequent in the treated groups and occurred more often and intensely as doses increased. Penile pain (Peto OR 7.39, 95% CI. 5.40-10.12) and minor urethral trauma (Peto OR 3.79, 95% CI. 1.88-7.65) were predominant. PGE1 was beneficial for many participants with ED of different aetiology. Adverse effects were proportional to dosage, albeit never serious. The use of PGE1 in ED could have been better interpreted if its effectiveness were compared by aetiology and with different forms of administrations, a longer follow-up were considered and more emphasis given to patient/partner relationships and quality of life.

The review of trials found that men using PGE1 reported more satisfactory sexual experiences. Higher doses gave greater benefits but also increased the adverse effects. The most common adverse effect is some pain, and men may prefer the urethral medication rather than injections.

10.1002/14651858.CD001784.pub2

cochrane-simplification-train-2942

cochrane-simplification-train-2942

Eleven studies met our inclusion criteria. Two studies did not report any outcome data relevant to the review, so the results of the review are based on nine trials that contributed data. Primary outcomes were perinatal mortality, serious maternal or infant outcomes, adverse drug reactions, birth before 48 hours of trial entry, birth before 34 weeks' gestation and preterm neonates delivered without a full course of antenatal steroids completed 24 hours before birth. The quality of evidence in included trials was mixed; only three of the trials were placebo controlled. The included trials examined seven different comparisons: intravenous (IV) ritodrine plus oral or IV magnesium (sulphate or gluconate) versus IV ritodrine alone (three trials, 231 women); IV ritodrine plus indomethacin suppositories versus IV ritodrine alone (one trial, 208 women); IV ritodrine plus vaginal progesterone versus IV ritodrine alone (one trial, 83 women); IV hexoprenaline sulphate plus IV magnesium hydrochloride versus IV hexoprenaline sulphate alone (one trial, 24 women); IV fenoterol plus oral naproxen versus IV fenoterol alone (one trial, 72 women); oral pentoxifylline plus IV magnesium sulphate plus IV fenoterol versus IV magnesium sulphate plus IV fenoterol (one trial, 125 women); and, IV terbutaline plus oral metoprolol versus IV terbutaline alone (one trial, 17 women). Few studies with small numbers of women were available for each comparison, hence very little data were pooled in meta-analysis. In all trials, not many of the primary outcomes were reported. Three trials examined intravenous (IV) ritodrine plus IV or oral magnesium (sulphate or gluconate) compared with IV ritodrine alone. One study, with 41 women, reported more adverse drug reactions in the group receiving the combined tocolytics (risk ratio (RR) 7.79, 95% confidence interval (CI) 1.11 to 54.80). Two trials reported discontinuation of therapy due to severe side effects (results were not combined due to high statistical heterogeneity, I² = 83%); one trial reported increased severe side effects in the group receiving IV ritodrine alone (RR 7.79, 95% CI 1.11 to 54.80, 41 women); in the other trial there was no clear difference between groups (RR 0.23, 95% CI 0.03 to 1.97, 107 women). Other primary outcomes were not reported. One trial assessed IV ritodrine plus indomethacin suppositories versus IV ritodrine alone. There were no significant differences between groups for perinatal mortality or serious neonatal morbidity. Results for other primary outcomes were not reported. There were no significant differences between groups receiving IV ritodrine plus vaginal progesterone compared with IV ritodrine alone for most outcomes reported, although the latency period (time from recruitment to delivery) was increased in the group receiving the combination of tocolytics. For other combinations of tocolytic agents, primary outcomes were rarely reported and for secondary outcomes results did not demonstrate differences between groups. It is unclear whether a combination of tocolytic drugs for preterm labour is more advantageous for women and/or newborns due to a lack of large, well-designed trials including the outcomes of interest. There are no trials of combination regimens using widely used tocolytic agents, such as calcium channel blockers (nifedipine) and/or oxytocin receptor antagonists (atosiban). Further trials are needed before specific conclusions on use of combination tocolytic therapy for preterm labour can be made.

Three trials examined the betamimetic drug ritodrine plus magnesium compared with ritodrine alone. The trials reported on adverse side effects, with inconsistency between the trials as to which treatment gave fewer severe side effects. Other outcomes were either not reported or not clearly different between treatment groups. One trial looked at ritodrine plus indomethacin versus ritodrine alone. There were no clear differences between groups for serious newborn ill health. Results for other outcomes were not clearly different. There were no clear differences between groups receiving ritodrine plus progesterone compared with ritodrine alone for most outcomes reported, although the time between giving the drugs and the birth was increased in the group receiving the combination of tocolytics. For other combinations of tocolytic agents, results did not demonstrate differences between groups. There were no trials of combination regimens using widely used tocolytic agents, such as calcium channel blockers (nifedipine) and oxytocin receptor antagonists (atosiban). Due to insufficient evidence, it is unclear if combination tocolytic regimens are more or less effective than using a single tocolytic drug, or if they have more adverse effects. Some widely used tocolytic drugs have not been examined in trials as part of combination regimens, so further research is needed.

10.1002/14651858.CD006169.pub2

cochrane-simplification-train-2943

cochrane-simplification-train-2943

We found four relevant studies providing data for 1809 employees, 60% of whom were allocated to the intervention group. All studies assessed outcomes immediately after the intervention had finished and the intervention duration varied between three to six months. All studies had usual treatment control conditions; however one study's usual treatment was an alternative physical activity programme while the other three had minimally active controls. In general, there was high risk of bias mainly due to lack of blinding, self reported outcome measurement, incomplete outcome data due to attrition, and most of the studies had not published protocols, which increases the likelihood of selective reporting. Three studies compared the pedometer programme to a minimally active control group, but the results for physical activity could not be combined because each study used a different measure of activity. One study observed an increase in physical activity under a pedometer programme, but the other two did not find a significant difference. For secondary outcomes we found improvements in body mass index, waist circumference, fasting plasma glucose, the quality of life mental component and worksite injury associated with the pedometer programmes, but these results were based on limited data from one or two small studies. There were no differences between the pedometer programme and the control group for blood pressure, a number of biochemical outcomes and the quality of life physical component. Sedentary behaviour and disease risk scores were not measured by any of the included studies. One study compared a pedometer programme and an alternative physical activity programme, but baseline imbalances made it difficult to distinguish the true improvements associated with either programme. Overall, there was insufficient evidence to assess the effectiveness of pedometer interventions in the workplace. There is a need for more high quality randomised controlled trials to assess the effectiveness of pedometer interventions in the workplace for increasing physical activity and improving subsequent health outcomes. To improve the quality of the evidence available, future studies should be registered in an online trials register, publish a protocol, allocate time and financial support to reducing attrition, and try to blind personnel (especially those who undertake measurement). To better identify the effects of pedometer interventions, future studies should report a core set of outcomes (total physical activity in METs, total time sitting in hours and minutes, objectively measured cardiovascular disease and type II diabetes risk factors, quality of life and injury), assess outcomes in the long term and undertake subgroup analyses based upon demographic subgroups (e.g. age, gender, educational status). Future studies should also compare different types of active intervention to test specific intervention components (eligibility, duration, step goal, step diary, settings), and settings (occupation, intervention provider). There was limited and low quality data providing insufficient evidence to assess the effectiveness of pedometer interventions in the workplace for increasing physical activity and improving subsequent health outcomes.

To assess this, we searched for randomised controlled trials of workplace health promotion interventions that involved the use of a pedometer undertaken in employed adults. Between 30th January and 6th February 2012 we searched a range of electronic libraries and references of relevant papers, retrieving 3282 potential papers. We eventually included four studies in the review. One study compared pedometer programmes with an alternative physical activity programme, but there were important baseline differences between the intervention and control groups that made it difficult to distinguish the true effect. The three remaining studies compared pedometer programmes with minimally active control groups. One study observed an improvement in physical activity in the pedometer programme, but two other studies found no significant difference between the pedometer group and the control group. We could not combine these results together, as each study used a different measure for physical activity, so it is not clear what the overall effect is. Single studies found beneficial changes in body mass index, fasting plasma glucose, the mental component of quality of life and worksite injury associated with the pedometer programmes as opposed to the control group. However, none of the studies identified consistent differences between the pedometer programme and the control group for waist circumference, blood pressure and quality of life outcomes. In addition, we judged the majority of included studies to have a high risk of bias, mainly due to participants and staff knowing who was in the intervention and who was in the control group, attrition of participants and not having published a protocol prior to running the study. We conclude that there was insufficient evidence to assess whether workplace pedometer interventions are of benefit. There is a need for further high quality randomised controlled trials to be undertaken with a range of health outcomes and assessment in the long term.

10.1002/14651858.CD009209.pub2

cochrane-simplification-train-2944

cochrane-simplification-train-2944

We identified 3745 citations through electronic searches and reviews of reference lists after deduplication of search results. We excluded 3619 records during title and abstract review and assessed 126 full-text papers for inclusion in the review. Only one study, providing data of 225 participants, met our eligibility criteria and compared agomelatine (25 mg/day) with placebo. We rated it as having high risk of attrition bias because nearly half of the participants left the study before completion. We rated the certainty of the evidence as very low for all outcomes, because of high risk of bias, indirectness, and imprecision. The main analysis based on data of 199 participants rendered an indeterminate result with wide confidence intervals (CIs) that may encompass both a relevant reduction as well as a relevant increase of SAD incidence by agomelatine (risk ratio (RR) 0.83, 95% CI 0.51 to 1.34; 199 participants; very low-certainty evidence). Also the severity of SAD may be similar in both groups at the end of the study with a mean SIGH-SAD (Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders) score of 8.3 (standard deviation (SD) 9.4) in the agomelatine group and 10.1 (SD 10.6) in the placebo group (mean difference (MD) -1.80, 95% CI -4.58 to 0.98; 199 participants; very low-certainty evidence). The incidence of adverse events and serious adverse events may be similar in both groups. In the agomelatine group, 64 out of 112 participants experienced at least one adverse event, while 61 out of 113 did in the placebo group (RR 1.06, 95% CI 0.84 to 1.34; 225 participants; very low-certainty evidence). Three out of 112 patients experienced serious adverse events in the agomelatine group, compared to 4 out of 113 in the placebo group (RR 0.76, 95% CI 0.17 to 3.30; 225 participants; very low-certainty evidence). No data on quality of life or interpersonal functioning were reported. We did not identify any studies on melatonin. Given the uncertain evidence on agomelatine and the absence of studies on melatonin, no conclusion about efficacy and safety of agomelatine and melatonin for prevention of SAD can currently be drawn. The decision for or against initiating preventive treatment of SAD and the treatment selected should consider patient preferences and reflect on the evidence base of all available treatment options.

The included study showed neither a clear effect in favour nor against agomelatine as a preventive treatment. In addition, the certainty of evidence for all outcomes was very low, making it impossible to draw any conclusions about the efficacy and safety of agomelatine for the prevention of winter depression. No evidence on melatonin for prevention of SAD was identified. Doctors need to discuss with persons with a history of SAD that currently evidence on agomelatine or melatonin for preventive treatment options for SAD is inconclusive, therefore treatment selection should be strongly based on peoples' preferences and reflect on the evidence base of all available treatment options. Review authors recommend that future studies should evaluate the efficacy of agomelatine or melatonin in preventing SAD and should directly compare these interventions against other treatment options, such as light therapy, antidepressants, or psychological therapies to determine the best treatment option for prevention of SAD.

10.1002/14651858.CD011271.pub3

cochrane-simplification-train-2945

cochrane-simplification-train-2945

We identified RCTs for the eight cardioprotective agents N-acetylcysteine, phenethylamines, coenzyme Q10, a combination of vitamins E and C and N-acetylcysteine, L-carnitine, carvedilol, amifostine and dexrazoxane (mostly for adults with advanced breast cancer). All studies had methodological limitations and for the first seven agents there were too few studies to allow pooling of results. None of the individual studies showed a cardioprotective effect. The 10 included studies on dexrazoxane enrolled 1619 patients. The meta-analysis for dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (risk ratio (RR) 0.29, 95% CI 0.20 to 0.41). No evidence was found for a difference in response rate or survival between the dexrazoxane and control groups. The results for adverse effects were ambiguous. No significant difference in the occurrence of secondary malignancies was identified. No definitive conclusions can be made about the efficacy of cardioprotective agents for which pooling of results was impossible. Dexrazoxane prevents heart damage and no evidence for a difference in response rate or survival between the dexrazoxane and control groups was identified. The evidence available did not allow us to reach any definite conclusions about adverse effects. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects for each individual patient.

Certain drugs might prevent this damage, but for many of these drugs, the review authors found no high quality evidence about whether they were effective in protecting the heart and they were unable to draw conclusions. For dexrazoxane, the review authors found 10 studies enrolling over 1600 patients. These studies provided evidence that dexrazoxane prevented heart damage without interfering with the anti-tumour effects of anthracycline treatment. Patients who got dexrazoxane with their anthracycline treatment had about one third of the risk of heart failure compared to patients who got anthracyclines without dexrazoxane. Dexrazoxane had no effect on survival. We can't be sure about whether it had any undesirable side effects.

10.1002/14651858.CD003917.pub4

cochrane-simplification-train-2946

cochrane-simplification-train-2946

Findings were based on the results of a single study with some design limitations. Data were available from one study involving 162 women with a multiple pregnancy. For the only reported primary outcome, perinatal mortality, we are uncertain whether specialised antenatal clinics makes any difference compared to standard care (risk ratio (RR) 1.02; 95% confidence interval (CI) 0.26 to 4.03; 324 infants, very low quality evidence). Women receiving specialised antenatal care were significantly more likely to birth by caesarean section (RR 1.38; 95% CI 1.06 to 1.81; 162 women, moderate quality evidence). Data were not reported in the study on the following primary outcomes: small-for-gestational age, very preterm birth or maternal death. There were no differences identified between specialised antenatal care and standard care for other secondary outcomes examined: postnatal depression (RR 0.48; 95% CI 0.19 to 1.20; 133 women, very low quality evidence), breastfeeding (RR 0.63; 95% CI 0.24 to 1.68; 123 women, very low quality evidence), stillbirth (RR 0.68; 0.12 to 4.04) or neonatal death (RR 2.05; 95% CI 0.19 to 22.39) (324 infants). There is currently limited information available from randomised controlled trials to assess the role of 'specialised' antenatal clinics for women with a multiple pregnancy compared with 'standard' antenatal care in improving maternal and infant health outcomes. The value of 'specialised' multiple pregnancy clinics in improving health outcomes for women and their infants requires evaluation in appropriately powered and designed randomised controlled trials.

We found one small study involving 162 women and their babies (searched date 31 May 2015). The quality of the study was very low to moderate for our outcomes. The study was too small to provide answers to our question as we were most interested in the chance of the babies being born too early, their health and whether they survived. We did find that mothers with multiple pregnancies were more likely to have a caesarean birth if they attended specialised multiple pregnancy clinics. There is insufficient good quality evidence to support the use of specialised clinics for women with multiple pregnancies. There is an urgent need for more good quality studies to answer this important question. A visual summary of some of the results from this review can be found here (on screen version) or here (for a printable version).

10.1002/14651858.CD005300.pub4

cochrane-simplification-train-2947

cochrane-simplification-train-2947

The searches identified two multicentre, randomized, double-blind controlled clinical trials eligible for inclusion in the review with a total of 78 participants (adults and children); one trial was done in people who were clinically stable, the other in people experiencing pulmonary exacerbations. These trials prospectively assessed whether the use of biofilm antimicrobial susceptibility testing improved microbiological and clinical outcomes in participants with cystic fibrosis who were infected with Pseudomonas aeruginosa. The primary outcome was the change in sputum Pseudomonas aeruginosa density from the beginning to the end of antibiotic therapy. Although the intervention was shown to be safe, the data from these two trials did not provide evidence that biofilm susceptibility testing was superior to conventional susceptibility testing either in terms of microbiological or lung function outcomes. One of the trials also measured risk and time to subsequent exacerbation as well as quality of life measures and did not demonstrate any difference between groups in these outcomes. Both trials had an overall low risk of bias and the quality of the evidence using GRADE criteria was deemed to be moderate to high for the outcomes selected. The current evidence is insufficient to recommend choosing antibiotics based on biofilm antimicrobial susceptibility testing rather than conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infections in people with cystic fibrosis. Biofilm antimicrobial susceptibility testing may be more appropriate in the development of newer, more effective formulations of drugs which can then be tested in clinical trials.

We included two trials, one run in the USA (in people who were clinically stable) and one run in Canada (in people who were having an exacerbation or respiratory flare up). A total of 78 people from these trials gave sputum samples. Bacteria from these samples were grown in either a liquid (34 samples) or biofilm (44 samples) with an equal chance of being grown in either one. Neither the individuals or their clinicians knew before or during the trial which method had been used for the sample from each person. A mixture of adults and children took part in the trials, with the average age being around 20 to 30 years. There were an equal number of men and women in both trials. Around half the people in the trials had two copies of the delta F508 gene and there were almost equal number of these in each group. Average lung function in both groups was similar. The main outcome of both trials was the decrease in the amount of bacteria in the sputum of people in each group after antibiotic treatment. There was no difference in the levels of bacteria found in the sputum or in the improvement in lung function between the two groups in either trial. In both trials, there was a similar number of individuals in each group who had either a mild or moderate side effect. There were no serious side effects reported by anyone in either study. The evidence does not show that one method of testing is better than the other and that people receiving antibiotics chosen on the basis of either method have equal chances of any side effects. The quality of the evidence was quite good as people had equal chances of being in either group and they did not know which testing group they were in. This means we don't think the trial results would have been affected because of this.

10.1002/14651858.CD009528.pub4

cochrane-simplification-train-2948

cochrane-simplification-train-2948

We included 10 randomised clinical trials with 474 participants. The trials compared terlipressin versus noradrenaline (seven trials), octreotide (one trial), midodrine and octreotide (one trial), or dopamine (one trial). All participants in both groups received albumin as cointervention. We classified two trials at low risk of bias and eight trials at high risk of bias in the assessment of mortality and all trials at high risk of bias for remaining outcomes. In five trials, investigators specifically stated that they did not receive funding from for-profit organisations. We had no information about the funding source from the remaining five trials. Terlipressin was not superior or inferior compared with other vasoactive drugs in regard to mortality when including the two trials with a low risk of bias (RR 0.92, 95% CI 0.63 to 1.36; 94 participants, very low quality evidence) or when including all 10 trials (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). One meta-analysis including nine trials suggested a beneficial effect of terlipressin on hepatorenal syndrome (RR 0.79, 95% CI 0.63 to 0.99; 394 participants; I² = 26%; very low quality evidence). Due to the high mortality of hepatorenal syndrome, the registration of other serious adverse events is uncertain, but comparing terlipressin and other vasoactive drugs we found no significant difference (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). Several trials did not report systematically of adverse events, but terlipressin seemed to increase the risks of diarrhoea or abdominal pain, or both (RR 3.50, 95% CI 1.19 to 10.27; 221 participants; 5 trials, I² = 0%). However, Trial Sequential Analyses found insufficient evidence to support or refute any differences between interventions for all outcomes. Considering reversal of hepatorenal syndrome, subgroup analyses on the type of other vasoactive drugs found that terlipressin was superior compared with midodrine and octreotide (RR 0.47, 95% CI 0.30 to 0.72) or octreotide alone (RR 0.56, 95% CI 0.33 to 0.96), but each subgroup only included one small trial. None of the remaining subgroup or sensitivity analyses found differences between terlipressin and other vasoactive drugs. We downgraded the evidence to very low quality because of the high risk of bias, imprecision, and the results of the Trial Sequential Analyses. This review found insufficient evidence to support or refute beneficial or harmful effects of terlipressin and albumin versus other vasoactive drugs and albumin. Additional research is needed to evaluate if clinically meaningful differences exist between interventions.

We included 10 clinical trials with 474 participants. Seven trials compared terlipressin and albumin versus noradrenaline and albumin. The remaining three trials compared terlipressin and albumin versus midodrine and octreotide, or octreotide alone, or dopamine. In total, 241 participants received terlipressin and 233 participants received other vasoactive drugs (drugs that change blood pressure; noradrenaline, octreotide, midodrine, or dopamine). In five trials, investigators specifically stated that they did not receive funding from organisations that could profit from the trial results. We did not have information about the funding source from the remaining five trials. Our analyses found uncertain evidence to support or refute terlipressin versus other vasoactive drugs in the treatment of hepatorenal syndrome when evaluating mortality or serious side effects. Our analyses suggested that treatment with terlipressin may have a beneficial effect on hepatorenal syndrome by reducing the number of participants with persistent hepatorenal syndrome. Additional analyses showed that the number of participants in the trials was too small for us to be sure about this. Accordingly, we found that important differences between terlipressin and other vasoactive drugs may be overlooked. We found that the evidence was of very low quality due to the high risk of bias and the small number of participants. We need additional large trials of a high quality to evaluate if terlipressin is more beneficial or safer than other vasoactive drugs.

10.1002/14651858.CD011532.pub2

cochrane-simplification-train-2949

cochrane-simplification-train-2949

Three small RCTs met our inclusion criteria and included a total of 148 participants. These compared three treatments with topical phenytoin: hydrocolloid dressings, triple antibiotic ointment and simple dressings. In the three RCTs, 79% of participants had grade II ulcers, and 21% of participants had grade I ulcers; no participants had grade III or IV ulcers. Two RCTs had a high risk of bias overall and the other RCT was at unclear risk of bias due to poor reporting. Two RCTs had three intervention arms and the other had two intervention arms. Two studies compared topical phenytoin with hydrocolloid dressing (84 participants analysed). The available data suggest that hydrocolloid dressings may improve ulcer healing compared to topical phenytoin (39.3% ulcers healed for phenytoin versus 71.4% ulcers healed for hydrocolloid dressings (RR 0.55, 95% CI 0.33 to 0.92; 56 participants, 1 study; low quality evidence). We downgraded the evidence twice: once due to serious limitations (high risk of bias) and once due to the small sample size and small number of events. Two studies compared topical phenytoin with simple dressings (81 participants analysed). From the available data, we are uncertain whether topical phenytoin improves ulcer healing compared to simple dressings (39.3% ulcers healed for phenytoin versus 29.6% ulcers healed for the simple dressing (RR 1.33, 95% CI 0.63 to 2.78; 55 participants, 1 study; very low quality evidence). This evidence was downgraded once due to serious limitations (high risk of bias) and twice due to the low number of outcome events and resulting wide CI which included the possibility of both increased healing and reduced healing. We therefore considered it to be insufficient to determine the effect of topical phenytoin on ulcer healing. One study compared topical phenytoin with triple antibiotic ointment, however, none of the outcomes of interest to this review were reported. No adverse drug reactions or interactions were detected in any of the three RCTs. Minimal pain was reported in all groups in one trial that compared topical phenytoin with hydrocolloid dressings and triple antibiotic ointment. This review has considered the available evidence and the result shows that it is uncertain whether topical phenytoin improves ulcer healing for patients with grade I and II pressure ulcers. No adverse events were reported from three small trials and minimal pain was reported in one trial. Therefore, further rigorous, adequately powered RCTs examining the effects of topical phenytoin for treating pressure ulcers, and to report on adverse events, quality of life and costs are necessary.

In September 2016 we searched for randomised controlled trials (RCTs) that compared topical phenytoin against other treatments for treating pressure ulcers. We found three small RCTs that included a total of 148 people with pressure ulcers. The average age of participants in two studies was 45 years and 75 years in one study. Twenty-one per cent of participants had grade I ulcers (the least severe type, with swollen but unbroken skin) and 79% had grade II ulcers (slightly more severe). No one had grade III or IV ulcers (the most severe types). The trials compared topical phenytoin with three other treatments for pressure ulcers: hydrocolloid dressings, triple antibiotic ointment, and simple dressings. The results of one study suggested that hydrocolloid dressings may slightly improve ulcer healing compared to topical phenytoin. However, we are uncertain whether topical phenytoin improves ulcer healing compared to simple dressings. The study which compared topical phenytoin with triple antibiotic ointment did not report any outcomes of interest to this review. It is uncertain whether topical phenytoin improves ulcer healing for patients with grade I and II pressure ulcers. No adverse events were reported from three small trials and minimal pain was reported in one trial. The trials did not report on some other measurements that we were interested in, such as cost of treatment and quality of life. Two RCTs had a high risk of bias overall, which might have affected the results, and another RCT did not report sufficient details about how it was conducted. Further rigorous, adequately powered RCTs are needed to find whether topical phenytoin is a helpful medication for treating pressure ulcers. This plain language summary is up to date as of September 2016.

10.1002/14651858.CD008251.pub2

cochrane-simplification-train-2950

cochrane-simplification-train-2950

We included 12 trials with 798 participants undergoing elective laparoscopic cholecystectomy randomised to different methods of intraperitoneal local anaesthetic instillation. All the trials were at high risk of bias. Most trials included only people with low anaesthetic risk. The comparisons included in the trials that met the eligibility criteria were the following; comparison of one local anaesthetic agent with another local anaesthetic agent (three trials); comparison of timing of delivery (six trials); comparison of different methods of delivery of the anaesthetic agent (two trials); comparison of location of the instillation of the anaesthetic agent (one trial); three trials reported mortality and morbidity. There were no mortalities or serious adverse events in either group in the following comparisons: bupivacaine (0/100 (0%)) versus lignocaine (0/106 (0%)) (one trial; 206 participants); just after creation of pneumoperitoneum (0/55 (0%)) versus end of surgery (0/55 (0%)) (two trials; 110 participants); just after creation of pneumoperitoneum (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (one trial; 30 participants); end of surgery (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (one trial; 30 participants). None of the trials reported quality of life, the time taken to return to normal activity, or the time taken to return to work. The differences in the proportion of people who were discharged as day-surgery and the length of hospital stay were imprecise in all the comparisons included that reported these outcomes (very low quality evidence). There were some differences in the pain scores on the visual analogue scale (1 to 10 cm) but these were neither consistent nor robust to fixed-effect versus random-effects meta-analysis or sensitivity analysis. The currently available evidence is inadequate to determine the effects of one method of local anaesthetic intraperitoneal instillation compared with any other method of local anaesthetic intraperitoneal instillation in low anaesthetic risk individuals undergoing elective laparoscopic cholecystectomy. Further randomised clinical trials of low risk of systematic and random errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their assessment.

We identified 12 randomised clinical trials involving 798 people undergoing planned laparoscopic cholecystectomy. The trials compared different methods addressing the various controversies mentioned above. The choice of the method of administration of the local anaesthetic was determined by a method similar to the toss of a coin so that the treatments compared were conducted in participants who were as similar as possible. There were no deaths or serious complications in either group in the comparisons that reported these. None of the trials reported quality of life, the time taken to return to normal activity, or the time taken to return to work. The differences in hospital stay between the methods being compared was imprecise in all the comparisons that reported hospital stay. Although there were some differences in the pain scores on the visual analogue scale (a chart that rates the amount of pain on a scale of 1 to 10 cm), these differences were neither consistent nor robust to different methods of statistical analysis. The evidence currently available is inadequate to determine the effects of one method of local anaesthetic intraperitoneal instillation compared with any other method of local anaesthetic intraperitoneal instillation in low anaesthetic risk individuals undergoing elective laparoscopic cholecystectomy. Most of the trials were of high risk of bias, that is, there is possibility of arriving at wrong conclusions overestimating benefits or underestimating harms of one method or the other because of the way that the study was conducted. The overall quality of evidence was very low. Further trials are necessary. Such trials should include outcomes such as quality of life, the time taken to return to normal activity, and the time taken to return to work, which are important for the person undergoing the procedure and the people who provide funds for the treatment.

10.1002/14651858.CD009060.pub2

cochrane-simplification-train-2951

cochrane-simplification-train-2951

We identified eight eligible trials (236 participants), which tested intravenous immunoglobulin (IVIg), interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Two trials of IVIg (22 and 11 participants, including 20 with antibodies against MAG), had comparable interventions and outcomes, but both were short-term trials. We also included two trials of rituximab with comparable interventions and outcomes. There were very few clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial and more responsive outcomes are being developed. A well-performed trial of IVIg, which was at low risk of bias, showed a statistical benefit in terms of improvement in mRS at two weeks and 10-metre walk time at four weeks, but these short-term outcomes are of questionable clinical significance. Cyclophosphamide failed to show any benefit in the single trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. Two trials of rituximab (80 participants) have been published, one of which (26 participants) was at high risk of bias. In the meta-analysis, although the data are of low quality, rituximab is beneficial in improving disability scales (Inflammatory Neuropathy Cause and Treatment (INCAT) improved at eight to 12 months (risk ratio (RR) 3.51, 95% confidence interval (CI) 1.30 to 9.45; 73 participants)) and significantly more participants improve in the global impression of change score (RR 1.86, 95% CI 1.27 to 2.71; 70 participants). Other measures did not improve significantly, but wide CIs do not preclude some effect. Reported adverse effects of rituximab were few, and mostly minor. There were few serious adverse events in the other trials. There is inadequate reliable evidence from trials of immunotherapies in anti-MAG paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. IVIg has a statistically but probably not clinically significant benefit in the short term. The meta-analysis of two trials of rituximab provides, however, low-quality evidence of a benefit from this agent. The conclusions of this meta-analysis await confirmation, as one of the two included studies is of very low quality. We require large well-designed randomised trials of at least 12 months' duration to assess existing or novel therapies, preferably employing unified, consistent, well-designed, responsive, and valid outcome measures.

Many of these therapies have been tried in non-randomised studies, but we found only eight small randomised controlled trials (RCTs), involving 236 participants, that met our criteria for inclusion. Two trials with 22 and 11 participants (20 with antibodies against MAG) suggest that IVIg may sometimes produce short-term measurable benefit and is relatively safe, but the benefit is of doubtful clinical significance. No severe adverse effects related to IVIg were reported in these trials. A trial of cyclophosphamide and corticosteroids showed some mild benefit. Two trials of rituximab demonstrated a positive benefit of rituximab, but this evidence was of low quality because of small numbers of participants and concerns about the design of one of the two studies. Reported adverse effects of rituximab were few, and mostly minor. Other trials did not allow us to draw conclusions about the efficacy of other agents and reported few serious adverse events. We need large, well-designed RCTs to assess the efficacy of the existing and new therapies, and better ways for doctors and researchers to detect changes that people report in response to treatments. The evidence is up to date to February 2016.

10.1002/14651858.CD002827.pub4

cochrane-simplification-train-2952

cochrane-simplification-train-2952

We included 12 studies randomising 310 patients, with data available for 266 patients after dropout. All but one study evaluated a fixed concentration of low dialysate [Na+], and one profiled dialysate [Na+]. Three studies were parallel group, and the remaining nine cross-over. Of the latter, only two used a washout between intervention and control periods. Most studies were short-term with a median (interquartile range) follow-up of 3 (3, 8.5) weeks. Two were of a single HD session, and two of a single week's HD. Half of the studies were conducted prior to 2000, and five reported use of obsolete HD practices. Risks of bias in the included studies were often high or unclear, lowering confidence in the results. Compared to neutral or high dialysate [Na+], low dialysate [Na+] had the following effects on "efficacy" endpoints: reduced interdialytic weight gain (10 studies: MD -0.35 kg, 95% CI -0.18 to -0.51; high certainty evidence); probably reduced predialysis mean arterial blood pressure (BP) (4 studies: MD -3.58 mmHg, 95% CI -5.46 to -1.69; moderate certainty evidence); probably reduced postdialysis mean arterial BP (MAP) (4 studies: MD -3.26 mmHg, 95% CI -1.70 to -4.82; moderate certainty evidence); probably reduced predialysis serum [Na+] (7 studies: MD -1.69 mM, 95% CI -2.36 to -1.02; moderate certainty evidence); may have reduced antihypertensive medication (2 studies: SMD -0.67 SD, 95% CI -1.07 to -0.28; low certainty evidence). Compared to neutral or high dialysate [Na+], low dialysate [Na+] had the following effects on "safety" endpoints: probably increased intradialytic hypotension events (9 studies: RR 1.56, 95% 1.17 to 2.07; moderate certainty evidence); probably increased intradialytic cramps (6 studies: RR 1.77, 95% 1.15 to 2.73; moderate certainty evidence). Compared to neutral or high dialysate [Na+], low dialysate [Na+] may make little or no difference to: intradialytic BP (2 studies: MD for systolic BP -3.99 mmHg, 95% CI -17.96 to 9.99; diastolic BP 1.33 mmHg, 95% CI -6.29 to 8.95; low certainty evidence); interdialytic BP (2 studies:, MD for systolic BP 0.17 mmHg, 95% CI -5.42 to 5.08; diastolic BP -2.00 mmHg, 95% CI -4.84 to 0.84; low certainty evidence); dietary salt intake (2 studies: MD -0.21g/d, 95% CI -0.48 to 0.06; low certainty evidence). Due to very low quality of evidence, it is uncertain whether low dialysate [Na+] changed extracellular fluid status, venous tone, arterial vascular resistance, left ventricular mass or volumes, thirst or fatigue. Studies did not examine cardiovascular or all-cause mortality, cardiovascular events, or hospitalisation. It is likely that low dialysate [Na+] reduces intradialytic weight gain and BP, which are effects directionally associated with improved outcomes. However, the intervention probably also increases intradialytic hypotension and reduces serum [Na+], effects that are associated with increased mortality risk. The effect of the intervention on overall patient health and well-being is unknown. Further evidence is needed in the form of longer-term studies in contemporary settings, evaluating end-organ effects in small-scale mechanistic studies using optimal methods, and clinical outcomes in large-scale multicentre RCTs.

We found 12 studies comparing low sodium levels in dialysis fluid with neutral or high sodium levels. Many studies were performed prior to 2000, studying technology and patients that are not always relevant today. Most were short-term studies, only lasting a few weeks. Our main findings in these studies were; that low sodium in dialysis fluid improves blood pressure and reduces gain of salt and water in between dialysis treatments, which are probably good things, but increases the number of cramps and low blood pressure events experienced by patients during dialysis, which are definitely bad things. The studies did not provide enough information about the participating patients for us to know which patients might benefit from low sodium dialysis fluid, and which patients might instead be harmed. The studies did not provide definitive information on the effect of low sodium dialysis fluids on heart structure and function, or patient quality of life and survival. We are uncertain about whether low sodium in dialysis fluid improves overall health and well-being for people on haemodialysis, since there are a mixture of probably good and bad effects, and available research studies were not designed (or designed well-enough) to learn about effects of the intervention on the heart or on overall patient health and well-being. Larger and up-to-date definitive studies are needed to evaluate the medium to long-term effects of low sodium levels in dialysis fluid, and better inform clinical practice.

10.1002/14651858.CD011204.pub2

cochrane-simplification-train-2953

cochrane-simplification-train-2953

We found few controlled trials. They were of short duration and enrolled small numbers of patients. Because of their poor internal validity, the characteristics of the populations studied, and the types of interventions and outcomes, none of the trials fitted our criteria for inclusion. However, all these trials found BtA to be superior to placebo as did large case-control and cohort studies, which reported that around 90% of patients benefited. There are no high quality, randomised, controlled efficacy data to support the use of Bt for blepharospasm. Despite this, other studies suggest that BtA is highly effective and safe for treating blepharospasm and support its use. The effect size (90% of patients benefit) seen in open studies makes it very difficult and probably unethical to perform new placebo-controlled trials of efficacy of BtA for blepharospasm. Future trials should explore technical factors such as the optimum treatment intervals, different injection techniques, doses, Bt types and formulations. Other issues include service delivery, quality of life, long-term efficacy, safety, and immunogenicity.

No randomised controlled trials with sufficient numbers of patients fitted the review criteria. Trials identified found BtA to be superior to placebo as did large case-control and cohort studies, with around 90% of patients benefiting. The most common adverse effects affected the eyes and were short lived.

10.1002/14651858.CD004900.pub2

cochrane-simplification-train-2954

cochrane-simplification-train-2954

We included 10 trials involving 1904 participants. The risk of bias was low in six studies. Four studies were open label and were rated as high risk of performance bias. One of these studies was also rated as high risk for attrition bias. Four trials reported on poor outcome (death, vegetative state, or severe disability) with a pooled risk ratio (RR) of 1.02 (95% confidence interval (CI) 0.91 to 1.15). All trials reported on death from all causes with a pooled RR of 1.00 (95% CI 0.85 to 1.18). In a trial that combined short-term antifibrinolytic treatment (< 72 hours) with preventative measures for cerebral ischaemia the RR for poor outcome was 0.85 (95% CI 0.64 to 1.14). Antifibrinolytic treatment reduced the risk of re-bleeding reported at the end of follow-up (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 participants), but there was heterogeneity (I² = 62%) between the trials. The pooled RR for reported cerebral ischaemia was 1.41 (95% CI 1.04 to 1.91, 83 per 1000 participants), again with heterogeneity between the trials (I² = 52%). Antifibrinolytic treatment showed no effect on the reported rate of hydrocephalus in five trials (RR 1.11, 95% CI 0.90 to 1.36). The current evidence does not support the use of antifibrinolytic drugs in the treatment of people with aneurysmal subarachnoid haemorrhage, even in those who have concomitant treatment strategies to prevent cerebral ischaemia. Results on short-term treatment are promising, but not conclusive. Further randomised trials evaluating short-term antifibrinolytic treatment are needed to evaluate its effectiveness.

This review included 10 trials, totaling 1904 participants that investigated the effect of these drugs in people with SAH. Antifibrinolytic treatment does indeed reduce the risk of rebleeding, but does not improve survival or the chance of being independent in everyday activities. This may be due to an increase in one of the other common complications of SAH. We conclude that antifibrinolytic treatment should not routinely be given to people with SAH, but new randomised trials are needed to establish if short-term treatment might be beneficial.

10.1002/14651858.CD001245.pub2

cochrane-simplification-train-2955

cochrane-simplification-train-2955

This update included 94 studies (62 new) with 9,821 participants. Most participants were women living in their own home. Most trials were judged at unclear risk of selection bias, generally reflecting inadequate reporting of the randomisation methods, but at high risk of performance bias relating to lack of participant blinding, which is largely unavoidable for these trials. Most studies only reported outcome up to the end of the exercise programme. There were eight categories of exercise programmes. These are listed below together with primary measures of balance for which there was some evidence of a statistically significant effect at the end of the exercise programme. Some trials tested more than one type of exercise. Crucially, the evidence for each outcome was generally from only a few of the trials for each exercise category. 1. Gait, balance, co-ordination and functional tasks (19 studies of which 10 provided primary outcome data): Timed Up & Go test (mean difference (MD) -0.82 s; 95% CI -1.56 to -0.08 s, 114 participants, 4 studies); walking speed (standardised mean difference (SMD) 0.43; 95% CI 0.11 to 0.75, 156 participants, 4 studies), and the Berg Balance Scale (MD 3.48 points; 95% CI 2.01 to 4.95 points, 145 participants, 4 studies). 2. Strengthening exercise (including resistance or power training) (21 studies of which 11 provided primary outcome data): Timed Up & Go Test (MD -4.30 s; 95% CI -7.60 to -1.00 s, 71 participants, 3 studies); standing on one leg for as long as possible with eyes closed (MD 1.64 s; 95% CI 0.97 to 2.31 s, 120 participants, 3 studies); and walking speed (SMD 0.25; 95% CI 0.05 to 0.46, 375 participants, 8 studies). 3. 3D (3 dimensional) exercise (including Tai Chi, qi gong, dance, yoga) (15 studies of which seven provided primary outcome data): Timed Up & Go Test (MD -1.30 s; 95% CI -2.40 to -0.20 s, 44 participants, 1 study); standing on one leg for as long as possible with eyes open (MD 9.60 s; 95% CI 6.64 to 12.56 s, 47 participants, 1 study), and with eyes closed (MD 2.21 s; 95% CI 0.69 to 3.73 s, 48 participants, 1 study); and the Berg Balance Scale (MD 1.06 points; 95% CI 0.37 to 1.76 points, 150 participants, 2 studies). 4. General physical activity (walking) (seven studies of which five provided primary outcome data). 5. General physical activity (cycling) (one study which provided data for walking speed). 6. Computerised balance training using visual feedback (two studies, neither of which provided primary outcome data). 7. Vibration platform used as intervention (three studies of which one provided primary outcome data). 8. Multiple exercise types (combinations of the above) (43 studies of which 29 provided data for one or more primary outcomes): Timed Up & Go Test (MD -1.63 s; 95% CI -2.28 to -0.98 s, 635 participants, 12 studies); standing on one leg for as long as possible with eyes open (MD 5.03 s; 95% CI 1.19 to 8.87 s, 545 participants, 9 studies), and with eyes closed ((MD 1.60 s; 95% CI -0.01 to 3.20 s, 176 participants, 2 studies); and the Berg Balance Scale ((MD 1.84 points; 95% CI 0.71 to 2.97 points, 80 participants, 2 studies). Few adverse events were reported but most studies did not monitor or report adverse events. In general, the more effective programmes ran three times a week for three months and involved dynamic exercise in standing. There is weak evidence that some types of exercise (gait, balance, co-ordination and functional tasks; strengthening exercise; 3D exercise and multiple exercise types) are moderately effective, immediately post intervention, in improving clinical balance outcomes in older people. Such interventions are probably safe. There is either no or insufficient evidence to draw any conclusions for general physical activity (walking or cycling) and exercise involving computerised balance programmes or vibration plates. Further high methodological quality research using core outcome measures and adequate surveillance is required.

This updated review includes 94 (62 new to this update) randomised controlled trials involving 9821 participants. Most participants were women living in their own home. Some studies included frail people residing in hospital or residential facilities. Many of the trials had flawed or poorly described methods that meant that their findings could be biased. Most studies only reported outcome up to the end of the exercise programme. Thus they did not check to see if there were any lasting effects. We chose to report on measures of balance that relate to everyday activities such as time taken to stand up, walk three metres, turn and return to sitting (Timed Up & Go test); ability to stand on one leg (necessary for safe walking in well lit and dark conditions), walking speed (better balance allows faster walking), and activities of daily living (Berg Balance Scale, comprising 14 items). These were our primary outcomes. There were eight categories of exercise programmes. These are listed below together with those measures of balance for which there was some evidence of a positive (statistically significant) effect from the specific type of exercise at the end of the exercise programme. Some trials tested more than one type of exercise. It is important to note that the evidence for each outcome was generally from only a few of the trials for each exercise category. 1. Gait, balance, co-ordination and functional tasks (19 studies of which 10 provided data for one or more primary outcomes). Positive effects of exercise were found for the Timed Up & Go test, walking speed, and the Berg Balance Scale. 2. Strengthening exercise (including resistance or power training) (21 studies of which 11 provided data for one or more primary outcomes). Positive effects were found for the Timed Up & Go Test; standing on one leg for as long as possible with eyes closed; and walking speed. 3. 3D (3 dimensional) exercise (including Tai Chi, qi gong, dance, yoga) (15 studies of which seven provided data for one or more primary outcomes). Positive effects were found for the Timed Up & Go Test; standing on one leg for as long as possible with eyes open, and with eyes closed; and the Berg Balance Scale. 4. General physical activity (walking) (seven studies of which five provided data for one or more primary outcomes). 5. General physical activity (cycling) (one study which provided data for walking speed). 6. Computerised balance training using visual feedback (two studies, neither of which provided data for any primary outcome). 7. Vibration platform used as intervention (three studies of which one provided data for the Timed Up & Go Test). 8. Multiple exercise types (combinations of the above) (43 studies of which 29 provided data for one or more primary outcomes). Positive effects were found for the Timed Up & Go Test; standing on one leg for as long as possible with eyes open, and with eyes closed; and the Berg Balance Scale. In general, effective programmes ran three times a week for three months and involved dynamic exercise in standing. Few adverse events were reported. The review concluded that there was weak evidence that some exercise types are moderately effective, immediately post intervention, in improving balance in older people. However, the missing data and compromised methods of many included trials meant that further high quality research is required.

10.1002/14651858.CD004963.pub3

cochrane-simplification-train-2956

cochrane-simplification-train-2956

We included seven randomised controlled trials (recruiting a total of 799 participants) evaluating four distinct models of care: multi-systemic therapy (MST) at home, specialist outpatient service, intensive home treatment and intensive home-based crisis intervention ('Homebuilders' model for crisis intervention). Young people receiving home-based MST experienced some improved functioning in terms of externalising symptoms and they spent fewer days out of school and out-of-home placement. At short term follow up the control group had a greater improvement in terms of adaptability and cohesion; this was not sustained at four months follow up. There were small, significant patient improvements reported in both groups in the trial evaluating the intensive home-based crisis intervention using the 'Homebuilders' model. No differences at follow up were reported in the two trials evaluating intensive home treatment, or in the trials evaluating specialist outpatient services. The quality of the evidence base currently provides very little guidance for the development of services. If randomised controlled trials are not feasible then consideration should be given to alternative study designs, such as prospective systems of audit conducted across several centres, as this has the potential to improve the current level of evidence. These studies should include baseline measurement at admission along with demographic data, and outcomes measured using a few standardised robust instruments.

This review found seven studies which evaluated whether these other services helped children and young people with mental health problems.  This review did not find any studies about intensive day treatment (where children attend treatment programmes during the day for a short period of time), intensive case management (health care professionals coordinate services and support for the children), therapeutic foster care (children live with specially trained foster parents) or residential care with inpatient care (children live in a residence, but not a hospital, which provides mental health care services). The studies evaluated four different types of services.  In Multisystemic therapy (MST) at home, therapists provide therapy to the child and the family together in their home.  Some behaviours in the children, improved with MST.  They also spent fewer days out of school and in hospital. Intensive home treatment provides children with therapy in their home to solve problems with the way they interact with other people in the home and to improve their psychological symptoms.  Children who received this type of service did not improve any more than children who did not.  Intensive home based crisis intervention (Homebuilders model for crisis intervention), focuses on the child and family to learn skills in relationship building, reframing problems, anger management, communication, and cognitive behavioural therapy.  Children with this service had small improvements. Specialist outpatient services are provided by a range of health care professionals in clinics.  Children who received this service did not improve any more than children who did not. The quality of some of the studies was not high and most did not have enough people to evaluate the true effect of the services.  The evidence we now have provides very little guidance for the development of these types of services.

10.1002/14651858.CD006410.pub2

cochrane-simplification-train-2957

cochrane-simplification-train-2957

We included 33 trials with 10,325 participants, of which 17 trials were new trials. Ten trials compared a daily multiple micronutrient supplement to placebo in doses up to 20 times the dietary reference intake, and one trial compared a daily standard dose with a high daily dose of multivitamins. Nineteen trials compared supplementation with single or dual micronutrients (such as vitamins A and D, zinc, and selenium) to placebo, and three trials compared different dosages or combinations of micronutrients. Multiple micronutrients We conducted analyses across antiretroviral therapy (ART)-naive adults (3 trials, 1448 participants), adults on antiretroviral therapy (ART) (1 trial, 400 participants), and ART-naive adults with concurrent active tuberculosis (3 trials, 1429 participants). Routine multiple micronutrient supplementation may have little or no effect on mortality in adults living with HIV (RR 0.91, 95% CI 0.72 to 1.15; 7 trials, 2897 participants, low certainty evidence). Routine supplementation for up to two years may have little or no effect on the average of mean CD4+ cell count (MD 26.40 cells/mm³, 95% CI −22.91 to 75.70; 6 trials, 1581 participants, low certainty evidence), or the average of mean viral load (MD −0.1 log10viral copies, 95% CI −0.26 to 0.06; 4 trials, 840 participants, moderate certainty evidence). One additional trial in ART-naïve adults did report an increase in the time to reach a CD4+ cell count < 250 cells/mm³ after two years of high dose supplementation in Botswana (HR 0.48, 95% CI 0.26 to 0.88; 1 trial, 439 participants). However, the trial authors reported this effect only in the trial arm that received multiple micronutrients plus selenium (not either supplementation alone), which is inconsistent with the findings of other trials that used similar combinations of micronutrients and selenium. In one additional trial that compared high-dose multiple micronutrient supplementation with standard doses in people on ART, peripheral neuropathy was lower with high dose supplements compared to standard dose (incidence rate ratio (IRR) 0.81, 95% CI 0.7 to 0.94; 1 trial, 3418 participants), but the trial was stopped early due to increased adverse events (elevated alanine transaminase (ALT) levels) in the high dose group. Single or dual micronutrients None of the trials of single or dual micronutrient supplements were adequately powered to assess for effects on mortality or morbidity outcomes. No clinically significant changes in CD4 cell count (data not pooled, 14 trials, 2370 participants, very low or low certainty evidence) or viral load (data not pooled, seven studies, 1334 participants, very low or low certainty evidence), were reported. Supplementation probably does increase blood concentrations of vitamin D and zinc (data not pooled, vitamin D: 4 trials, 299 participants, zinc: 4 trials, 484 participants, moderate certainty evidence) and may also increase blood concentrations of vitamin A (data not pooled, 3 trials, 495 participants, low certainty evidence), especially in those who are deficient. The analyses of the available trials have not revealed consistent clinically important benefits with routine multiple micronutrient supplementation in people living with HIV. Larger trials might reveal small but important effects. These findings should not be interpreted as a reason to deny micronutrient supplements for people living with HIV where specific deficiencies are found or where the person's diet is insufficient to meet the recommended daily allowance of vitamins and minerals.

Cochrane researchers conducted a review of the effects of micronutrient supplements for people living with HIV. This is an update of a Cochrane Review previously published in 2010. After searching for relevant trials up to 18 November 2016, the review authors included 33 trials. Thirteen of these trials included people not on HIV treatment and were conducted in Thailand, Peru, and eight African countries. Nineteen trials included people on HIV treatment and were conducted in North America, Europe, Brazil, Singapore, Thailand, Botswana, and Uganda. One trial from China did not state whether people living with HIV were on treatment or not. Some trials looked at the effects of taking supplements with multiple micronutrients whereas others looked at supplementation with single vitamins or minerals. What are micronutrient supplements and how might they help people living with HIV? Micronutrient supplements contain vitamins or minerals, or both, that are essential to good health. Many of these vitamins play important roles in maintaining the human immune system, which helps to fight off infections. Infection with HIV causes a progressive destruction of the immune system, which leaves people vulnerable to frequent infections. Many people living with HIV, especially in low-income countries, are also undernourished and many consume diets deficient that these essential micronutrients. Supplementation could therefore help people living with HIV to stay healthy for longer by strengthening their immune system or assisting recovery from infections. What the research says Multiple micronutrients Providing a daily supplement that contains multiple vitamins and minerals may have little or no effect on reducing deaths in people living with HIV, whether they are taking antiretroviral drugs or not (low certainty evidence). Daily supplements may have little or no effect on HIV disease progression as measured by CD4 cell count (low certainty evidence) or HIV viral load (low or moderate certainty evidence). Single or dual micronutrients We do not know whether supplements that contain single vitamins or minerals reduce deaths (very low certainty evidence) or slow disease progression (very low/low certainty evidence) in people living with HIV. Supplementation with vitamin A, D, zinc, or selenium may improve the level of each vitamin in a person's blood, especially those with low levels before supplementation (low/moderate certainty evidence). These findings do not mean that an adequate dietary intake for people living with HIV is not important. It is also not a reason to deny micronutrient supplements for those in whom a deficiency has been clinically demonstrated, or who are unlikely to meet the recommended daily allowance of vitamins and minerals.

10.1002/14651858.CD003650.pub4

cochrane-simplification-train-2958

cochrane-simplification-train-2958

We identified one additional study enrolling 38 participants for inclusion in this update, for a total of nine studies reporting on 544 infants. In general, the quality of the studies was low, mainly owing to lack of blinding and small sample sizes. Six studies enrolling 424 infants compared CL versus ND. No study reported on weight at three or six months. One study (n = 40) found no statistically significant difference in weight at four months between CL and ND groups. In another study (n = 62), the ratio of day-night activity before discharge favoured the CL group (mean difference (MD) 0.18, 95% confidence interval (CI) 0.17 to 0.19), indicating 18% more activity during the day than during the night in the CL group compared with the ND group. Two studies (n = 189) reported on retinopathy of prematurity (stage ≥ 3) and reported no statistically significant differences between CL and ND groups (typical risk ratio (RR) 0.53, 95% CI 0.25 to 1.11, I2 = 0%; typical risk difference (RD) -0.09, 95% CI -0.19 to 0.01, I2 = 0%). Two studies (n = 77) reported length of hospital stay (days) and noted a significant reduction in length of stay between CL and ND groups favouring the CL group (weighted mean difference (WMD) -13 days, 95% CI -23 to -2, I2 = 0%; no heterogeneity). The quality of the evidence according to GRADE was low for this outcome. One study (n = 37) reported less crying at 11 weeks' corrected age (CA) in the CL group compared with the ND group (MD -0.57 hours/24 h, 95% CI -1.09 to -0.05). Tests for heterogeneity were not applicable. Three studies enrolling 120 infants compared CL versus CBL. Two studies (n = 79) reported significantly shorter length of stay in the CL group compared with the CBL group (WMD -16.5 days, 95% CI -26.2 to -6.8, I2 = 0%; no heterogeneity). The quality of the evidence according to GRADE was low for this outcome. One study (n = 41) reported higher mean weight at three months' CA among infants cared for in the CL nursery (P value < 0.02) and a lower mean number of hours spent awake in 24 hours at three months of age (P value < 0.005). Data could not be entered into RevMan or GRADE. One study (n = 41) reported shorter time on the ventilator in the CL compared with the CBL group (MD -18.2 days, 95% CI -31.40 to -5.0). One study (n = 41) reported a shorter time to first oral feeding in the CL group (MD -6.8 days, 95% CI -13.29 to -0.31). We identified no safety issues. Trials assessing the effects of CL have enrolled 544 infants. No study reported on our primary outcome of weight at three or six months. Results from one additional study strengthen our findings that CL versus CBL shortens length of stay, as does CL versus ND. The quality of the evidence on both comparisons for this outcome according to GRADE was low. Future research should focus on comparing CL versus ND.

We included a total of nine randomised and quasi-randomised trials, which enrolled 544 infants. To our knowledge, no studies included in this review were funded by industry. No study reported on weight at three or six months. One study reported improved growth at three months of age in infants exposed to cycled light compared with those exposed to continuous bright light. Another study found no difference in weight at four months of age. Length of hospital stay was shortened with cycled light in the nursery compared with near darkness or with continuous bright light. Only a few outcomes reached statistical significance, which is likely to be due to the small number of infants enrolled in these studies, but trends for most outcomes (weight gain, incidence of retinopathy of prematurity, time spent crying) favoured cycled light over near darkness, and cycled light over continuous bright light. The quality of the evidence on outcomes assessed was low because the interventions could not be blinded to caregivers, and few infants were enrolled in these studies.

10.1002/14651858.CD006982.pub4

cochrane-simplification-train-2959

cochrane-simplification-train-2959

We included 12 RCTs (1249 participants), three more than the previous Cochrane review, comparing physiotherapy with no intervention. Five trials (246 participants) evaluated conventional techniques (vibration and percussion plus postural drainage), and seven trials (1003 participants) evaluated passive flow-oriented expiratory techniques: slow passive expiratory techniques in four trials, and forced passive expiratory techniques in three trials. Conventional techniques failed to show a benefit in the primary outcome of change in severity status of bronchiolitis measured by means of clinical scores (five trials, 241 participants analysed). Safety of conventional techniques has been studied only anecdotally, with one case of atelectasis, the collapse or closure of the lung resulting in reduced or absent gas exchange, reported in the control arm of one trial. Slow passive expiratory techniques failed to show a benefit in the primary outcomes of severity status of bronchiolitis and in time to recovery (low quality of evidence). Three trials analysing 286 participants measured severity of bronchiolitis through clinical scores, with no significant differences between groups in any of these trials, conducted in patients with moderate and severe disease. Only one trial observed a transient significant small improvement in the Wang clinical score immediately after the intervention in patients with moderate severity of disease. There is very low quality evidence that slow passive expiratory techniques seem to be safe, as two studies (256 participants) reported that no adverse effects were observed. Forced passive expiratory techniques failed to show an effect on severity of bronchiolitis in terms of time to recovery (two trials, 509 participants) and time to clinical stability (one trial, 99 participants analysed). This evidence is of high quality and corresponds to patients with severe bronchiolitis. Furthermore, there is also high quality evidence that these techniques are related to an increased risk of transient respiratory destabilisation (risk ratio (RR) 5.4, 95% confidence interval (CI) 1.6 to 18.4, one trial) and vomiting during the procedure (RR 10.2, 95% CI 1.3 to 78.8, one trial). Results are inconclusive for bradycardia with desaturation (RR 1.0, 95% CI 0.2 to 5.0, one trial) and bradycardia without desaturation (RR 3.6, 95% CI 0.7 to 16.9, one trial), due to the limited precision of estimators. However, in mild to moderate bronchiolitis patients, forced expiration combined with conventional techniques produced an immediate relief of disease severity (one trial, 13 participants). None of the chest physiotherapy techniques analysed in this review (conventional, slow passive expiratory techniques or forced expiratory techniques) have demonstrated a reduction in the severity of disease. For these reasons, these techniques cannot be used as standard clinical practice for hospitalised patients with severe bronchiolitis. There is high quality evidence that forced expiratory techniques in severe patients do not improve their health status and can lead to severe adverse events. Slow passive expiratory techniques provide an immediate and transient relief in moderate patients without impact on duration. Future studies should test the potential effect of slow passive expiratory techniques in mild to moderate non-hospitalised patients and patients who are respiratory syncytial virus (RSV) positive. Also, they could explore the combination of chest physiotherapy with salbutamol or hypertonic saline.

The evidence is current to July 2015. This review has included 12 trials with a total of 1249 participants. By type of chest physiotherapy, five trials tested vibration and percussion techniques in 246 participants, three trials tested forced expiratory techniques in 624 participants, and four trials tested slow flow techniques in 375 participants. Vibration and percussion techniques produce a thorax (chest) oscillation by fast compression or percussion with the physiotherapist's hands. Neither manoeuvre was shown to improve the clinical scores of patients with acute bronchiolitis in the trials. These techniques did not show improvements in respiratory measurements, time on oxygen therapy or length of hospital stay. There were no data on time to recovery from acute bronchiolitis, use of bronchodilators or steroids, or parents' assessment of physiotherapy benefit. The trials included in this review did not present data on adverse effects related to the intervention, but the literature cites cases of relevant adverse effects such as rib fractures related to these techniques. Forced expiratory techniques consist of suddenly increasing the expiratory flow by compressing the thorax or the abdomen. In participants with severe bronchiolitis, such techniques failed to reduce time to recovery or time to clinical stability when compared to no physiotherapy. They also failed to improve clinical scores, oxygen saturation or respiratory rates except in mild to moderate bronchiolitis patients. There were no data on secondary outcomes such as duration of oxygen supplementation, length of hospital stay, or use of bronchodilators and steroids. Two studies reported no significant differences in parents' impression of the benefit of physiotherapy compared to controls. One of the trials reported a higher number of transient episodes of vomiting and respiratory instability after forced expiratory physiotherapy. This trial found no differences for bradycardias (decreases in heart rate), with and without desaturation (reduced oxygen levels in blood). Slow flow techniques consist of compressing the rib cage and the abdominal cavity gradually and gently from the mid-expiratory phase up to the end of exhalation. Slow flow techniques showed an overall lack of benefit on clinical scores of severity of the disease. However, in two trials they provided either a short-lived relief in terms of clinical scores or a decrease in the need for oxygen support in children with moderate bronchiolitis. There were no changes in length of hospital stay, use of bronchodilators or steroids. There were no data on changes in time to recovery, change in respiratory measurements, or parents' impression of physiotherapy benefit. No severe adverse events were reported in the trials. Vibration and percussion techniques are not recommended in routine practice in hospital settings due to a lack of benefit and risk of potential adverse events. There is high quality evidence that forced expiratory techniques in severe bronchiolitis present no clinical benefit, while being related to adverse effects such as vomiting, bradycardia with desaturation, or transient respiratory destabilisation. There is low quality evidence that suggests that slow flow techniques do not provide a clear overall benefit, but could provide some transient benefits in some children with bronchiolitis. Except for one trial, related to forced expiration, the included trials are at unclear or high risk of bias. The risk of bias of the trials and the imprecision of the estimates led to the low quality of evidence for the effect of slow flow techniques on clinical scores. Further trials are needed before reaching firm conclusions.

10.1002/14651858.CD004873.pub5

cochrane-simplification-train-2960

cochrane-simplification-train-2960

We included four trials in which 3267 children aged two to 35 months participated. Analysis showed that zinc supplementation in addition to standard antibiotic therapy in children with severe and non-severe pneumonia failed to show a statistically significant effect on time-to-clinical recovery (hazard ratio 1.02; 95% confidence interval (CI) 0.93 to 1.11). Similary, zinc supplementation in children with severe pneumonia, as an adjunct to standard antibiotic therapy, did not show a statistically significant effect on time-to-recovery from tachypnoea (respiratory rate > 50 breaths per minute) (hazard ratio 1.13; 95% CI 0.82 to 1.57) and time-to-recovery from chest in-drawing (hazard ratio 1.08; 95% CI 0.88 to 1.31) as compared to the control group. Zinc supplementation in children with severe pneumonia also showed a non-significant effect on time-to-hospital discharge as compared to the control (hazard ratio 1.04; 95% CI 0.89 to 1.22). Evidence provided in this review is insufficient to recommend the use of zinc as an adjunct to standard antibiotic therapy for pneumonia in children aged two to 35 months.

The review authors found four randomised control trials of adequate quality evaluating the impact of zinc supplementation as an adjunct to antibiotics for pneumonia in children. These studies were conducted in Bangladesh, Nepal and India, in which 3267 children aged two to 35 months were randomly assigned to receive zinc or placebo. No serious adverse events were observed. Analysis did not show any significant effect on the clinical recovery of patients in terms of time-to-recovery from tachypnoea (respiratory rate > 50 breaths per minute) and time-to-recovery from chest indrawing. It also showed non-significant effects of the intervention on the time-to-hospital discharge. Evidence provided in this review is insufficient to recommend use of zinc as an adjunct to standard antibiotic therapy for pneumonia in children aged two to 35 months.

10.1002/14651858.CD007368.pub2

cochrane-simplification-train-2961

cochrane-simplification-train-2961

Twenty-one studies (772 participants) were included in this review with two additional 2012 studies identified as 'awaiting classification'. Physical training was well tolerated with no adverse effects reported. None of the studies mentioned worsening of asthma symptoms following physical training. Physical training showed marked improvement in cardiopulmonary fitness as measured by a statistically and clinically significant increase in maximum oxygen uptake (mean difference (MD) 4.92 mL/kg/min; 95% confidence interval (CI) 3.98 to 5.87; P < 0.00001; 8 studies on 267 participants); however, no statistically significant effects were observed for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), minute ventilation at maximal exercise (VEmax) or peak expiratory flow rate (PEFR). Meta-analysis of four studies detected a statistically significant increase in maximum heart rate, and following a sensitivity analysis and removal of two studies significance was maintained (MD 3.67 bpm; 95% CI 0.90 to 3.44; P = 0.01). Although there were insufficient data to pool results due to diverse reporting tools, there was some evidence to suggest that physical training may have positive effects on health-related quality of life, with four of five studies producing a statistically and clinically significant benefit. This review demonstrated that physical training showed significant improvement in maximum oxygen uptake, though no effects were observed in other measures of pulmonary function. Physical training was well tolerated among people with asthma in the included studies and, as such, people with stable asthma should be encouraged to participate in regular exercise training, without fear of symptom exacerbation. More research is needed to understand the mechanisms by which physical activity impacts asthma management.

The review of trials found that exercise training (including running, gymnastics, cycling, swimming, weights and walking) was well tolerated among the study participants. This review also found that physical training improved cardiopulmonary fitness and showed some positive effects for health-related quality of life. However, physical training had no significant effect on resting lung function. In summary, people with stable asthma should be encouraged to participate in regular exercise training that is within their capacity without fear of worsening of their asthma symptoms.

10.1002/14651858.CD001116.pub4

cochrane-simplification-train-2962

cochrane-simplification-train-2962

Five studies including a total of 1146 participants met the inclusion criteria for this review. As ever with systematic reviews of complex interventions, studies varied by design (cluster and individually randomised), duration (2.5 to 9 months), setting (school, day camp, primary care) and intervention content. Most risk of bias concerns were related to blinding and incomplete reporting, which limited the meta-analyses that could be performed. Studies generally controlled well for selection and attrition biases. All participants were between 11 and 17 years of age. Asthma diagnosis and severity varied, as did smoking prevalence. Three studies used the Triple A programme; one of these studies tested the addition of a smoke-free pledge; another delivered peer support group sessions and mp3 messaging to encourage adherence; and the third compared a peer-led asthma day camp with an equivalent camp led by healthcare practitioners. We had low confidence in all findings owing to risk of bias, inconsistency and imprecision. Results from an analysis of asthma-related quality of life based on the prespecified random-effects model were imprecise and showed no differences (MD 0.40, 95% confidence interval (CI) -0.02 to 0.81); a sensitivity analysis based on a fixed-effect model and a responder analysis suggested small benefit may be derived for this outcome. Most other results were summarised narratively and did not show an important benefit of the intervention; studies provided no analysable data on asthma exacerbations or unscheduled visits (data were skewed), and one study measuring adherence reported a drop in both groups. Effects on asthma control favoured the intervention but findings were not statistically significant. Results from two studies with high levels of baseline smoking showed some promise for self-efficacy to stop smoking, but overall nicotine dependence and smoking-related knowledge were not significantly better in the intervention group. Investigators did not report adverse events. Although weak evidence suggests that lay-led and peer support interventions could lead to a small improvement in asthma-related quality of life for adolescents, benefits for asthma control, exacerbations and medication adherence remain unproven. Current evidence is insufficient to reveal whether routine use of lay-led or peer support programmes is beneficial for adolescents receiving asthma care. Ongoing and future research may help to identify target populations for lay-led and peer support interventions, along with attributes that constitute a successful programme.

We found five studies including 1146 adolescents with asthma. Studies varied by design, duration (2.5 to 9 months), setting (school, day camp, primary care) and the way that peer support or lay-led sessions were given. Asthma severity varied, as did the number who smoked. Three studies used a programme called Triple A (Adolescent Asthma Action), by which older adolescents are trained to deliver sessions to younger students; one of these studies tested the addition of a pledge to stop smoking; another delivered peer support group sessions including messages played through an mp3 player to encourage adherence; and the third compared an asthma day camp led by peers against one led by nurses and doctors. Adolescents who received peer support had better quality of life than those in the control group, although this varied with how results were analysed, so we were uncertain. Most other outcomes did not show an important benefit of the intervention. These studies provided very little information about asthma attacks or unscheduled visits during the trial, and we couldn't be sure whether the intervention was beneficial in terms of asthma control. Results from two studies in which a lot of the adolescents smoked showed some promise that adolescents had the confidence to stop, but overall nicotine dependence and smoking-related knowledge were not much better than in controls. Studies provided no reports of adverse events. We can't be sure of the results because most outcomes were rated by people who knew the group to which adolescents were assigned, and this can affect how people behave and respond to questions. Some studies didn't report everything they said they would, or reported information that we could not analyse. Sometimes study results didn't agree with results of other studies, and often we could not say for certain whether adolescents received benefit. For these reasons, we have low confidence in all study findings.

10.1002/14651858.CD012331.pub2

cochrane-simplification-train-2963

cochrane-simplification-train-2963

Two studies involving 1002 participants compared personal assistance versus usual care. Whilst personal assistance was generally preferred over other services, some people prefer other services. Personal assistance may have some benefits for some recipients and may benefit caregivers. Paid assistance probably substitutes for informal care and may cost government more than alternatives; however, some evidence suggests it may reduce costs. The total costs to recipients and society are unknown. Research in this field is limited. Personal assistance is expensive and difficult to organise, especially in places that do not already have services in place, but its total cost relative to other services is unknown. When implementing new programmes, recipients could be randomly assigned to different forms of assistance (e.g. organised by individual users versus organised through a cooperative). While advocates may support personal assistance for myriad reasons, this review demonstrates that further studies are required to determine which models of assistance are most effective and efficient for particular people.

This review investigated the effectiveness of personal assistance versus any other form of care for adults with both physical and intellectual impairments. A literature search identified 2 studies that met the inclusion criteria, which included 1002 participants. They suggested that personal assistance may be preferred over other services; however, some people prefer other models of care. This review indicates that personal assistance may have some benefits for some recipients and their informal caregivers. Paid assistance might substitute for informal care and cost government more than alternative arrangements; however, the relative total costs to recipients and society are unknown.

10.1002/14651858.CD006860.pub2

cochrane-simplification-train-2964

cochrane-simplification-train-2964

New searches in 2013 did not identify any relevant new studies. All six included studies used a single dose of triptan to treat an attack of moderate to severe pain intensity. Subcutaneous sumatriptan was given to 131 participants at a 6 mg dose, and 88 at a 12 mg dose. Oral or intranasal zolmitriptan was given to 231 participants at a 5 mg dose, and 223 at a 10 mg dose. Placebo was given to 326 participants. Triptans were more effective than placebo for headache relief and pain-free responses. By 15 minutes after treatment with subcutaneous sumatriptan 6 mg, 48% of participants were pain-free and 75% had no pain or mild pain (17% and 32% respectively with placebo). NNTs for subcutaneous sumatriptan 6 mg were 3.3 (95% CI 2.4 to 5.0) and 2.4 (1.9 to 3.2) respectively. Intranasal zolmitriptan 10 mg was of less benefit, with 12% of participants pain-free and 28% with no or mild pain (3% and 7% respectively with placebo). NNTs for intranasal zolmitriptan 10 mg were 11 (6.4 to 49) and 4.9 (3.3 to 9.2) respectively. Based on limited data, subcutaneous sumatriptan 6 mg was superior to intranasal zolmitriptan 5 mg or 10 mg for rapid (15 minute) responses, which are important in this condition. Oral routes of administration are not appropriate.

The review found six studies examining two different triptans. The number of people in the studies was limited. Within 15 minutes of using subcutaneous sumatriptan 6 mg, almost 8 in 10 participants had no worse than mild pain, and 5 in 10 were pain-free. Within 15 minutes of using intranasal zolmitriptan 5 mg, about 3 in 10 had no worse than mild pain, and 1 in 10 was pain-free. Adverse events were more common with a triptan than with placebo but they were generally of mild to moderate severity. Cluster headache is an awful thing to have. More research on how to get better pain relief faster, and to more patients, would be welcome.

10.1002/14651858.CD008042.pub3

cochrane-simplification-train-2965

cochrane-simplification-train-2965

We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%. Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period. Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial. One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo. Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.

We included in this review trials comparing daily use of corticosteroids, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. Twenty-five trials involving 8471 children with mild to moderate persistent asthma (5128 treated with ICS and 3343 treated with placebo or non-steroidal drugs) were included in this review. Eighty percent of these trials were conducted in more than two different centres and were called multi-centre studies; five were international multi-centre studies conducted in high-income and low-income countries across Africa,Asia-Pacifica, Europe and the Americas. Sixty-eight percent were financially supported by pharmaceutical companies. Meta-analysis (a statistical technique that combines the results of several studies and provides a high level of evidence) suggests that children treated daily with ICS may grow approximately half a centimeter per year less than those not treated with these medications during the first year of treatment. The magnitude of ICS-related growth reduction may depend on the type of drug. Growth reduction seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. Evidence provided by this review allows us to conclude that daily use of ICS can cause a small reduction in height in children up to 18 years of age with persistent asthma; this effect seems minor compared with the known benefit of these medications for asthma control. Eleven of 25 trials did not report how they guaranteed that participants had an equal chance of receiving ICS or placebo or non-steroidal drugs. All but six trials did not report how researchers were kept unaware of the treatment assignment list. However, this methodological limitation may not significantly affect the quality of evidence because the results remained almost unchanged when we excluded these trials from the analysis.

10.1002/14651858.CD009471.pub2

cochrane-simplification-train-2966

cochrane-simplification-train-2966

We included 48 studies (224 reports) that involved 7803 randomised participants. Of these, three studies were conducted in children (346 participants). The 2009 review included 30 studies (94 reports, 5949 participants). Risk of bias was assessed as low for sequence generation in 19 studies and allocation concealment in 14 studies. Incomplete outcome data were adequately addressed in 22 studies and 37 were free of selective reporting. The 48 included studies evaluated three different comparisons: steroid avoidance or withdrawal compared with steroid maintenance, and steroid avoidance compared with steroid withdrawal. For the adult studies there was no significant difference in patient mortality either in studies comparing steroid withdrawal versus steroid maintenance (10 studies, 1913 participants, death at one year post transplantation: RR 0.68, 95% CI 0.36 to 1.30) or in studies comparing steroid avoidance versus steroid maintenance (10 studies, 1462 participants, death at one year after transplantation: RR 0.96, 95% CI 0.52 to 1.80). Similarly no significant difference in graft loss was found comparing steroid withdrawal versus steroid maintenance (8 studies, 1817 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.17, 95% CI 0.72 to 1.92) and comparing steroid avoidance versus steroid maintenance (7 studies, 1211 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.09, 95% CI 0.64 to 1.86). The risk of acute rejection significantly increased in patients treated with steroids for less than 14 days after transplantation (7 studies, 835 participants: RR 1.58, 95% CI 1.08 to 2.30) and in patients who were withdrawn from steroids at a later time point after transplantation (10 studies, 1913 participants, RR 1.77, 95% CI 1.20 to 2.61). There was no evidence to suggest a difference in harmful events, such as infection and malignancy, in adult kidney transplant recipients. The effect of steroid withdrawal in children is unclear. This updated review increases the evidence that steroid avoidance and withdrawal after kidney transplantation significantly increase the risk of acute rejection. There was no evidence to suggest a difference in patient mortality or graft loss up to five year after transplantation, but long-term consequences of steroid avoidance and withdrawal remain unclear until today, because prospective long-term studies have not been conducted.

Our review looked at data relating to 7803 kidney transplant recipients. We assessed the risk of bias in all studies and found that most were unblinded, about half did not report funding sources or how they randomised and allocated study participants. We found that the risk of acute rejection significantly increased with both steroid-reducing treatments among adults who received kidney transplants. There was no little or no difference in the numbers of deaths or loss of transplanted kidneys for both steroid-reducing strategies within five years after kidney transplantation. Side effects, such as infection, cancer or diabetes after transplantation did not differ between groups of patients whose steroids were discontinued compared with those who continued to take steroids. The effect of steroid withdrawal in children is unclear. There was no evidence to suggest a difference in patient mortality or graft loss up to five year after transplantation, but longer-term consequences of steroid avoidance and withdrawal still remain unclear.

10.1002/14651858.CD005632.pub3

cochrane-simplification-train-2967

cochrane-simplification-train-2967

We included 25 trials randomising a total of 12,503 participants. All trials were at high risk of bias, and the quality of evidence according to GRADE was low to very low. We included 22 trials where the participants presented with ST-elevation myocardial infarction, 1 trial where participants presented with non-ST-elevation myocardial infarction, and 2 trials where participants presented with a mix of acute coronary syndromes. Meta-analyses at maximum follow-up showed no evidence of a difference when comparing drug-eluting stents with bare-metal stents on the risk of all-cause mortality or major cardiovascular events. The absolute risk of death was 6.97% in the drug-eluting stents group compared with 7.74% in the bare-metal stents group based on the risk ratio (RR) of 0.90 (95% confidence interval (CI) 0.78 to 1.03, 11,250 participants, 21 trials/22 comparisons, low-quality evidence). The absolute risk of a major cardiovascular event was 6.36% in the drug-eluting stents group compared with 6.63% in the bare-metal stents group based on the RR of 0.96 (95% CI 0.83 to 1.11, 10,939 participants, 19 trials/20 comparisons, very low-quality evidence). The results of Trial Sequential Analysis showed that we did not have sufficient information to confirm or reject our anticipated risk ratio reduction of 10% on either all-cause mortality or major cardiovascular events at maximum follow-up. Meta-analyses at maximum follow-up showed evidence of a benefit when comparing drug-eluting stents with bare-metal stents on the risk of a serious adverse event. The absolute risk of a serious adverse event was 18.04% in the drug-eluting stents group compared with 23.01% in the bare-metal stents group based on the RR of 0.80 (95% CI 0.74 to 0.86, 11,724 participants, 22 trials/23 comparisons, low-quality evidence), and Trial Sequential Analysis confirmed this result. When assessing each specific type of adverse event included in the serious adverse event outcome separately, the majority of the events were target vessel revascularisation. When target vessel revascularisation was analysed separately, meta-analysis showed evidence of a benefit of drug-eluting stents, and Trial Sequential Analysis confirmed this result. Meta-analyses at maximum follow-up showed no evidence of a difference when comparing drug-eluting stents with bare-metal stents on the risk of cardiovascular mortality (RR 0.91, 95% CI 0.76 to 1.09, 9248 participants, 14 trials/15 comparisons, very low-quality evidence) or myocardial infarction (RR 0.98, 95% CI 0.82 to 1.18, 10,217 participants, 18 trials/19 comparisons, very low-quality evidence). The results of the Trial Sequential Analysis showed that we had insufficient information to confirm or reject our anticipated risk ratio reduction of 10% on cardiovascular mortality and myocardial infarction. No trials reported results on quality of life or angina. The current evidence suggests that drug-eluting stents may lead to fewer serious adverse events compared with bare-metal stents without increasing the risk of all-cause mortality or major cardiovascular events. However, our Trial Sequential Analysis showed that there currently was not enough information to assess a risk ratio reduction of 10% for all-cause mortality, major cardiovascular events, cardiovascular mortality, or myocardial infarction, and there were no data on quality of life or angina. The evidence in this review was of low to very low quality, and the true result may depart substantially from the results presented in this review. More randomised clinical trials with low risk of bias and low risks of random errors are needed if the benefits and harms of drug-eluting stents for acute coronary syndrome are to be assessed properly. More data are needed on the outcomes all-cause mortality, major cardiovascular events, quality of life, and angina to reduce the risk of random error.

We searched scientific databases from their inception to January 2017 and found 25 trials where people were randomly allocated to either a group receiving drug-eluting stents or a group receiving bare-metal stents. The 25 trials (26 comparisons) included 12,503 adults with a mean age of 60.8 years. The people receiving drug-eluting stents did seem to have a reduced risk of experiencing a serious adverse event compared with those receiving bare-metal stents, without affecting the risk of dying from any cause or specifically heart disease, or of having a heart attack. The serious adverse event likely to be avoided by those receiving drug-eluting stents seems to be repeat balloon angioplasty. No data were reported on quality of life or chest pain (angina) after receiving the stent. The evidence should be interpreted with caution, as we judged the quality to be low to very low due to limitations of the included randomised clinical trials. The reason for the very low-quality judgement was mainly due to all included trials being at high risk of bias. Consequently, the results may show more benefit of drug-eluting stents than the 'real life' effect would show. Furthermore, most of the outcomes in our review lacked sufficient statistical power. Future well-designed randomised clinical trials may therefore change the above-mentioned results.

10.1002/14651858.CD012481.pub2

cochrane-simplification-train-2968

cochrane-simplification-train-2968

We included three new studies (201 participants) in this updated review, for a total of nine studies (455 participants). All but one study employed placebo as the control group intervention. For the primary outcome, antifibrinolytic drugs decreased the amount of perioperative blood loss by 427 mL (95% confidence interval (CI) 251 to 603 mL), for a reduction of over 20% versus placebo. We rated the quality of evidence for our primary outcome as low on the basis of unclear risk of bias for several domains in most studies and the small total number of participants. For secondary outcomes, fewer participants receiving antifibrinolytic drugs received transfusion (allogeneic or autologous) versus those receiving placebo (risk ratio (RR) 0.65, 95% CI 0.50 to 0.85, number needed to treat to prevent one additional harmful outcome (NNTp) 5; very low-quality evidence). Only two studies specifically evaluated the number of participants transfused with only allogeneic blood (risk difference (RD) -0.15, 95% CI -0.26 to -0.03, NNTp 7; very low-quality evidence). Antifibrinolytic drugs decreased the volume of blood transfused by 327 mL (95% CI -186 to -469 mL; low-quality evidence). No study reported deaths in active or control groups. Data were insufficient to allow performance of meta-analysis for any safety outcome. No studies adequately described their methods in assessing safety. The only adverse event of note occurred in one study, when three participants in the placebo group developed postoperative deep vein thrombosis. Since the last published version of this review (2008), we have found three new studies. Additional evidence shows that antifibrinolytics reduce the requirement for both autologous and allogeneic blood transfusion. Limited evidence of low to very low quality supports the use of antifibrinolytic drugs for reducing blood loss and decreasing the risk, and volume, of transfusion in children undergoing scoliosis surgery. Evidence is insufficient to support the use of a particular agent, although tranexamic acid may be preferred, given its widespread availability. The optimal dose regimen for any of these three agents has not been established. Although adverse events appear to occur infrequently, evidence is insufficient to confirm the safety of these agents, particularly for rare but potentially catastrophic events. No long-term safety data are available.

The antifibrinolytic drugs evaluated in this systematic review were aprotinin, tranexamic acid and aminocaproic acid. We found nine studies that enrolled a total of 455 participants, aged 18 years or younger, who received either antifibrinolytic drugs or a placebo. Total enrolment in each study ranged from 36 participants to 80 participants. Two of the studies evaluated aprotinin, four tranexamic acid and four aminocaproic acid. One study compared aminocaproic acid with tranexamic acid. The other studies administered placebo to the control group. Studies that evaluated aprotinin and aminocaproic acid used high doses (when reported). Of the studies that evaluated tranexamic acid, two used high doses, one used low doses and one did not describe the dose given. Five studies evaluated idiopathic scoliosis (scoliosis with no known cause), and four evaluated both idiopathic scoliosis and scoliosis that occurred as the result of another disease, such as cerebral palsy. Of the nine included studies, five reported how long patients were assessed. Follow-up ranged from one to 10 days after surgery, or lasted for the participant's length of stay in the hospital. Two studies received grants from organizations of healthcare professionals, and one was sponsored by a pharmaceutical company. The remaining studies did not report sources of funding. Antifibrinolytic drugs reduced the amount of blood lost during, or immediately after, surgery, by 427 millilitres (mL) (more than a 20% reduction in blood loss) and the amount of blood transfused during the same period by 327 mL. The number of children who received transfusions, either through blood from a donor or through a combination of blood from a donor and their own saved blood, was also significantly decreased. We assessed the quality of the evidence for all of these findings as low or very low because of the small numbers of participants, some concerns about study designs and imprecision in study findings. No children included in any studies died, and very few adverse events were reported, although three children receiving placebo in one study developed a clot. However, these studies may not have adequately looked for adverse events, or study authors might not have reported them fully. Also, the number of children evaluated was too small and the time of follow-up too short to allow review authors to draw any conclusions about their safety. This systematic review showed that antifibrinolytic drugs reduce blood loss and decrease the number of children receiving blood transfusions and the amount of blood transfused, but the evidence supporting any of these findings is not very strong. The safety of antifibrinolytic drugs remains unclear.

10.1002/14651858.CD006883.pub3

cochrane-simplification-train-2969

cochrane-simplification-train-2969

Twelve trials randomised 694 diabetic participants to intensive control and 709 diabetic participants to conventional glycaemic control. The duration of the intervention ranged from just the duration of the surgical procedure up to 90 days. The number of participants ranged from 13 to 421, and the mean age was 64 years. Comparison of intensive with conventional glycaemic control demonstrated the following results for our predefined primary outcomes: analysis restricted to studies with low or unclear detection or attrition bias for infectious complications showed a risk ratio (RR) of 0.46 (95% confidence interval (CI) 0.18 to 1.18), P = 0.11, 627 participants, eight trials, moderate quality of the evidence (grading of recommendations assessment, development and evaluation - (GRADE)). Evaluation of death from any cause revealed a RR of 1.19 (95% CI 0.89 to 1.59), P = 0.24, 1365 participants, 11 trials, high quality of the evidence (GRADE). On the basis of a posthoc analysis, there is the hypothesis that intensive glycaemic control may increase the risk of hypoglycaemic episodes if longer-term outcome measures are analysed (RR 6.92, 95% CI 2.04 to 23.41), P = 0.002, 724 patients, three trials, low quality of the evidence (GRADE). Analysis of our predefined secondary outcomes revealed the following findings: cardiovascular events had a RR of 1.03 (95% CI 0.21 to 5.13), P = 0.97, 682 participants, six trials, moderate quality of the evidence (GRADE) when comparing the two treatment modalities; and renal failure also did not show significant differences between intensive and regular glucose control (RR 0.61, 95% CI 0.34 to 1.08), P = 0.09, 434 participants, two trials, moderate quality of the evidence (GRADE). We did not meta-analyse length of hospital stay and intensive care unit (ICU) stay due to substantial unexplained heterogeneity. Mean differences between intensive and regular glucose control groups ranged from -1.7 days to 2.1 days for ICU stay and between -8 days to 3.7 days for hospital stay (moderate quality of the evidence (GRADE)). One trial assessed health-related quality of life in 12/37 (32.4%) of participants in the intervention group and 13/44 (29.5%) of participants in the control group, and did not show an important difference (low quality of the evidence (GRADE)) in the measured physical health composite score of the short-form 12-item health survey (SF-12). None of the trials examined the effects of the interventions in terms of costs. The included trials did not demonstrate significant differences for most of the outcomes when targeting intensive perioperative glycaemic control compared with conventional glycaemic control in patients with diabetes mellitus. However, posthoc analysis indicated that intensive glycaemic control was associated with an increased number of patients experiencing hypoglycaemic episodes. Intensive glycaemic control protocols with near-normal blood glucose targets for patients with diabetes mellitus undergoing surgical procedures are currently not supported by an adequate scientific basis. We suggest that insulin treatment regimens, patient- and health-system relevant outcomes, and time points for outcome measures should be defined in a thorough and uniform way in future studies.

We identified 12 randomised controlled clinical trials investigating perioperative control of blood sugar levels. The perioperative period is the time period surrounding a patient's surgical procedure, involving ward admission, anaesthesia, surgery and recovery, and includes the preoperative (before operation), intraoperative (during operation) and postoperative (after operation) phases of surgery. We included a total of 694 diabetic participants randomised to perioperative intensive glucose control and 709 diabetic participants randomised to conventional or regular glucose control in our analyses. The trials were conducted in all continents except for Africa. The mean duration of the intervention period varied from a few hours to 90 days. The mean age of the participants was 64 years. Despite attaining lower blood glucose concentrations during the perioperative period, intensive blood glucose control did not significantly reduce the risk of relevant postoperative outcomes such as infectious complications, death from any cause, cardiovascular complications, renal failure and length of intensive care unit (ICU) and hospital stay. Due to posthoc evaluation of data, there is some evidence that targeting intensive glucose control increases the risk of hypoglycaemic episodes, but confirmation is needed from additional studies. One study assessed health-related quality of life in 12/37 (32%) participants in the intensive glucose intervention group and 13/44 (30%) participants in the regular glucose control group, and did not show an important difference. None of the studies investigated the cost-effects of the interventions. Based on the results of our review, the best approach for how to handle blood glucose control during surgery in patients with diabetes mellitus is not clear. We suggest that insulin treatment regimens, patient- and health-system relevant outcomes, and time points for outcome measures should be defined in a thorough and uniform way in future studies.

10.1002/14651858.CD007315.pub2

cochrane-simplification-train-2970

cochrane-simplification-train-2970

We included in the meta-analysis six RCTs which met the pre-defined selection criteria, involving a total of 568 participants. Quality of data reporting was heterogeneous among these studies with a lack of detailed information in the early studies. The primary outcome of overall survival was not significantly changed by the addition of ATG for the prophylaxis of GVHD (harms ratio (HR) 0.88; 95% CI 0.67 to 1.15, P = 0.33). The incidence of treatment-requiring or severe acute GVHD (grade II to IV) was significantly lower in patients who received ATG (risk ratio (RR) 0.68; 95% CI 0.55 to 0.85, P = 0.009; number needed to treat (NNT) 8). Also, the incidence of severe acute GVHD (grade III to IV) was significantly reduced (HR 0.53; 95% CI 0.33 to 0.85, P = 0.0005; NNT 7) but comparable data were available for rabbit ATG only. However, pooled study results regarding the incidence of acute GVHD of all grades (I to IV) showed no significant benefit of ATG treatment (RR 0.89; 95% CI 0.74 to 1.06, P = 0.20). Meta-analysis of data regarding the incidence of overall chronic GVHD (both, limited and extensive) was not possible. Nevertheless, studies reporting on extensive chronic GVHD (only studies evaluating rabbit ATG) suggested a lower incidence of extensive chronic GVHD whereas others that only reported on overall chronic GVHD did not show an advantage for ATG. Pooled results regarding the incidence of relapse were not significantly different (RR 1.13; 95% CI 0.75 to 1.68, P = 0.56), as well as pooled results regarding non-relapse mortality (HR 0.82; 95% CI 0.55 to 1.24, P = 0.35). Due to the lack of comparable data, we could not perform meta-analysis of data regarding the incidence of chronic GVHD, relapse-related mortality, progression-free survival, quality of life, adverse events and engraftment. Our systematic review suggests that the addition of ATG during allogeneic HSCT significantly reduces the incidence of severe grades (II to IV) of acute GvHD, whereas the incidence of overall acute GVHD (grades I to IV) was not significantly lowered. This indicates a reduction of the severity but not the incidence of acute GVHD. However, this effect did not lead to a significant improvement of overall survival, which may be due to the severe potential side effects of the consecutively increased immunosuppression. Furthermore, future research is needed to clarify the effect of ATG on the incidence and severity of chronic GVHD and consequently on all aspects of quality of life. From the currently available data, no recommendation on the general use of ATG in allogeneic HSCT can be supported. Therefore, a careful consideration of the use of ATG based on the patient's condition and the risk factors of the transplantation setting should be made.

In this systematic review, we included six randomised controlled trials comprising 568 adult patients. In summary, we found evidence that the addition of ATG reduced the occurrence of only the severe forms (grade II to IV) of acute GVHD with a number needed to treat (NNT) of 8 concerning grade II to IV acute GVHD and a NNT of 7 concerning acute GVHD grade III to IV. This means that eight or seven patients have to be treated with ATG, respectively, in order to prevent one case of severe acute GVHD. However, neither overall survival nor the overall occurrence rate of acute GVHD was improved by the use of ATG. Moreover, we did not find a difference between ATG treated patients and those who did not receive ATG regarding relapse of the underlying disease or non-relapse mortality. The effect of ATG on quality of life after stem cell transplantation, which would be an important issue, has not been evaluated in randomised studies so far.

10.1002/14651858.CD009159.pub2

cochrane-simplification-train-2971

cochrane-simplification-train-2971

We deemed six studies (309 participants), based on adult populations with intellectual disabilities, suitable for inclusion in the current version of this review. These studies examined a range of cognitive-behavioural therapy (CBT) approaches: anger management (three studies (n = 235); one individual therapy and two group-based); relaxation (one study; n = 12), mindfulness based on meditation (one study; n = 34), problem solving and assertiveness training (one study; n = 28). We were unable to include any studies using behavioural interventions. There were no studies of children. Only one study reported moderate quality of evidence for outcomes of interest as assessed by the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We judged the evidence for the remaining studies to be of very low to low quality. Most studies were at risk of bias in two or more domains: one study did not randomly allocate participants and in two studies the process of randomisation was unclear; in one study there was no allocation concealment and in three studies this was unclear; blinding of assessors did not occur in three studies; incomplete outcome data were presented in one study and unclear in two studies; there was selective reporting in one study; and other biases were present in one study and unclear in four studies. Three of the six studies showed some benefit of the intervention on improving anger ratings. We did not conduct a meta-analysis, as we considered the studies too heterogeneous to combine (e.g. due to differences in the types of participants, sample size interventions, and outcome measures). Follow-up data for anger ratings for both the treatment and control groups were available for two studies. Only one of these studies (n = 161) had adequate long-term data (10 months), which found some benefit of treatment at follow-up (continued improvement in anger coping skills as rated by key workers; moderate-quality evidence). Two studies (n = 192) reported some evidence that the intervention reduces the number of incidents of aggression and one study (n = 28) reported evidence that the intervention improved mental health symptoms. One study investigated the effects of the intervention on quality of life and cost of health and social care utilisation. This study provided moderate-quality evidence, which suggests that compared to no treatment, behavioural or cognitive-behavioural interventions do not improve quality of life at 16 weeks (n = 129) or at 10 months follow-up (n = 140), or reduce the cost of health service utilisation (n = 133). Only one study (n = 28) assessed adaptive functioning. It reported evidence that assertiveness and problem-solving training improved adaptive behaviour. No studies reported data on adverse events. The existing evidence on the effectiveness of behavioural and cognitive-behavioural interventions on outwardly-directed aggression in children and adults with intellectual disabilities is limited. There is a paucity of methodologically sound clinical trials and a lack of long-term follow-up data. Given the impact of such behaviours on the individual and his or her support workers, effective interventions are essential. We recommend that randomised controlled trials of sufficient power are carried out using primary outcomes that include reduction in outward-directed aggressive behaviour, improvement in quality of life, and cost effectiveness.

We searched a number of electronic databases in April 2014 to ensure that the review was up-to-date. We included six studies in the review with a total number of 309 participants. Three studies examined anger management, one study examined assertiveness training and problem solving, one study examined 'mindfulness' based on meditation, and one study examined modified relaxation. All the studies were conducted in community settings apart from one, which was conducted in a forensic inpatient setting. Five of these studies were small, comprising between 12 and 40 participants, and one was a large study of 179 participants, which was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme. Information on funding was not available for the other studies. Follow-up data were available only for two studies. We found improved outcomes in five studies, including reduction in anger ratings and in aggressive incidents, at the end of treatment. One study found improvements in anger coping skills as reported by key workers at 16 weeks and 10 months, but no other long-term benefit. One large study did not find improvements in quality of life or reduced costs to health services. Due to differences in the types of interventions, populations and assessments, we could not combine the results of the studies. There was one large study which presented moderate-quality data on the outcomes of interest. The other included studies were small and of poor methodological quality. Based on a 'Grades of Recommendation, Assessment, Development and Evaluation' (GRADE) assessment, we judged the quality of evidence on the outcomes of interest to range from very low to moderate quality. Moreover, the diversity of the interventions and participant groups makes it difficult for us to draw firm conclusions about the effectiveness of any particular approach. Therefore, more good-quality studies with longer-term follow-up data are needed.

10.1002/14651858.CD003406.pub4

cochrane-simplification-train-2972

cochrane-simplification-train-2972

Our search retrieved 1311 unique citations, of which 1289 were excluded after title and abstract screening. Of the remaining 22, we excluded 19 because they were empirical studies that were not randomized, quasi-randomized or cluster-randomized controlled trials (n = 12), because they were review articles (n = 3), because they described protocols only (n = 2), they were conducted among cigarette smokers only (n = 1), or they had only a three-month follow-up (n = 1). We identified three controlled trials which tested cessation interventions for waterpipe smokers. Studies were carried out in Egypt (Mohlman 2013), Pakistan (Dogar 2014), and the US (Lipkus 2011). One was a randomized controlled trial and two were cluster-randomized trials. Two studies tested individual-level interventions, and one tested a community-level intervention. Two studies included only behavioural interventions, and one study (Dogar 2014) included two intervention groups: one behavioural, and the other behavioural with bupropion. The Lipkus and Mohlman studies delivered waterpipe-specific interventions, and the Dogar study delivered a non-specific tobacco intervention. Due to study variation we did not pool results, and intervention effects are reported descriptively. Compared to control groups, waterpipe smoking cessation rates were higher in the intervention groups in all three studies, with a significant difference in two studies. For the Dogar study, the RRs for waterpipe smoking abstinence at 25 weeks among waterpipe-only smokers were 2.2 (95% confidence interval (CI) 1.3 to 3.8; 180 participants) in the behavioural group, and 2.5 (95% CI 1.3 to 4.7; 84 participants) in the behavioural plus bupropion group. In our analysis we have combined both groups, to give a RR of 2.28 (95% CI 1.36 to 3.83; 200 participants). The Mohlman study delivered a RR in male waterpipe-smokers at one year in favour of the intervention of 3.25 (95% CI 1.19 to 8.89). Although the literature on waterpipe cessation interventions remains sparse, the reviewed studies provide a basis for developing interventions in this area. The lack of statistically significant effects in one of the three studies is not unexpected, given the small and pilot nature of the studies. The studies highlight important design and content issues that need to be considered for future cessation trials in waterpipe smokers. These include building on the vast experience developed in the study of smoking cessation interventions in cigarette smokers, whilst including components and assessment tools that address the specific aspects of waterpipe smoking, such as its social dimension, unique experiences, and cues.

We searched for controlled trials in the Cochrane Tobacco Addiction Review Group specialized register, in June 2015. We also searched a number of electronic databases, including MEDLINE, EMBASE, PsycINFO and CINAHL, using a variety of names and spellings for waterpipe use ('waterpipe' or 'narghile' or 'arghile' or 'shisha' or 'goza' or 'narkeela' or 'hookah' or 'hubble bubble'). We searched for published and unpublished trials in any language, and especially in areas where waterpipe use is widespread. We identified three studies that tested behavioural methods to help waterpipe smokers to quit. Two were waterpipe-specific interventions and one was a non-specific tobacco intervention.One small, pilot study was set in the USA, and delivered a Powerpoint presentation online to 91 college students who were using waterpipe. One study was a secondary analysis of data from 264 waterpipe smokers who were part of a trial that enrolled people suspected of having tuberculosis from 33 healthcare clinics in Pakistan. Clinics were randomly assigned to deliver a behavioural intervention versus control (usual care), or a behavioural intervention plus medication (bupropion) versus control (usual care). The third study, set in Egypt, targeted both cigarette and waterpipe smokers, and was a community-based programme. In all three trials, the percentage of participants who stopped smoking waterpipe was higher in the intervention groups than in the control groups, although this was a statistically significant finding in only two of the trials. People who received either behavioural treatment or behavioural treatment plus buproprion were more likely to quit waterpipe smoking at six months follow-up than those who received usual care. Men smoking waterpipe in the Egyptian study were more likely to have quit at one year follow-up in the intervention villages than in the control villages. These studies provide support to suggest that cessation interventions may help waterpipe smokers to quit. However, further larger studies are needed to build on this. The trials were all rated at very low quality of evidence, as they were relatively small studies, with at least one high risk of bias.

10.1002/14651858.CD005549.pub3

cochrane-simplification-train-2973

cochrane-simplification-train-2973

Twelve trials involving 1586 women met inclusion criteria for this review. One trial did not report on the outcomes of interest in this review. Risk of bias of included studies: The included studies generally were of low quality based on inadequate reporting of methodology. Only three trials had low risk of bias for random sequence generation and one had low risk of bias for allocation concealment and participant blinding. Most studies were either high risk of bias or uncertain in these key areas. Comparison 1: Ethanol versus placebo/control (two trials, 77 women) Compared to controls receiving pain medications and dextrose solution, ethanol did not improve any of the primary outcomes: birth < 48 hours after trial entry (one trial, 35 women; risk ratio (RR) 0.93, 95% confidence interval (CI) 0.43 to 2.00), or neonatal mortality (one trial, 35 women; RR 1.06, 95% CI 0.31 to 3.58). Serious maternal adverse events and perinatal mortality were not reported by either of the two trials in this comparison. Maternal adverse events (overall) were not reported but one trial (42 women) reported that there were no maternal adverse events that required stopping or changing drug) in either group. One trial did report delay until delivery but this outcome was reported as a median with no mention of the standard deviation (median 19 days in ethanol group versus "less than 1" day in the glucose/water group). There were no differences in any secondary outcomes reported: preterm birth < 34 weeks or < 37 weeks; serious infant outcome; fetal alcohol syndrome/fetal alcohol spectrum disorder; or small-for-gestational age. Comparison 2: Ethanol versus other tocolytic (betamimetics) (nine trials, 1438 women) Compared to betamimetics (the only tocolytic used as a comparator in these studies), ethanol was associated with no clear difference in the rate of birth < 48 hours after trial entry (two trials, 130 women; average RR 1.12, 95% CI 0.53 to 2.37, Tau² = 0.19, I² = 59%), similar rates of perinatal mortality (six trials, 698 women; RR1.20, 95% CI 0.78 to 1.84), higher rates of neonatal mortality (eight trials, 1238 women; RR 1.43, 95% CI 1.02 to 2.02), higher rates of preterm birth < 34 weeks (two trials, 599 women; RR 1.56, 95% CI 1.11 to 2.19), higher rates of neonatal respiratory distress syndrome (three trials, 823 women; RR 1.76, 95% CI 1.33 to 2.33), and higher rates of low birthweight babies < 2500 g (five trials, 834 women; RR 1.30, 95% CI 1.09 to 1.54). These outcomes are likely all related to the lower incidence of preterm birth seen with other tocolytics, which for all these comparisons were betamimetics. Serious maternal adverse events were not reported in any of the nine trial reports. However, ethanol had a trend towards a lower rate of maternal adverse events requiring stopping or changing the drug (three trials, 214 women; RR 0.25, 95% CI 0.06 to 0.97). There were no differences in other secondary outcomes of preterm birth < 37 weeks, number of days delivery was delayed, or overall maternal adverse events. Planned sensitivity analysis, excluding quasi-randomized trials did not substantially change the results of the primary outcome analyses with the exception of neonatal mortality which no longer showed a clear difference between the ethanol and other tocolytic groups (3 trials, 330 women; RR 1.49, 95% CI 0.82 to 2.72). This review is based on evidence from twelve studies which were mostly low quality. There is no evidence that to suggest that ethanol is an effective tocolytic compared to placebo. There is some evidence that ethanol may be better tolerated than other tocolytics (in this case betamimetics), but this result is based on few studies and small sample size and therefore should be interpreted with caution. Ethanol appears to be inferior to betamimetics for preventing preterm birth in threatened preterm labor. Ethanol is generally no longer used in current practice due to safety concerns for the mother and her baby. There is no need for new studies to evaluate the use of ethanol for preventing preterm birth in threatened preterm labour. However, it would be useful for long-term follow-up studies on the babies born to mothers from the existing studies in order to assess the risk of long-term neurodevelopmental status.

We searched for trials evidence on 31 May 2015 and found 12 trials total involving 1586 women, some comparing ethanol with a placebo and others comparing ethanol with other tocolytics (in this instance, all betamimetics). The trials included in this review were considered to be mostly low quality studies. For our comparison of ethanol versus placebo control (two trials, 77 women). We found that ethanol was no better than placebo (sugar water) for any of the outcomes studied: birth <48 hours after trial entry (one trial, 35 women) or neonatal mortality (one trial, 35 women). Serious maternal adverse events and perinatal mortality was not reported. There was no differences between groups for other outcomes: preterm birth < 37 weeks or < 34 weeks, serious infant outcome, fetal alcohol syndrome/fetal alcohol spectrum disorder, or small-for-gestational age. We also compared ethanol with other tocolytic drugs (nine trials involving 1438 women; all trials studied betamimetic drugs). We found that ethanol was worse than other betamimetic drugs at postponing birth until after 34 weeks' gestation and led to a higher rate of low birthweight babies, babies with breathing problems at birth and neonatal death (although there was no clear difference in neonatal deaths when we restricted our analyses to the better quality studies), However, we did find that, compared to betamimetics, ethanol was associated with a trend for fewer maternal side effects that required stopping or changing the drug, though this result is based on three small trials. There were no differences in other secondary outcomes of preterm birth < 37 weeks, number of days delivery was delayed, or overall maternal adverse events. Overall, we found no evidence that ethanol was better than a placebo at postponing preterm labor and birth. Whilst there was some evidence to suggest that ethanol may be better tolerated than betamimetics, we found that ethanol was not as effective as betamimetics at postponing preterm labor and birth. None of the studies were long-term ones and thus none of them reported on the risk of giving ethanol on the babies developing fetal alcohol syndrome, which can cause mental retardation. There is no need for new studies to evaluate the use of ethanol for preventing preterm birth. However, it would be useful for long-term follow-up studies on the babies born to mothers from the existing studies in order to assess the risk of long-term neurodevelopmental status.

10.1002/14651858.CD011445.pub2

cochrane-simplification-train-2974

cochrane-simplification-train-2974

Ninteen studies were included, reporting on 57 MEDLINE filters and 13 EMBASE filters. Thirty MEDLINE and four EMBASE filters were tested in an evaluation study where the performance of one or more filters was tested against one or more gold standards. The reported outcome measures varied. Some studies reported specificity as well as sensitivity if a reference set containing non-gold standard records in addition to gold standard records was used. In some cases, the original development study did not report any performance data on the filters. Original performance from the development study was not available for 17 filters that were subsequently tested in evaluation studies. All 19 studies reported the sensitivity of the filters that they developed or evaluated, nine studies reported the specificities and 14 studies reported the precision. No filter which had original performance data from its development study, and was subsequently tested in an evaluation study, had what we defined a priori as acceptable sensitivity (> 90%) and precision (> 10%). In studies that developed MEDLINE filters that were evaluated in another study (n = 13), the sensitivity ranged from 55% to 100% (median 86%) and specificity from 73% to 98% (median 95%). Estimates of performance were lower in eight studies that evaluated the same 13 MEDLINE filters, with sensitivities ranging from 14% to 100% (median 73%) and specificities ranging from 15% to 96% (median 81%). Precision ranged from 1.1% to 40% (median 9.5%) in studies that developed MEDLINE filters and from 0.2% to 16.7% (median 4%) in studies that evaluated these filters. A similar range of specificities and precision were reported amongst the evaluation studies for MEDLINE filters without an original performance measure. Sensitivities ranged from 31% to 100% (median 71%), specificity ranged from 13% to 90% (median 55.5%) and precision from 1.0% to 11.0% (median 3.35%). For the EMBASE filters, the original sensitivities reported in two development studies ranged from 74% to 100% (median 90%) for three filters, and precision ranged from 1.2% to 17.6% (median 3.7%). Evaluation studies of these filters had sensitivities from 72% to 97% (median 86%) and precision from 1.2% to 9% (median 3.7%). The performance of EMBASE search filters in development and evaluation studies were more alike than the performance of MEDLINE filters in development and evaluation studies. None of the EMBASE filters in either type of study had a sensitivity above 90% and precision above 10%. None of the current methodological filters designed to identify reports of primary DTA studies in MEDLINE or EMBASE combine sufficiently high sensitivity, required for systematic reviews, with a reasonable degree of precision. This finding supports the current recommendation in the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy that the combination of methodological filter search terms with terms for the index test and target condition should not be used as the only approach when conducting formal searches to inform systematic reviews of DTA.

A systematic review of a particular diagnostic test for a disease aims to bring together and assess all the available research evidence. Bibliographic databases are usually searched by combining terms for the disease with terms for the diagnostic test. However, depending on the topic area, the number of articles retrieved by such searches may be very large. Methodological filters consisting of text words and database indexing terms have been developed in the hope of improving the searches by increasing their precision when these filters are added to the search terms for the disease and diagnostic test. On the other hand, using filters to identify records for diagnostic reviews may miss relevant studies while at the same time not making a big difference to the number of studies that have to be assessed for inclusion. This review assessed the performance of 70 filters (reported in 19 studies) for identifying diagnostic studies in the two main bibliographic databases in health, MEDLINE and EMBASE. The results showed that search filters do not perform consistently, and should not be used as the only approach in formal searches to inform systematic reviews of diagnostic studies. None of the filters reached our minimum criteria of a sensitivity greater than 90% and a precision above 10%.

10.1002/14651858.MR000022.pub3

cochrane-simplification-train-2975

cochrane-simplification-train-2975

Three trials met eligibility criteria. A 16-week behaviour therapy intervention was used in two trials, and a 12-week cognitive-behaviour therapy intervention in the third. Duration of follow-up varied, ranging from 0 to 12 months. Two trials (total 166 participants) provided data comparing combination with psychotherapy alone (both using behaviour therapy). No statistically significant differences were observed in response during the intervention (relative risk (RR) for combination 1.25, 95% CI 0.78 to 2.03, P = 0.35), at the end of the intervention (RR 0.78, 0.45 to 1.35, P = 0.37), or at the last follow-up time point, although the follow-up data suggested that the combination might be inferior to behaviour therapy alone (RR 0.62, 0.36 to 1.07, P = 0.08). One trial (77 participants) compared combination with a benzodiazepine alone. No differences were found in response during the intervention (RR 1.57, 0.83 to 2.98, P = 0.17). Although the combination appeared to be superior to the benzodiazepine alone at the end of treatment (RR 3.39, 1.03 to 11.21, P = 0.05) the finding was only borderline statistically significant, and no significant differences were observed at the 7-month follow-up (RR 2.31, 0.79 to 6.74, P = 0.12). The review established the paucity of high quality evidence investigating the efficacy of psychotherapy combined with benzodiazepines for panic disorder. Currently, there is inadequate evidence to assess the clinical effects of psychotherapy combined with benzodiazepines for patients who are diagnosed with panic disorder.

This review included randomised controlled trials comparing the combination of psychotherapy and a benzodiazepine with either the psychotherapy or the benzodiazapine alone for people with panic disorder. We were able to include only three trials in this review. Two could be used in the comparison of the combination of psychotherapy and benzodiazepine versus psychotherapy alone and one in the comparison of the combination with benzodiazepine. These comparisons involved just 166 patients and 77 patients, respectively. These small numbers make it difficult to detect any differences between combination treatments and either treatment alone. The trials which compared the combination of treatments with psychotherapy alone (both using behaviour therapy) indicated no differences in response between the two approaches, either during the intervention, at the end of the intervention, or at the last follow-up time point. The trial which compared the combination of treatments with a benzodiazepine alone demonstrated no differences in response during the intervention. Although the combination of treatments appeared to be more effective than the benzodiazepine alone at the end of treatment, no significant differences were observed at the 7-month follow-up. Before evidence-based treatment recommendations are possible, more randomised controlled trials are required, comparing the combination of psychotherapy and benzodiazepines with either treatment alone, and involving enough people to be able to detect a true difference between the treatments if one exists.

10.1002/14651858.CD005335.pub2

cochrane-simplification-train-2976

cochrane-simplification-train-2976

Seven trials were included with a total of 426 children studied (274 with oral prednisone vs. placebo, 106 with intravenous steroids vs placebo and 46 with nebulised budesonide vs prednisolone). A significant number of steroid treated children were discharged early after admission (>4 hours) with an OR of 7.00 (95% CI: 2.98 to 16.45) and NNT of 3 (95%CI: 2 to 8). The length of stay was shorter in the steroid groups with a WMD of -8.75 hours (95% CI: -19.23 to 1.74). There were no significant differences between groups in pulmonary function or oxygen saturation measurements. Children treated with steroids in hospital were less likely to relapse within one to three months with OR 0.19 (95%CI: 0.07 to 0.55) and NNT of 3 (95%CI: 2 to 7). The single small study that compared nebulised budesonide to oral prednisone failed to demonstrate equivalence or a difference between each therapy. Systemic corticosteroids produce some improvements for children admitted to hospital with acute asthma. The benefits may include earlier discharge and fewer relapses. Inhaled or nebulised corticosteroids cannot be recommended as equivalent to systemic steroids at this time. Further studies examining differing doses and routes of administration for corticosteroids will clarify the optimal therapy.

This review asked the question "do steroid drugs help children admitted to hospital with asthma?" We found that steroids given by mouth or through an intravenous tube help children recover from acute asthma. The benefits may include earlier discharge or a shorter stay in hospital. Children were less likely to come back to hospital in the one to three months following the admission. However, the evidence was not overwhelming due to the limited number of studies available and different medicines used. Further research needs to concentrate on the best medications to use and the best route of administration.

10.1002/14651858.CD002886

cochrane-simplification-train-2977

cochrane-simplification-train-2977

Two RCTs met our inclusion criteria, involving a total of 827 participants. Both studies only recruited children with acute URTIs (adults were not involved in either study): 558 children from 61 general practices in England and Wales; and 269 primary care doctors who provided data on 33,792 patient-doctor consultations in Kentucky, USA. The UK study had a high risk of bias due to lack of blinding and the US cluster-randomised study had a high risk of bias because the methods to allocate participants to treatment groups was not clear, and there was evidence of baseline imbalance. In both studies, clinicians provided written information to parents of child patients during primary care consultations: one trained general practitioners (GPs) to discuss an eight-page booklet with parents; the other conducted a factorial trial with two comparison groups (written information compared to usual care and written information plus prescribing feedback to clinicians compared to prescribing feedback alone). Doctors in the written information arms received 25 copies of two-page government-sponsored pamphlets to distribute to parents. Compared to usual care, we found moderate quality evidence (one study) that written information significantly reduced the number of antibiotics used by patients (RR 0.53, 95% CI 0.35 to 0.80; absolute risk reduction (ARR) 20% (22% versus 42%)) and had no significant effect on reconsultation rates (RR 0.79, 95% CI 0.47 to 1.32), or parent satisfaction with consultation (RR 0.95, 95% CI 0.87 to 1.03). Low quality evidence (two studies) demonstrated that written information also reduced antibiotics prescribed by clinicians (RR 0.47, 95% CI 0.28 to 0.78; ARR 21% (20% versus 41%); and RR 0.84, 95% CI 0.81 to 0.86; 9% ARR (45% versus 54%)). Neither study measured resolution of symptoms, patient knowledge about antibiotics for acute URTIs, or complications for this comparison. Compared to prescribing feedback, we found low quality evidence that written information plus prescribing feedback significantly increased the number of antibiotics prescribed by clinicians (RR 1.13, 95% CI 1.09 to 1.17; absolute risk increase 6% (50% versus 44%)). Neither study measured reconsultation rate, resolution of symptoms, patient knowledge about antibiotics for acute URTIs, patient satisfaction with consultation or complications for this comparison. Compared to usual care, moderate quality evidence from one study showed that trained GPs providing written information to parents of children with acute URTIs in primary care can reduce the number of antibiotics used by patients without any negative impact on reconsultation rates or parental satisfaction with consultation. Low quality evidence from two studies shows that, compared to usual care, GPs prescribe fewer antibiotics for acute URTIs but prescribe more antibiotics when written information is provided alongside prescribing feedback (compared to prescribing feedback alone). There was no evidence addressing resolution of patients' symptoms, patient knowledge about antibiotics for acute URTIs, or frequency of complications. To fill evidence gaps, future studies should consider testing written information on antibiotic use for adults with acute URTIs in high- and low-income settings provided without clinician training and presented in different formats (such as electronic). Future study designs should endeavour to ensure blinded outcome assessors. Study aims should include measurement of the effect of written information on the number of antibiotics used by patients and prescribed by clinicians, patient satisfaction, reconsultation, patients' knowledge about antibiotics, resolution of symptoms, and complications.

We found two studies that included children with upper airway infections: one involved 558 children who were recruited from 61 general practices in England and Wales; and another of 269 doctors who provided data on 33,792 patient-doctor consultations in Kentucky, USA. Participants were children accompanied by an adult. One study trained general practitioners (GPs) to discuss written information with parents, and in the other, doctors distributed copies of government-sponsored pamphlets to parents. Both studies were funded by government bodies and one was also funded by Pfizer (a pharmaceutical company). Providing a booklet and explanation by a specially-trained doctor reduced the number of antibiotics children consumed by 20% (from 42% to 22%) without affecting parent satisfaction with consultation or numbers of return visits for the same illness. Compared to the doctor’s usual practice, two studies showed that providing a booklet reduced the proportion of children prescribed an antibiotic by 9% to 21%. When doctors were also given feedback on their antibiotic prescribing along with providing a booklet to parents, the proportion of children prescribed an antibiotic increased by 6% (from 44% to 50%). None of the included studies assessed if people were better informed, how long symptoms lasted, or if people had complications. Evidence quality was moderate to low. Doctors and parents knew when written information had been used. One study had a high risk of bias because study groups were not comparable at baseline, so we can be less confident of its findings. Studies were set in the UK and USA, so results are not applicable to lower-income countries, nor for different primary healthcare services, including settings where prescriptions are unnecessary to obtain antibiotics.

10.1002/14651858.CD011360.pub2

cochrane-simplification-train-2978

cochrane-simplification-train-2978

We included 31 trials with a total of 2257 participants in the subacute or chronic stages of stroke. The methodological quality of most of the included trials was not high. The quality of evidence for the main outcomes was low or very low based on the assessment by the system of Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Two trials compared real acupuncture plus baseline treatment with sham acupuncture plus baseline treatment. There was no evidence of differences in the changes of motor function and quality of life between real acupuncture and sham acupuncture for people with stroke in the convalescent stage. Twenty-nine trials compared acupuncture plus baseline treatment versus baseline treatment alone. Compared with no acupuncture, for people with stroke in the convalescent phase, acupuncture had beneficial effects on the improvement of dependency (activity of daily living) measured by Barthel Index (nine trials, 616 participants; mean difference (MD) 9.19, 95% confidence interval (CI) 4.34 to 14.05; GRADE very low), global neurological deficiency (seven trials, 543 participants; odds ratio (OR) 3.89, 95% CI 1.78 to 8.49; GRADE low), and specific neurological impairments including motor function measured by Fugl-Meyer Assessment (four trials, 245 participants; MD 6.16, 95% CI 4.20 to 8.11; GRADE low), cognitive function measured by the Mini-Mental State Examination (five trials, 278 participants; MD 2.54, 95% CI 0.03 to 5.05; GRADE very low), depression measured by the Hamilton Depression Scale (six trials, 552 participants; MD -2.58, 95% CI -3.28 to -1.87; GRADE very low), swallowing function measured by drinking test (two trials, 200 participants; MD -1.11, 95% CI -2.08 to -0.14; GRADE very low), and pain measured by the Visual Analogue Scale (two trials, 118 participants; MD -2.88, 95% CI -3.68 to -2.09; GRADE low). Sickness caused by acupuncture and intolerance of pain at acupoints were reported in a few participants with stroke in the acupuncture groups. No data on death, the proportion of people requiring institutional care or requiring extensive family support, and all-cause mortality were available in all included trials. From the available evidence, acupuncture may have beneficial effects on improving dependency, global neurological deficiency, and some specific neurological impairments for people with stroke in the convalescent stage, with no obvious serious adverse events. However, most included trials were of inadequate quality and size. There is, therefore, inadequate evidence to draw any conclusions about its routine use. Rigorously designed, randomised, multi-centre, large sample trials of acupuncture for stroke are needed to further assess its effects.

We identified 31 studies to July 2015 for inclusion in the review. These included a total of 2257 participants who had had a stroke more than one month previously. They all investigated acupuncture aimed at promoting recovery compared with no acupuncture or sham acupuncture. Outcomes included measures of daily activities (activities of daily living), neurological function, movement, cognition, depression, swallowing, pain, and quality of life. Most of the studies (29/31) were conducted in China; the studies varied considerably with respect to the time of stroke, specific techniques used, and the frequency of acupuncture. We found some evidence that acupuncture improved activities of daily living and a number of aspects of neurological function. However, these conclusions were based on studies with low quality evidence. No serious side effects were reported and there was no information on the effects of acupuncture on death or the need for institutional care. It proved difficult to reliably determine the quality of the evidence because of poor reporting of study characteristics. Therefore, we have described most conclusions as having low or very low quality evidence.

10.1002/14651858.CD004131.pub3

cochrane-simplification-train-2979

cochrane-simplification-train-2979

We included one randomised clinical trial with 61 participants (43 male and 18 female) with colorectal cancer with liver metastases: 22 received transarterial embolisation (TAE; hepatic artery embolisation), 19 received transarterial chemoembolisation (TACE; 5-fluorouracil hepatic artery infusion chemotherapy with degradable microspheres), and 20 received 'no active therapeutic intervention' as a control. Most tumours were synchronous, unresectable metastases involving up to 75% of the liver. Participants were followed for a minimum of seven months. The trial was at high risk of bias. Very-low-certainty evidence found inconclusive results for mortality at 44 months between the TAE and TACE versus no intervention groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.06; 61 participants). Local recurrence was reported in 10 participants without any details about the group allocation. Very-low-certainty evidence found little or no difference in mortality between the TAE and no intervention groups (RR 0.91, 95% CI 0.75 to 1.10; 42 participants). Median survival was 7 months from trial entry (range 2 to 44 months) in the TAE group and 7.9 months (range 1 to 26 months) in the control group, and 8.7 months after diagnosis (range 2 to 49 months) in the TAE group and 9.6 months (range 1 to 27 months) in the control group. The trial authors reported the differences were not statistically significant. There were no reported side effects in the control group. In the TAE group, 18 participants experienced short-term symptoms of 'post-embolisation syndrome', which were relieved with symptomatic treatment; one participant also had a local puncture site haematoma. Very-low-certainty evidence found little or no difference in mortality between the TACE and no intervention groups (RR 0.83, 95% CI 0.65 to 1.07; 39 participants). Median survival in the TACE group was 10.7 months (range 3 to 38 months) from trial entry, and 13.0 months (range 3 to 38 months) after diagnosis. The trial authors reported that differences between groups were not statistically significant. All participants experienced short-term nausea, with or without vomiting, immediately after treatment; one participant developed a wound infection, and one developed deep vein thrombosis. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life. Cancer Research Campaign, a non-profit organisation, provided a grant for the trial; Pharmacia Ltd. delivered the Port-a-Cath arterial delivery systems and degradable starch microspheres. We identified one ongoing trial comparing TACE plus chemotherapy versus chemotherapy alone in people with unresectable colorectal liver metastases who failed with first-line chemotherapy (NCT03783559). Based on one, small randomised trial at high risk of bias, the evidence is very uncertain about the effect of TAE or TACE versus no active therapeutic intervention on mortality for people with liver metastases as the true effect may be substantially different. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life. Short-term, minor adverse events were recorded in the intervention groups only. Large trials, following current standards of conduct and reporting, are required to explore the benefits and harms of TAE or TACE compared with no intervention or placebo in people with resectable and unresectable liver metastasis.

We last searched for evidence on 20 December 2019. We included one randomised trial from earlier searches. This trial randomly assigned people with colorectal liver metastases that could not be surgically removed, to one of three intervention groups: TAE (22 participants), TACE (19 participants), and a control group (20 participants) that received no active therapeutic intervention. Cancer Research Campaign, a non-profit organisation, provided a grant for the study; Pharmacia Ltd. delivered the Port-a-Cath arterial delivery systems and degradable starch microspheres. Trial participants were followed for a minimum of seven months. Mortality at 44 months from trial entry was 86% in the TAE group, 79% in the TACE group, and 95% in the control group. Median survival after trial entry was 7.0 months in the TAE group, 10.7 months in the TACE group, and 7.9 months in the control group. Median survival from diagnosis was 8.7 months in the TAE group, 13.0 months in the TACE group, and 9.6 months in the control group. Local recurrence was reported in 10 participants, without further details of their treatment group. None of the participants in the control group reported side effects; 82% of the TAE group experienced short-term pain, nausea, vomiting, and high temperature, which got better with symptomatic treatment, and there was one report of bruising at the puncture site. TACE recipients reported short-term nausea, with or without vomiting, after most of the treatment sessions, and short-lived pain or discomfort; there was one wound infection, and one case of deep vein thrombosis. All the results were inconclusive between groups. The evidence from one small randomised clinical trial showed neither beneficial nor harmful effects of TAE or TACE compared to no intervention, in people with liver metastases, measured by mortality. We did not find data on the other outcomes of interest. We judged the evidence to be of very low certainty. The identified trial was small, at high risk of bias, and with inconclusive results.

10.1002/14651858.CD009498.pub4

cochrane-simplification-train-2980

cochrane-simplification-train-2980

This updated review includes 12 studies (6177 women), 11 in women in labour for whom a vaginal birth was intended, and one in women where an assisted birth was anticipated. Two were trials each with more than 1000 women (Argentina and the UK), and the rest were smaller (from Canada, Germany, Spain, Ireland, Malaysia, Pakistan, Columbia and Saudi Arabia). Eight trials included primiparous women only, and four trials were in both primiparous and multiparous women. For risk of bias, allocation was adequately concealed and reported in nine trials; sequence generation random and adequately reported in three trials; blinding of outcomes adequate and reported in one trial, blinding of participants and personnel reported in one trial. For women where an unassisted vaginal birth was anticipated, a policy of selective episiotomy may result in 30% fewer women experiencing severe perineal/vaginal trauma (RR 0.70, 95% CI 0.52 to 0.94; 5375 women; eight RCTs; low-certainty evidence). We do not know if there is a difference for blood loss at delivery (an average of 27 mL less with selective episiotomy, 95% CI from 75 mL less to 20 mL more; two trials, 336 women, very low-certainty evidence). Both selective and routine episiotomy have little or no effect on infants with Apgar score less than seven at five minutes (four trials, no events; 3908 women, moderate-certainty evidence); and there may be little or no difference in perineal infection (RR 0.90, 95% CI 0.45 to 1.82, three trials, 1467 participants, low-certainty evidence). For pain, we do not know if selective episiotomy compared with routine results in fewer women with moderate or severe perineal pain (measured on a visual analogue scale) at three days postpartum (RR 0.71, 95% CI 0.48 to 1.05, one trial, 165 participants, very low-certainty evidence). There is probably little or no difference for long-term (six months or more) dyspareunia (RR1.14, 95% CI 0.84 to 1.53, three trials, 1107 participants, moderate-certainty evidence); and there may be little or no difference for long-term (six months or more) urinary incontinence (average RR 0.98, 95% CI 0.67 to 1.44, three trials, 1107 participants, low-certainty evidence). One trial reported genital prolapse at three years postpartum. There was no clear difference between the two groups (RR 0.30, 95% CI 0.06 to 1.41; 365 women; one trial, low certainty evidence). Other outcomes relating to long-term effects were not reported (urinary fistula, rectal fistula, and faecal incontinence). Subgroup analyses by parity (primiparae versus multiparae) and by surgical method (midline versus mediolateral episiotomy) did not identify any modifying effects. Pain was not well assessed, and women's preferences were not reported. One trial examined selective episiotomy compared with routine episiotomy in women where an operative vaginal delivery was intended in 175 women, and did not show clear difference on severe perineal trauma between the restrictive and routine use of episiotomy, but the analysis was underpowered. In women where no instrumental delivery is intended, selective episiotomy policies result in fewer women with severe perineal/vaginal trauma. Other findings, both in the short or long term, provide no clear evidence that selective episiotomy policies results in harm to mother or baby. The review thus demonstrates that believing that routine episiotomy reduces perineal/vaginal trauma is not justified by current evidence. Further research in women where instrumental delivery is intended may help clarify if routine episiotomy is useful in this particular group. These trials should use better, standardised outcome assessment methods.

We prepared this edition of this review by updating the methods and searching for evidence from the medical literature on 14 September 2016. The review now includes 11 randomised controlled trials (with 5977 women) that compared episiotomy as needed (selective episiotomy) with routine episiotomy in terms of benefits and harms for mother and baby in women at low risk of instrumental delivery. The trials were from ten different countries. In women where health staff were only conducting selective episiotomy, there may be 30% fewer with severe perineal trauma at birth compared with women where a policy of routine episiotomy was applied (eight trials, 5375 women, low-certainty evidence). We do not know if there is a difference in average blood loss between the groups (two trials, very low-certainty evidence). There is probably no difference in Apgar less than seven at five minutes, with no events in either groups (moderate-certainty evidence). We do not know if there is a difference in the number of women with moderate or severe perineal pain three days after giving birth (one trial, 165 women, very low-certainty evidence) but careful assessment of women's pain was not well carried out in the included trials. There may be little or no difference in the number of women developing perineal infection (two trials, low-certainty evidence); and there is probably little or no difference in women reporting painful sexual intercourse six months or more after delivery (three trials, 1107 women, moderate-certainty evidence); for urinary incontinence six months or more after delivery, there may be little or no difference between the groups. One study reported genital prolapse three years after the birth and there was no clear difference between groups (low-certainty evidence). Other important outcomes relating to long-term effects were not reported in these trials (urinary fistula, rectal fistula, and faecal incontinence). One trial examined selective episiotomy compared with routine episiotomy in women for whom an operative vaginal birth was intended. The results showed no clear difference in severe perineal trauma between the restrictive and routine use of episiotomy. Women's views on the different policies were not reported. Overall, the findings show that selective use of episiotomy in women (where a normal delivery without forceps is anticipated) means that fewer women have severe perineal trauma. Thus the rationale for conducting routine episiotomies to prevent severe perineal trauma is not justified by current evidence, and we could not identify any benefits of routine episiotomy for the baby or the mother. More research is needed in order to inform policy in women where an instrumental birth is planned and episiotomy is often advocated. Outcomes could be better standardised and measured.

10.1002/14651858.CD000081.pub3

cochrane-simplification-train-2981

cochrane-simplification-train-2981

We included two RCTs conducted in Taiwan with a total of 131 participants. We did not perform a meta-analysis as the trials were assessing different outcomes. Neither trial met our pre-defined primary outcome criteria of myopia progression defined as one diopter mean change. Only one trial reported the changes of axial length without non-significant difference among groups and both trials reported that several children experienced mild pain during acupuncture stimulation. Two trials are included in this review but no conclusions can be drawn for the benefit of co-acupressure for slowing progress of myopia in children. Further evidence in the form of RCTs are needed before any recommendations can be made for the use of acupuncture treatment in clinical use. These trials should compare acupuncture to placebo and have large sample sizes. Other types of acupuncture (such as auricular acupuncture) should be explored further as well as compliance with treatment for at least six months or longer. Axial length elongation of the eye should be investigated for at least one year. The potential to reduce/eliminate pain from acupuncture experienced by children should also be reviewed.

This review aimed to assess the effectiveness and safety of acupuncture in slowing the progression of myopia in children and adolescents. We included two studies conducted in Taiwan with a total of 131 school children and did not combine the results as the two trials assessed different outcomes. One study found no significant difference in changes in the length of the eyes. Both studies found several children experienced mild pain while pressing and dropped out. The included studies in this review were unable to provide evidence of the effect of acupuncture for slowing the progression of myopia. More trials should be conducted where acupuncture is compared to placebo, other types of acupuncture are investigated, compliance with treatment for at least six months is explored and axial length elongation of the eye should be for at least one year.

10.1002/14651858.CD007842.pub2

cochrane-simplification-train-2982

cochrane-simplification-train-2982

We included six trials randomising 359 participants, 178 to T-tube drainage and 181 to primary closure. All trials were at high risk of bias. There was no significant difference in mortality between the two groups (4/178 (weighted percentage 1.2%) in the T-tube group versus 1/181 (0.6%) in the primary closure group; RR 2.25; 95% CI 0.55 to 9.25; six trials). There was no significant difference in the serious morbidity rate between the two groups (24/136 (weighted serious morbidity rate, 145 events per 1000 patients) in the T-tube group versus 9/136 (weighted serious morbidity rate, 66 events per 1000 patients) in the primary closure group; RaR 2.19; 95% CI 0.98 to 4.91; four trials). Quality of life and return to work were not reported in any of the trials. The operating time was significantly longer in the T-tube drainage group compared with the primary closure group (MD 28.90 minutes; 95% CI 17.18 to 40.62 minutes; one trial). The hospital stay was significantly longer in the T-tube drainage group compared with the primary closure group (MD 4.72 days; 95% CI 0.83 days to 8.60 days; five trials). T-tube drainage appeared to result in significantly longer operating time and hospital stay compared with primary closure without any apparent evidence of benefit on clinically important outcomes after open common bile duct exploration. Based on the currently available evidence, there is no justification for the routine use of T-tube drainage after open common bile duct exploration in patients with common bile duct stones. T-tube drainage should not be used outside well designed randomised clinical trials. More randomised trials comparing the effects of T-tube drainage versus primary closure after open common bile duct exploration may be needed. Such trials should be conducted with low risk of bias and assessing the long-term beneficial and harmful effects of T-tube drainage, including long-term complications such as bile stricture and recurrence of common bile duct stones.

We identified a total of six trials including 359 participants of whom 178 had primary closure and 181 patients had T-tube drainage after open exploration of the common bile duct. All six trials were at high risk of bias (risk of overestimating the benefits and underestimating the harms of the intervention or the control). There was no significant difference in mortality (12 deaths per 1000 participants in the T-tube drainage group versus 6 deaths per 1000 participants in the primary closure group) or in the serious complication rate after surgery between the two groups (approximately 145 complications per 1000 participants in the T-tube drainage group versus 66 complications per 1000 participants in the primary closure group). Although the number of deaths and complication rates in the primary closure group appeared to be less than half those in the T-tube group, there is a possibility that this was not a true observation but rather a difference that occurred by chance (similar to there being one chance in eight of flipping a coin and having it come up heads or tails three times in a row). For this reason we cannot be sufficiently confident that a true effect exists, and we term such a difference as not being statistically significant. None of the trials reported quality of life or the time taken for patients to return to work. The average operating time was significantly longer in the T-tube drainage group than in the primary closure group (by about 30 minutes). The average hospital stay was significantly longer in the T-tube group than in the primary closure group (by about five days). Use of a T-tube appears to increase the cost without providing any benefit to the patients. Further randomised trials with low risk of bias (low chance of arriving at the wrong conclusions because of prejudice by healthcare providers, researchers, or patients) and low risk of random errors (arriving at wrong conclusions because of chance) are necessary to confirm whether the use of T-tubes is justified anymore. Until the results from such trials are available, we discourage the routine use of T-tube after open common bile duct exploration.

10.1002/14651858.CD005640.pub3

cochrane-simplification-train-2983

cochrane-simplification-train-2983

We included 84 RCTs with 8234 participants in this review. Six trials (N = 658) did not report any of the outcomes of interest for this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. The treatments assessed in these 78 trials included antibiotics, antioxidants, aprotinin, atropine, calcitonin, cimetidine, EDTA (ethylenediaminetetraacetic acid), gabexate, glucagon, iniprol, lexipafant, NSAIDs (non-steroidal anti-inflammatory drugs), octreotide, oxyphenonium, probiotics, activated protein C, somatostatin, somatostatin plus omeprazole, somatostatin plus ulinastatin, thymosin, ulinastatin, and inactive control. Apart from the comparison of antibiotics versus control, which included a large proportion of participants with necrotising pancreatitis, the remaining comparisons had only a small proportion of patients with this condition. Most trials included either only participants with severe acute pancreatitis or included a mixture of participants with mild acute pancreatitis and severe acute pancreatitis (75 trials). Overall, the risk of bias in trials was unclear or high for all but one of the trials. Source of funding: seven trials were not funded or funded by agencies without vested interest in results. Pharmaceutical companies partially or fully funded 21 trials. The source of funding was not available from the remaining trials. Since we considered short-term mortality as the most important outcome, we presented only these results in detail in the abstract. Sixty-seven studies including 6638 participants reported short-term mortality. There was no evidence of any differences in short-term mortality in any of the comparisons (very low-quality evidence). With regards to other primary outcomes, serious adverse events (number) were lower than control in participants taking lexipafant (rate ratio 0.67, 95% CI 0.46 to 0.96; N = 290; 1 study; very low-quality evidence), octreotide (rate ratio 0.74, 95% CI 0.60 to 0.89; N = 770; 5 studies; very low-quality evidence), somatostatin plus omeprazole (rate ratio 0.36, 95% CI 0.19 to 0.70; N = 140; 1 study; low-quality evidence), and somatostatin plus ulinastatin (rate ratio 0.30, 95% CI 0.15 to 0.60; N = 122; 1 study; low-quality evidence). The proportion of people with organ failure was lower in octreotide than control (OR 0.51, 95% CI 0.27 to 0.97; N = 430; 3 studies; very low-quality evidence). The proportion of people with sepsis was lower in lexipafant than control (OR 0.26, 95% CI 0.08 to 0.83; N = 290; 1 study; very low-quality evidence). There was no evidence of differences in any of the remaining comparisons in these outcomes or for any of the remaining primary outcomes (the proportion of participants experiencing at least one serious adverse event and the occurrence of infected pancreatic necrosis). None of the trials reported heath-related quality of life. Very low-quality evidence suggests that none of the pharmacological treatments studied decrease short-term mortality in people with acute pancreatitis. However, the confidence intervals were wide and consistent with an increase or decrease in short-term mortality due to the interventions. We did not find consistent clinical benefits with any intervention. Because of the limitations in the prognostic scoring systems and because damage to organs may occur in acute pancreatitis before they are clinically manifest, future trials should consider including pancreatitis of all severity but power the study to measure the differences in the subgroup of people with severe acute pancreatitis. It may be difficult to power the studies based on mortality. Future trials in participants with acute pancreatitis should consider other outcomes such as complications or health-related quality of life as primary outcomes. Such trials should include health-related quality of life, costs, and return to work as outcomes and should follow patients for at least three months (preferably for at least one year).

We included 84 RCTs with 8234 participants in this review. Six trials (658 participants) did not report any of the outcomes of interest for this review. In the remaining 78 trials, 210 participants were excluded after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. Apart from the comparison of whether antibiotics should be used, the other comparisons included only a small percentage of people with pancreatic necrosis (an extremely severe form of pancreatitis, which results in pancreatic destruction). Most trials included only the severe form of acute pancreatitis or included both mild and severe forms of pancreatitis. Source of funding: seven trials were not funded or were funded by agencies without vested interest in results. Twenty-one trials were partly or fully funded by pharmaceutical companies. The source of funding was not available from the remaining trials. The overall quality of evidence was low for all the measures because the trials were at unclear or high risk of bias (a systematic error or deviation from the truth that affects the results, favouring one treatment over another) and were small trials. As a result, further studies are required on this topic. Sixty-seven studies including 6638 participants reported short-term deaths. Overall, an average 12% of people who received only supportive care died. There was no evidence that any of the treatments decreased short-term deaths. There was evidence that various treatments might be beneficial in a number of outcomes; however, these results were not consistent, and we cannot make any conclusions as to whether any of the treatments may be beneficial. None of the trials reported health-related quality of life. In conclusion, based on low quality evidence, there is no evidence that any drug treatment added on to supportive care decreases short-term deaths. Future trials in participants with acute pancreatitis should include health-related quality of life, costs, and return to work as outcomes and should follow patients for at least three months (preferably for at least one year).

10.1002/14651858.CD011384.pub2

cochrane-simplification-train-2984

cochrane-simplification-train-2984

We included 14 studies (of which six have been published since the first version of this review in 2013), with a total of 1358 participants. We found studies that investigated exercises, predischarge home visits for hospitalised patients, the provision of single lens distance vision glasses instead of multifocal glasses, a servo-assistive rollator and non-invasive brain stimulation for preventing falls. Exercise compared to control for preventing falls in people after stroke The pooled result of eight studies showed that exercise may reduce the rate of falls but we are uncertain about this result (rate ratio 0.72, 95% CI 0.54 to 0.94, 765 participants, low-quality evidence). Sensitivity analysis for single exercise interventions, omitting studies using multiple/multifactorial interventions, also found that exercise may reduce the rate of falls (rate ratio 0.66, 95% CI 0.50 to 0.87, 626 participants). Sensitivity analysis for the effect in the chronic phase post stroke resulted in little or no difference in rate of falls (rate ratio 0.58, 95% CI 0.31 to 1.12, 205 participants). A sensitivity analysis including only studies with low risk of bias found little or no difference in rate of falls (rate ratio 0.88, 95% CI 0.65 to 1.20, 462 participants). Methodological limitations mean that we have very low confidence in the results of these sensitivity analyses. For the outcome of number of fallers, we are very uncertain of the effect of exercises compared to the control condition, based on the pooled result of 10 studies (risk ratio 1.03, 95% CI 0.90 to 1.19, 969 participants, very low quality evidence). The same sensitivity analyses as described above gives us very low certainty that there are little or no differences in number of fallers (single interventions: risk ratio 1.09, 95% CI 0.93 to 1.28, 796 participants; chronic phase post stroke: risk ratio 0.94, 95% CI 0.73 to 1.22, 375 participants; low risk of bias studies: risk ratio 0.96, 95% CI 0.77 to 1.21, 462 participants). Other interventions for preventing falls in people after stroke We are very uncertain whether interventions other than exercise reduce the rate of falls or number of fallers. We identified very low certainty evidence when investigating the effect of predischarge home visits (rate ratio 0.85, 95% CI 0.43 to 1.69; risk ratio 1.48, 95% CI 0.71 to 3.09; 85 participants), provision of single lens distance glasses to regular wearers of multifocal glasses (rate ratio 1.08, 95% CI 0.52 to 2.25; risk ratio 0.74, 95% CI 0.47 to 1.18; 46 participants) and a servo-assistive rollator (rate ratio 0.44, 95% CI 0.16 to 1.21; risk ratio 0.44, 95% CI 0.16 to 1.22; 42 participants). Finally, transcranial direct current stimulation (tDCS) was used in one study to examine the effect on falls post stroke. We have low certainty that active tDCS may reduce the number of fallers compared to sham tDCS (risk ratio 0.30, 95% CI 0.14 to 0.63; 60 participants). At present there exists very little evidence about interventions other than exercises to reduce falling post stroke. Low to very low quality evidence exists that this population benefits from exercises to prevent falls, but not to reduce number of fallers. Fall research does not in general or consistently follow methodological gold standards, especially with regard to fall definition and time post stroke. More well-reported, adequately-powered research should further establish the value of exercises in reducing falling, in particular per phase, post stroke.

After searching the literature, we included 14 studies with a total of 1358 participants. We found studies that investigated various interventions for preventing falls: physical exercises; predischarge home visits for hospitalised patients; the provision of single lens distance vision glasses instead of multifocal glasses; a servo-assistive rollator; and non-invasive brain stimulation. Included studies conducted their investigations in early to chronic inpatient, outpatient, and community dwelling settings. None Exercises appear to reduce the rate of falls, but not the number of people falling post stroke. Among the studies that used exercises as an intervention condition, the majority of studies asked participants to solely perform exercises. One study offered exercises together with additional components, such as educational sessions about falls. Another study offered exercises together with a comprehensive risk assessment and subsequent referrals, such as a review by an optometrist or new shoes, leading to a personalised programme for preventing falls. Besides exercises, several other interventions aiming to prevent falls post stroke were investigated in the literature. One study administered non-invasive brain stimulation to people after stroke and the results showed a potential to decrease the number of people falling, but this study needs to be replicated before consideration in clinical practice. There is no evidence at the moment that predischarge home visits, single lens distance vision glasses instead of multifocal glasses or a servo-assistive rollator reduce the rate of falls or the number of people falling. None of the included studies reported serious harm related to the intervention conditions. In summary: there is little evidence that interventions other than exercises are beneficial for preventing falls in people after stroke. The main reason is that there were only a limited number of studies focusing on people after stroke or that included a stroke subgroup in the study. In addition, studies related to falling do not consistently follow known methodological guidelines, particularly in fall definition and time post stroke. More well-reported, consensual research with an adequate number of participants might further establish the value of exercises in reducing falling post stroke. The quality of the evidence regarding rate of falls and number of fallers ranged from very low to low across the five comparisons, meaning that we have very low to low certainty in these results. The main reasons for downgrading the evidence were the lack of blinding of fall outcome and the majority of comparisons including only one study.

10.1002/14651858.CD008728.pub3

cochrane-simplification-train-2985

cochrane-simplification-train-2985

Fourteen unique trials with 1497 randomised participants were included. Antifungal prophylaxis did not reduce mortality (RR 0.90, 95% CI 0.57 to 1.44). In liver transplant recipients, a significant reduction in IFIs was demonstrated for fluconazole (RR 0.28, 95% CI 0.13 to 0.57). Although less data were available for itraconazole and liposomal amphotericin B, indirect comparisons and one direct comparative trial suggested similar efficacy. Fluconazole prophylaxis did not significantly increase invasive infections or colonisation with fluconazole-resistant fungi. In renal and cardiac transplant recipients, neither ketoconazole nor clotrimazole significantly reduced invasive infections. Overall, the strength and precision of comparisons however were limited by a paucity of data. For liver transplant recipients, antifungal prophylaxis with fluconazole significantly reduces the incidence of IFIs with no definite mortality benefit. Given a 10% incidence of IFI, 14 liver transplant recipients would require fluconazole prophylaxis to prevent one infection. In transplant centres where the incidence of IFIs is high, or in situations where the individual risk is great, antifungal prophylaxis should be considered.

This review found that fluconazole, used as a preventive drug, significantly reduced the number of invasive fungal infections in liver transplant patients. More studies are needed to determine how effective antifungal drugs are for pancreas, heart, kidney and lung transplant patients.

10.1002/14651858.CD004291.pub2

cochrane-simplification-train-2986

cochrane-simplification-train-2986

We identified two new studies (89 participants) in this updated review. A total of 11 studies (1760 participants) met the entry criteria of the review, one of which accounted for 68% of recruited participants. The quality of evidence ranged from low to moderate owing to an unclear risk of bias across many studies, lack of blinding and low participant numbers for some outcomes. Eight of the studies compared LVRS versus standard medical care, one compared two closure techniques (stapling vs laser ablation), one looked at the effect of buttressing the staple line on the effectiveness of LVRS and one compared traditional 'resectional' LVRS with a non-resectional surgical approach. Participants completed a mandatory course of pulmonary rehabilitation/physical training before the procedure commenced. Short-term mortality was higher for LVRS (odds ratio (OR) 6.16, 95% confidence interval (CI) 3.22 to 11.79; 1489 participants; five studies; moderate-quality evidence) than for control, but long-term mortality favoured LVRS (OR 0.76, 95% CI 0.61 to 0.95; 1280 participants; two studies; moderate-quality evidence). Participants identified post hoc as being at high risk of death from surgery were those with particularly impaired lung function, poor diffusing capacity and/or homogenous emphysema. Participants with upper lobe-predominant emphysema and low baseline exercise capacity showed the most favourable outcomes related to mortality, as investigators reported no significant differences in early mortality between participants treated with LVRS and those in the control group (OR 0.87, 95% CI 0.23 to 3.29; 290 participants; one study), as well as significantly lower mortality at the end of follow-up for LVRS compared with control (OR 0.45, 95% CI 0.26 to 0.78; 290 participants; one study). Trials in this review furthermore provided evidence of low to moderate quality showing that improvements in lung function parameters other than forced expiratory volume in one second (FEV1), quality of life and exercise capacity were more likely with LVRS than with usual follow-up. Adverse events were more common with LVRS than with control, specifically the occurrence of (persistent) air leaks, pulmonary morbidity (e.g. pneumonia) and cardiovascular morbidity. Although LVRS leads to an increase in quality-adjusted life-years (QALYs), the procedure is relatively costly overall. Lung volume reduction surgery, an effective treatment for selected patients with severe emphysema, may lead to better health status and lung function outcomes, specifically for patients who have upper lobe-predominant emphysema with low exercise capacity, but the procedure is associated with risks of early mortality and adverse events.

This review examined the research published up to the 14th of April, 2016, and identified 11 studies involving 1760 participants. Eight of the studies compared LVRS versus standard medical care, one compared two closure techniques (stapling vs laser ablation), one looked at the effect of buttressing the staple line on the effectiveness of LVRS and one compared a traditional approach to LVRS with a 'non-resectional' surgical approach. All participants completed a mandatory course of pulmonary rehabilitation/physical training before the procedure commenced. This review found that people undergoing LVRS were at increased risk of death at three months after the procedure. By the end of follow-up, death rates were lower for participants treated with LVRS than for those given standard medical care. Participants who were characterised by poor lung function with a particular distribution of diseased tissue in their lungs were at higher risk of death at three months and throughout one large study. One study identified a group of participants who responded better to LVRS than other participants, making them especially suitable for this treatment. The benefit of surgery for surviving participants was significant in terms of quality of life, exercise capacity and lung function, but costs of the procedure are relatively high, and patients had a greater chance of adverse events after the procedure. The quality of the data reported is low to moderate in nature owing to some methodological issues of the trials (lack of blinding, unclear risk of bias). The results presented in this review are largely dominated by one influential study, which accounted for 68% of the participants.

10.1002/14651858.CD001001.pub3

cochrane-simplification-train-2987

cochrane-simplification-train-2987

We included seven trials (more than 60,000 women): four in high-income countries with individual randomisation; three in low- and middle-income countries with cluster randomisation (clinics as the unit of randomisation). Most of the data included in the review came from the three large, well-designed cluster-randomised trials that took place in Argentina, Cuba, Saudi Arabia, Thailand and Zimbabwe. All results have been adjusted for the cluster design effect. All of the trials were at some risk of bias as blinding of women and staff was not feasible with this type of intervention. For primary outcomes, evidence was graded as being of moderate or low quality, with downgrading decisions due to risks of bias and imprecision of effects. The number of visits for standard care varied, with fewer visits in low- and middle- income country trials. In studies in high-income countries, women in the reduced visits groups, on average, attended between 8.2 and 12 times. In low- and middle- income country trials, many women in the reduced visits group attended on fewer than five occasions, although in these trials the content as well as the number of visits was changed, so as to be more 'goal-oriented'. Perinatal mortality was increased for those randomised to reduced visits rather than standard care, and this difference was borderline for statistical significance (risk ratio (RR) 1.14; 95% confidence interval (CI) 1.00 to 1.31; five trials, 56,431 babies; moderate-quality evidence). In the subgroup analysis, for high-income countries the number of deaths was small (32/5108), and there was no clear difference between the groups (RR 0.90; 95% CI 0.45 to 1.80, two trials); for low- and middle-income countries perinatal mortality was significantly higher in the reduced visits group (RR 1.15; 95% CI 1.01 to 1.32, three trials). There was no clear difference between groups for our other primary outcomes: maternal death (RR 1.13, 95%CI 0.50 to 2.57, three cluster-randomised trials, 51,504 women, low-quality evidence); hypertensive disorders of pregnancy (various definitions including pre-eclampsia) (RR 0.95, 95% CI 0.80 to 1.12, six studies, 54,108 women, low-quality evidence); preterm birth (RR 1.02, 95% CI 0.94 to 1.11; seven studies, 53,661 women, moderate-quality evidence); and small-for-gestational age (RR 0.99, 95% CI 0.91 to 1.09, four studies 43,045 babies, moderate-quality evidence). Reduced visits were associated with a reduction in admission to neonatal intensive care that was borderline for significance (RR 0.89; 95% CI 0.79 to 1.02, five studies, 43,048 babies, moderate quality evidence). There were no clear differences between the groups for the other secondary clinical outcomes. Women in all settings were less satisfied with the reduced visits schedule and perceived the gap between visits as too long. Reduced visits may be associated with lower costs. In settings with limited resources where the number of visits is already low, reduced visits programmes of antenatal care are associated with an increase in perinatal mortality compared to standard care, although admission to neonatal intensive care may be reduced. Women prefer the standard visits schedule. Where the standard number of visits is low, visits should not be reduced without close monitoring of fetal and neonatal outcome.

The review set out to compare studies where women receiving standard care were compared with women attending on a reduced number of occasions. We included seven randomised controlled trials involving more than 60,000 women. We assessed studies for risk of bias and graded the quality of the evidence. The trials were carried out in both high-income (four trials) and low- and middle-income countries (three trials). In high-income countries the number of visits was reduced to around eight. In lower-income countries many women in the reduced visits group attended for care on fewer than five occasions, although the content of visits was altered so as to focus on specific goals. In this review there was no strong evidence of differences between groups receiving a reduced number of antenatal visits compared with standard care on the number of preterm births or low birthweight babies (moderate-quality evidence). However, there was some evidence from these trials that in low- and middle-income countries perinatal mortality may be increased with reduced visits (low-quality evidence) although there may have been fewer admissions to neonatal intensive care but the evidence for this latter outcome was not strong. There was no clear difference between groups for our other primary outcomes including maternal death and hypertensive disorders of pregnancy (including pre-eclampsia). There was evidence that women in all settings were less satisfied with the reduced schedule of visits; for some women the gap between visits was perceived as too long. Reduced visits may be associated with lower costs.

10.1002/14651858.CD000934.pub3

cochrane-simplification-train-2988

cochrane-simplification-train-2988

We included 49 trials (56 comparisons) with 3342 participants. Data were available for: (1) pharmacological interventions with placebo (with 20 pharmacological comparisons); (2) one of various forms of non-invasive brain stimulation with sham stimulation or usual care (with eight non-invasive brain stimulation comparisons); (3) one of various forms of psychological therapy with usual care and/or attention control (with 16 psychological therapy comparisons); (4) pharmacological intervention and various forms of psychological therapy with pharmacological intervention and usual care and/or attention control (with two comparisons); and (5) non-invasive brain stimulation and pharmacological intervention with pharmacological intervention and sham stimulation or usual care (with 10 comparisons). We found no trials for the following comparisons: (6) pharmacological intervention and various forms of psychological therapy interventions versus placebo and psychological therapy; (7) pharmacological intervention and non-invasive brain stimulation versus placebo plus non-invasive brain stimulation; (8) non-invasive brain stimulation and one of various forms of psychological therapy versus non-invasive brain stimulation plus usual care and/or attention control; and (9) non-invasive brain stimulation and one of various forms of psychological therapy versus sham brain stimulation or usual care plus psychological therapy. Treatment effects observed: very low-certainty evidence from eight trials suggests that pharmacological interventions decreased the number of people meeting study criteria for depression (RR 0.70, 95% CI 0.55 to 0.88; 1025 participants) at end of treatment, and very low-certainty evidence from six trials suggests that pharmacological interventions decreased the number of people with less than 50% reduction in depression scale scores at end of treatment (RR 0.47, 95% CI 0.32 to 0.69; 511 participants) compared to placebo. No trials of non-invasive brain stimulation reported on meeting study criteria for depression at end of treatment. Only one trial of non-invasive brain stimulation reported on the outcome <50% reduction in depression scale scores; thus, we were unable to perform a meta-analysis for this outcome. Very low-certainty evidence from six trials suggests that psychological therapy decreased the number of people meeting the study criteria for depression at end of treatment (RR 0.77, 95% CI 0.62 to 0.95; 521 participants) compared to usual care/attention control. No trials of combination therapies reported on the number of people meeting the study criteria for depression at end of treatment. Only one trial of combination (non-invasive brain stimulation and pharmacological intervention) therapy reported <50% reduction in depression scale scores at end of treatment. Thus, we were unable to perform a meta-analysis for this outcome. Five trials reported adverse events related to the central nervous system (CNS) and noted significant harm in the pharmacological interventions group (RR 1.55, 95% CI 1.12 to 2.15; 488 participants; very low-certainty evidence). Four trials found significant gastrointestinal adverse events in the pharmacological interventions group (RR 1.62, 95% CI 1.19 to 2.19; 473 participants; very low-certainty evidence) compared to the placebo group. No significant deaths or adverse events were found in the psychological therapy group compared to the usual care/attention control group. Non-invasive brain stimulation interventions and combination therapies resulted in no deaths. Very low-certainty evidence suggests that pharmacological or psychological therapies can reduce the prevalence of depression. This very low-certainty evidence suggests that pharmacological therapy, psychological therapy, non-invasive brain stimulation, and combined interventions can reduce depressive symptoms. Pharmacological intervention was associated with adverse events related to the CNS and the gastrointestinal tract. More research is required before recommendations can be made about the routine use of such treatments.

We included trials that reported on the use of pharmacological, non-invasive brain stimulation, psychological, and combination therapy interventions to treat depression after stroke. Mean age of participants ranged from 54 to 78 years. Studies were from Asia (30), Europe (11), North America (6), and Australia (2). We included 49 trials (56 treatments) involving 3342 participants. Pharmacological treatments resulted in fewer people meeting the study criteria for depression and less than 50% reduction in depression scale scores at end of treatment. Psychological therapy reduced the number of people meeting the study criteria for depression at end of treatment. More people in the pharmacological treatment group reported central nervous system (in five trials) and gastrointestinal side effects (in four trials) than in the placebo groups. Information on side effects of other treatments was not provided. Estimates of treatment effects were imprecise due to small numbers in most studies and recruitment of people with very different baseline characteristics. We rated the certainty of evidence as very low due to these and other limitations in study design. Antidepressant drugs may benefit people with persistent depressive symptoms after stroke, but care is required in their use, as little is known about their side effects. Psychological therapy may offer a treatment option. Future research should include a broader group of people with stroke.

10.1002/14651858.CD003437.pub4

cochrane-simplification-train-2989

cochrane-simplification-train-2989

We included five trials with a total of 1115 women and their babies (922 women and their babies contributed outcome data). Four of the five included trials had small sample sizes with one large trial that recruited 855 women and babies. All five included trials had a moderate risk of bias. When comparing women receiving additional exercise interventions with those having routine antenatal care, there was no significant difference in GDM incidence (three trials, 826 women, risk ratio (RR) 1.10, 95% confidence interval (CI) 0.66 to 1.84), caesarean section (two trials, 934 women, RR 1.33, 95% CI 0.97 to 1.84) or operative vaginal birth (two trials, 934 women, RR 0.83, 95% CI 0.58 to 1.17). No trial reported the infant primary outcomes prespecified in the review. None of the five included trials found significant differences in insulin sensitivity. Evidence from one single large trial suggested no significant difference in the incidence of developing pregnancy hyperglycaemia not meeting GDM diagnostic criteria, pre-eclampsia or admission to neonatal ward between the two study groups. Babies born to women receiving exercise interventions had a non-significant trend to a lower ponderal index (mean difference (MD) -0.08 gram x 100 m3, 95% CI -0.18 to 0.02, one trial, 84 infants). No significant differences were seen between the two study groups for the outcomes of birthweight (two trials, 167 infants, MD -102.87 grams, 95% CI -235.34 to 29.60), macrosomia (two trials, 934 infants, RR 0.91, 95% CI 0.68 to 1.22), or small-for-gestational age (one trial, 84 infants, RR 1.05, 95% CI 0.25 to 4.40) or gestational age at birth (two trials, 167 infants, MD -0.04 weeks, 95% CI -0.37 to 0.29) or Apgar score less than seven at five minutes (two trials, 919 infants, RR 1.00, 95% CI 0.27 to 3.65). None of the trials reported long-term outcomes for women and their babies. No information was available on health services costs. There is limited randomised controlled trial evidence available on the effect of exercise during pregnancy for preventing pregnancy glucose intolerance or GDM. Results from three randomised trials with moderate risk of bias suggested no significant difference in GDM incidence between women receiving an additional exercise intervention and routine care. Based on the limited data currently available, conclusive evidence is not available to guide practice. Larger, well-designed randomised trials, with standardised behavioural interventions are needed to assess the effects of exercise on preventing GDM and other adverse pregnancy outcomes including large-for-gestational age and perinatal mortality. Longer-term health outcomes for both women and their babies and health service costs should be included. Several such trials are in progress. We identified another seven trials which are ongoing and we will consider these for inclusion in the next update of this review.

This review aimed to assess the effects of physical exercise for pregnant women in preventing glucose intolerance or GDM and was based on limited evidence from five randomised controlled trials. Two trials involved obese women. The trials provided data from 922 women and their babies and were of moderate risk of bias. The exercise programs including individualised exercise with regular advice, weekly supervised group exercise session or home-based stationary cycling, either supervised or unsupervised, had no clear effect on preventing GDM (three trials with 826 women screened at 18 to 36 weeks' gestation), or improving insulin sensitivity (five trials) compared with standard antenatal care with normal daily activities. Based on these limited data, conclusive evidence is not available to guide practice. Larger, well-designed randomised trials are needed. Several such trials are in progress. We identified another seven trials which are ongoing and we will consider these for inclusion in the next update.

10.1002/14651858.CD009021.pub2

cochrane-simplification-train-2990

cochrane-simplification-train-2990

Thirteen studies on 6000 participants met the inclusion criteria. Four used mepolizumab, four used reslizumab, and five used benralizumab. One study in benralizumab was terminated early due to sponsor decision and contributed no data. The studies were predominantly on people with severe eosinophilic asthma, which was similarly but variably defined. Eight included children over 12 years but these results were not reported separately. We deemed the risk of bias to be low, with all studies contributing data being of robust methodology. We considered the quality of the evidence for all comparisons to be high overall using the GRADE scheme, with the exception of intravenous mepolizumab because this is not currently a licensed delivery route. All of the anti-IL-5 treatments assessed reduced rates of 'clinically significant' asthma exacerbation (defined by treatment with systemic corticosteroids for three days or more) by approximately half in participants with severe eosinophilic asthma on standard of care (at least medium-dose inhaled corticosteroids (ICS)) with poorly controlled disease (either two or more exacerbations in the preceding year or Asthma Control Questionnaire (ACQ) 1.5 or more). Non-eosinophilic participants treated with benralizumab also showed a significant reduction in exacerbation rates, but no data were available for non-eosinophilic participants, and mepolizumab or reslizumab. We saw modest improvements in validated HRQoL scores with all anti-IL-5 agents in severe eosinophilic asthma. However these did not exceed the minimum clinically important difference for ACQ and Asthma Quality of Life Questionnaire (AQLQ), with St. George's Respiratory Questionnaire (SGRQ) only assessed in two studies. The improvement in HRQoL scores in non-eosinophilic participants treated with benralizumab, the only intervention for which data were available in this subset, was not statistically significant, but the test for subgroup difference was negative. All anti-IL-5 treatments produced a small but statistically significant improvement in mean pre-bronchodilator forced expiratory flow in one second (FEV1) of between 0.08 L and 0.11 L. There were no excess serious adverse events with any anti-IL-5 treatment, and indeed a reduction in favour of mepolizumab that could be due to a beneficial effect on asthma-related serious adverse events. There was no difference compared to placebo in adverse events leading to discontinuation with mepolizumab or reslizumab, but significantly more discontinued benralizumab than placebo, although the absolute numbers were small (36/1599 benralizumab versus 9/998 placebo). Mepolizumab, reslizumab and benralizumab all markedly reduced blood eosinophils, but benralizumab resulted in almost complete depletion, whereas a small number remained with mepolizumab and reslizumab. The implications for efficacy and/or adverse events are unclear. Overall our study supports the use of anti-IL-5 treatments as an adjunct to standard of care in people with severe eosinophilic asthma and poor control. These treatments roughly halve the rate of asthma exacerbations in this population. There is limited evidence for improved HRQoL scores and lung function, which may not meet clinically detectable levels. There were no safety concerns regarding mepolizumab or reslizumab, and no excess serious adverse events with benralizumab, although there remains a question over adverse events significant enough to prompt discontinuation. Further research is needed on biomarkers for assessing treatment response, optimal duration and long-term effects of treatment, risk of relapse on withdrawal, non-eosinophilic patients, children (particularly under 12 years), and comparing anti-IL-5 treatments to each other and, in people eligible for both, to anti-immunoglobulin E. For benralizumab, future studies should closely monitor rates of adverse events prompting discontinuation.

Thirteen studies compared mepolizumab, reslizumab or benralizumab to a placebo in 6000 people with asthma, most with severe disease. We summarised the results as they related to the occurrence of asthma attacks requiring additional treatment, quality of life, breathing tests, effects on a blood biomarker, and side effects. We found that participants with severe asthma, who had high numbers of a certain type of inflammatory cell (eosinophils) in the blood, benefited from taking mepolizumab, reslizumab or benralizumab through reduced asthma attacks. There were small improvements in quality of life and breathing tests, but these may be too small to be detected by patients. We agree with international guidelines that say that these treatments can be added to standard treatment for people with severe asthma. However, we think that further research is needed to clarify some aspects, such as how to assess treatment response and how long to give treatment for. The evidence included in this review is provided by very well-designed studies. We consider these studies to be at low risk of bias in the following important respects: the procedure that determined who received which treatment, the blinding processes and the clarity of detail concerning participants who did not complete the study. Overall the evidence was high to moderate quality.

10.1002/14651858.CD010834.pub3

cochrane-simplification-train-2991

cochrane-simplification-train-2991

We identified 71 RCTs randomly assigning 73,062 people with COPD to 184 treatment arms of interest. Trials were similar with regards to methodology, inclusion and exclusion criteria and key baseline characteristics. Participants were more often male, aged in their mid sixties, with FEV1 predicted normal between 40% and 50% and with substantial smoking histories (40+ pack-years). The risk of bias was generally low, although missing information made it hard to judge risk of selection bias and selective outcome reporting. Fixed effects were used for SGRQ analyses, and random effects for Trough FEV1 analyses, based on model fit statistics and deviance information criteria (DIC). SGRQ SGRQ data were available in 42 studies (n = 54,613). At six months, 39 pairwise comparisons were made between 18 treatments in 25 studies (n = 27,024). Combination LABA/ICS was the highest ranked intervention, with a mean improvement over placebo of -3.89 units at six months (95% credible interval (CrI) -4.70 to -2.97) and -3.60 at 12 months (95% CrI -4.63 to -2.34). LAMAs and LABAs were ranked second and third at six months, with mean differences of -2.63 (95% CrI -3.53 to -1.97) and -2.29 (95% CrI -3.18 to -1.53), respectively. Inhaled corticosteroids were ranked fourth (MD -2.00, 95% CrI -3.06 to -0.87). Class differences between LABA, LAMA and ICS were less prominent at 12 months. Indacaterol and aclidinium were ranked somewhat higher than other members of their classes, and formoterol 12 mcg, budesonide 400 mcg and formoterol/mometasone combination were ranked lower within their classes. There was considerable overlap in credible intervals and rankings for both classes and individual treatments. Trough FEV1 Trough FEV1 data were available in 46 studies (n = 47,409). At six months, 41 pairwise comparisons were made between 20 treatments in 31 studies (n = 29,271). As for SGRQ, combination LABA/ICS was the highest ranked class, with a mean improvement over placebo of 133.3 mL at six months (95% CrI 100.6 to 164.0) and slightly less at 12 months (mean difference (MD) 100, 95% CrI 55.5 to 140.1). LAMAs (MD 103.5, 95% CrI 81.8 to 124.9) and LABAs (MD 99.4, 95% CrI 72.0 to 127.8) showed roughly equivalent results at six months, and ICSs were the fourth ranked class (MD 65.4, 95% CrI 33.1 to 96.9). As with SGRQ, initial differences between classes were not so prominent at 12 months. Indacaterol and salmeterol/fluticasone were ranked slightly better than others in their class, and formoterol 12, aclidinium, budesonide and formoterol/budesonide combination were ranked lower within their classes. All credible intervals for individual rankings were wide. This network meta-analysis compares four different classes of long-acting inhalers for people with COPD who need more than short-acting bronchodilators. Quality of life and lung function were improved most on combination inhalers (LABA and ICS) and least on ICS alone at 6 and at 12 months. Overall LAMA and LABA inhalers had similar effects, particularly at 12 months. The network has demonstrated the benefit of ICS when added to LABA for these outcomes in participants who largely had an FEV1 that was less than 50% predicted, but the additional expense of combination inhalers and any potential for increased adverse events (which has been established by other reviews) require consideration. Our findings are in keeping with current National Institute for Health and Care Excellence (NICE) guidelines.

We found 71 relevant studies, but not all measured the outcomes we were interested in. Forty-two studies were included in the quality of life analyses (measured on St George's Respiratory Questionnaire), and 46 were included in the lung function analyses. Evidence from good quality and similar trials supported LABA/ICS combinations as the most likely treatment strategy to bring the greatest improvement to quality of life and lung function. Combination therapy gave an average benefit of 3.9 units over placebo at six months. LAMAs and LABAs were ranked second and third at six months (-2.63 and -2.29 units, respectively), especially when unreliable trials were not included, but a large degree of overlap in the estimates was noted. Combination LABA/ICS was the highest ranked class for trough forced expiratory volume in one second (FEV1), with mean improvement over placebo of 133 mL at six months (95% credible Interval (CrI) 101 to 164). As was the case for SGRQ, LAMAs (mean difference (MD) 104, 95% CrI 82 to 125) were ranked just ahead of LABAs (MD 99, 95% CrI 72 to 128) at six months, and ICSs were the lowest ranked class (MD 65, 95% CrI 33 to 97). For both outcomes, the effects of LABA and ICS used alone appeared to increase when used together for six months, but initial differences between the treatment classes were less obvious after a year of treatment. Quality of life and lung function were improved most on combination inhalers (LABA and ICS) and least on ICS alone at 6 and 12 months. Overall LAMA and LABA inhalers had similar effects, particularly at 12 months. The network has demonstrated the benefit of ICS when added to LABA for these outcomes in participants who largely had an FEV1that was less than 50% predicted, but the additional expense of combination inhalers and any potential for increased adverse events (which has been shown by other reviews) require consideration. Our findings are in keeping with current National Institute for Health and Care Excellence (NICE) guidelines.

10.1002/14651858.CD010844.pub2

cochrane-simplification-train-2992

cochrane-simplification-train-2992

Only two trials of limited quality met our inclusion criteria. One study compared two biphasic pills and one triphasic pill, each containing levonorgestrel and ethinyl estradiol. No important differences emerged, and the frequency of discontinuation due to medical problems was similar with all three pills. The other trial compared a biphasic pill containing norethindrone (Ortho 10/11) with a triphasic pill containing levonorgestrel (Triphasil) and with another triphasic containing norethindrone (Ortho 7/7/7). The biphasic pill had inferior cycle control compared with the levonorgestrel triphasic. The odds ratio of cycles with intermenstrual bleeding was 1.70 (95% confidence interval (CI) 1.29 to 2.24) for the biphasic compared with the triphasic levonorgestrel pill. The odds ratio of cycles without withdrawal bleeding was 6.48 (95% CI 3.13 to 13.39). In contrast, cycle control with the biphasic pill was comparable to that of the triphasic containing the same progestin (norethindrone). The available evidence is limited and the internal validity of these trials is questionable. Given the high losses to follow up, these reports may even be considered observational. Given that caveat, the biphasic pill containing norethindrone was associated with inferior cycle control compared with the triphasic pill containing levonorgestrel. The choice of progestin may be more important than the phasic regimen in determining bleeding patterns.

We did a computer search for studies of birth control pills with two phases versus pills with three phases. We also wrote to researchers and manufacturers to find other trials. We included randomized trials in any language. We found only two trials that looked at two-phase versus three-phase birth control pills. The studies did not have good methods and the authors did not report all their methods. Many women dropped out of the studies, which affects what can be said about the results. One study compared two types of two-phase pills with a three-phase pill. The pills did not differ in any major ways, including the numbers of women who stopped using the pills due to health problems. The other trial compared a two-phase pill with two different three-phase pills. The two-phase pill had worse bleeding patterns than the three-phase pill with a different hormone (levonorgestrel). In contrast, bleeding with the two-phase pill was like that of the three-phase pill with the same hormone (norethindrone). The type of hormone may be more important than the phases for cycle control. These trials did not provide enough evidence to say if three-phase pills worked any better than two-phase types for birth control, bleeding patterns, or staying on the pill. More research would be needed to show whether three-phase pills were better than two-phase pills. However, two-phase pills are not used enough to justify further research.

10.1002/14651858.CD003283.pub2

cochrane-simplification-train-2993

cochrane-simplification-train-2993

No RCTs were identified. Five observational studies (N = 7199) met the inclusion criteria. The studies scored well on the Newcastle-Ottawa scale, but due to the nature of observational studies, a high risk of bias was assigned to all the studies. Three studies were pooled to assess the rate of cancer detected in the surveillance group compared to the non-surveillance group. The studies found a significantly higher rate of cancer detection in the non surveillance group compared to the surveillance group. CRC was detected in 1.83% (53/2895) of patients in the surveillance group compared to 3.17% (135/4256) of patients in the non-surveillance group (OR 0.58, 95% CI 0.42 to 0.80; P = 0.0009). Four studies were pooled to assess the death rate associated with CRC in patients who underwent surveillance compared to patients who did not undergo surveillance. There was a significantly lower death rate associated with CRC in the surveillance group compared to the non-surveillance group. Eight per cent (15/176) of patients in the surveillance group died from CRC compared to 22% (79/354) of patients in the non-surveillance group (OR 0.36, 95% CI 0.19 to 0.69, P=0.002). Data were pooled from two studies to examine the rate of early stage versus late stage colorectal cancer (Duke stages A & B compared to Duke stages C & D) in patients who underwent surveillance compared to patients who do not undergo surveillance. A significantly higher rate of early stage CRC (Duke A & B) was detected in the surveillance group compared to the non-surveillance group. Sixteen per cent (17/110) of patients in the surveillance group had early stage CRC compared to 8% (9/117) of patients in the non-surveillance group (OR 5.40, 95% CI 1.51 to 19.30; P = 0.009). A higher rate of late stage CRC (Duke C & D) was observed in the non-surveillance group compared to the surveillance group. Nine per cent (10/110) of patients in the surveillance group had late stage CRC compared to 16% (19/117) of patients in the non-surveillance group (OR 0.46, 95% CI 0.08 to 2.51; P = 0.37). A GRADE analysis indicated that the quality of the data was very low for all of these outcomes. The included studies did not report on the other pre-specified outcomes including time to cancer detection, time to death and adverse events. The current data suggest that colonoscopic surveillance in IBD may reduce the development of both CRC and the rate of CRC-associated death through early detection, although the quality of the evidence is very low. The detection of earlier stage CRC in the surveillance group may explain some of the survival benefit observed. RCTs assessing the efficacy of endoscopic surveillance in people with IBD are unlikely to be undertaken due to ethical considerations.

Five observational studies with 7199 patients were used to compare endoscopic surveillance to non-surveillance. The key findings of the review were that a higher rate of cancer occurred in the non-surveillance group compared to the surveillance group, and that a lower rate of colon cancer-associated death was demonstrated in the surveillance group compared to the non-surveillance group. In patients undergoing surveillance, the odds of colon cancer development were reduced by 42% and the odds of death associated with colon cancer was reduced by 64%. Surveillance resulted in detection of a higher rate of early stage colorectal cancer in the surveillance group compared to the non surveillance group which may explain the improved survival seen with surveillance. The overall quality of the evidence is very low due to the nature of observation studies and the low number of events. Nonetheless, these results suggest that endoscopic surveillance in people with IBD may reduce the development of colon cancer through early detection and may also reduce the chances of dying from colon cancer.

10.1002/14651858.CD000279.pub4

cochrane-simplification-train-2994

cochrane-simplification-train-2994

The review included 31 trials (10 of which were new for this update) involving 1817 women from 14 countries. Overall, trials were of small-to-moderate size, with follow-ups generally less than 12 months and many were at moderate risk of bias. There was considerable variation in the intervention's content and duration, study populations and outcome measures. There was only one study of women with MUI and only one study with UUI alone, with no data on cure, cure or improvement, or number of episodes of UI for these subgroups. Symptomatic cure of UI at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT groups were eight times more likely to report cure (56% versus 6%; risk ratio (RR) 8.38, 95% confidence interval (CI) 3.68 to 19.07; 4 trials, 165 women; high-quality evidence). For women with any type of UI, PFMT groups were five times more likely to report cure (35% versus 6%; RR 5.34, 95% CI 2.78 to 10.26; 3 trials, 290 women; moderate-quality evidence). Symptomatic cure or improvement of UI at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT groups were six times more likely to report cure or improvement (74% versus 11%; RR 6.33, 95% CI 3.88 to 10.33; 3 trials, 242 women; moderate-quality evidence). For women with any type of UI, PFMT groups were two times more likely to report cure or improvement than women in the control groups (67% versus 29%; RR 2.39, 95% CI 1.64 to 3.47; 2 trials, 166 women; moderate-quality evidence). UI-specific symptoms and quality of life (QoL) at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT group were more likely to report significant improvement in UI symptoms (7 trials, 376 women; moderate-quality evidence), and to report significant improvement in UI QoL (6 trials, 348 women; low-quality evidence). For any type of UI, women in the PFMT group were more likely to report significant improvement in UI symptoms (1 trial, 121 women; moderate-quality evidence) and to report significant improvement in UI QoL (4 trials, 258 women; moderate-quality evidence). Finally, for women with mixed UI treated with PFMT, there was one small trial (12 women) reporting better QoL. Leakage episodes in 24 hours at the end of treatment: PFMT reduced leakage episodes by one in women with SUI (mean difference (MD) 1.23 lower, 95% CI 1.78 lower to 0.68 lower; 7 trials, 432 women; moderate-quality evidence) and in women with all types of UI (MD 1.00 lower, 95% CI 1.37 lower to 0.64 lower; 4 trials, 349 women; moderate-quality evidence). Leakage on short clinic-based pad tests at the end of treatment: women with SUI in the PFMT groups lost significantly less urine in short (up to one hour) pad tests. The comparison showed considerable heterogeneity but the findings still favoured PFMT when using a random-effects model (MD 9.71 g lower, 95% CI 18.92 lower to 0.50 lower; 4 trials, 185 women; moderate-quality evidence). For women with all types of UI, PFMT groups also reported less urine loss on short pad tests than controls (MD 3.72 g lower, 95% CI 5.46 lower to 1.98 lower; 2 trials, 146 women; moderate-quality evidence). Women in the PFMT group were also more satisfied with treatment and their sexual outcomes were better. Adverse events were rare and, in the two trials that did report any, they were minor. The findings of the review were largely supported by the 'Summary of findings' tables, but most of the evidence was downgraded to moderate on methodological grounds. The exception was 'participant-perceived cure' in women with SUI, which was rated as high quality. Based on the data available, we can be confident that PFMT can cure or improve symptoms of SUI and all other types of UI. It may reduce the number of leakage episodes, the quantity of leakage on the short pad tests in the clinic and symptoms on UI-specific symptom questionnaires. The authors of the one economic evaluation identified for the Brief Economic Commentary reported that the cost-effectiveness of PFMT looks promising. The findings of the review suggest that PFMT could be included in first-line conservative management programmes for women with UI. The long-term effectiveness and cost-effectiveness of PFMT needs to be further researched.

The 31 included trials involved 1817 women from 14 countries. The studies included women with stress, urgency or mixed urinary incontinence. The women were allocated randomly to either receive or not receive PFMT and the effects were compared. We looked at whether the condition was 'cured,' or 'cured or improved.' We also looked at symptoms, the effect on quality of life (QoL) and the frequency and amount of urine lost. Eight studies were publicly funded. Three received grants from public and private sources. Two received grants from private sources, while two studies received no funding. Sixteen studies did not declare their funding sources. The quality of the evidence we looked at was mostly moderate, which means we can have some confidence in the results. Cure of urinary incontinence after PFMT: women with stress urinary incontinence in the PFMT group were, on average, eight times more likely to report being cured. Women with any type of urinary incontinence in the PFMT group were, on average, five times more likely to report being cured. Cure or improvement of urinary incontinence after PFMT: women with stress urinary incontinence in PFMT groups were, on average, six times more likely to report they were cured or improved. Women with all type of urinary incontinence in the PFMT group were roughly twice as likely to report they were cured or improved. Leakage episodes after PFMT: women with stress urinary incontinence and women with all types of urinary incontinence in the PFMT group had one fewer leakage episode in 24 hours. PFMT appeared to reduce leakage episodes in women with urgency urinary incontinence alone. For women with stress and all types of urinary incontinence, their incontinence symptoms and QoL were improved in the PFMT groups. Women were more satisfied with the PFMT treatment, while those in the control groups were more likely to seek further treatment. Negative side effects of performing PFMT were rare and, in the two trials that did report them, the side effects were minor. The authors of the one economic evaluation identified for the Brief Economic Commentary reported that the cost-effectiveness of PFMT looks promising.

10.1002/14651858.CD005654.pub4

cochrane-simplification-train-2995

cochrane-simplification-train-2995

We included 15 RCTs involving 1007 participants in this third review update. One trial compared abdominal with perineal approaches to surgery, three trials compared fixation methods, three trials looked at the effects of lateral ligament division, one trial compared techniques of rectosigmoidectomy, two trials compared laparoscopic with open surgery, and two trials compared resection with no resection rectopexy. One new trial compared rectopexy versus rectal mobilisation only (no rectopexy), performed with either open or laparoscopic surgery. One new trial compared different techniques used in perineal surgery, and another included three comparisons: abdominal versus perineal surgery, resection versus no resection rectopexy in abdominal surgery and different techniques used in perineal surgery. The heterogeneity of the trial objectives, interventions and outcomes made analysis difficult. Many review objectives were covered by only one or two studies with small numbers of participants. Given these caveats, there is insufficient data to say which of the abdominal and perineal approaches are most effective. There were no detectable differences between the methods used for fixation during rectopexy. Division, rather than preservation, of the lateral ligaments was associated with less recurrent prolapse but more postoperative constipation. Laparoscopic rectopexy was associated with fewer postoperative complications and shorter hospital stay than open rectopexy. Bowel resection during rectopexy was associated with lower rates of constipation. Recurrence of full-thickness prolapse was greater for mobilisation of the rectum only compared with rectopexy. There were no differences in quality of life for patients who underwent the different kinds of prolapse surgery. The lack of high quality evidence on different techniques, together with the small sample size of included trials and their methodological weaknesses, severely limit the usefulness of this review for guiding practice. It is impossible to identify or refute clinically important differences between the alternative surgical operations. Longer follow-up with current studies and larger rigorous trials are needed to improve the evidence base and to define the optimum surgical treatment for full-thickness rectal prolapse.

Whether surgery is performed through a cut in the abdomen or a cut through the anus (known as a perineal approach), it makes no difference with regard to reappearance of the prolapse or appearance of postoperative complications. When surgeons perform the operation through a small hole in the abdomen (laparoscopic or keyhole surgery) recovery may be faster than for open abdominal surgery. When constipation is one of the main symptoms, bowel resection (removing part of the bowel) during prolapse repair may help. There was no difference in the results when different types of repair were used during the perineal (anal) approach. There was no particular concern about different types of surgery described in this review. Although 15 studies were included in this review, many of them had different comparisons and some had poor methods, limiting the usefulness of the findings. However, longer follow-up of patients in these studies, together with results from ongoing trials, may provide some information in the future.

10.1002/14651858.CD001758.pub3

cochrane-simplification-train-2996

cochrane-simplification-train-2996

The search yielded 39 studies. We included five studies in the review with a total of 884 participants. We excluded 31 studies and designated three as awaiting assessment. The data from the included studies provide some evidence that hydroxyzine is more effective than placebo for GAD (odds ratio (OR) 0.30, 95% CI 0.15 to 0.58) and that it is also acceptable/tolerable (OR 1.00, 95% CI 0.63 to 1.58) (OR 1.49, 95% CI 0.92 to 2.40). Compared to other anxiolytic agents (benzodiazepines and buspirone), hydroxyzine was equivalent in terms of efficacy, acceptability and tolerability (hydroxyzine vs chloridiazepoxide: OR 0.75, 95% CI 0.35 to 1.62; hydroxyzine vs buspirone efficacy OR 0.76, 95% CI 0.40 to 1.42). In terms of side effects, hydroxyzine was associated with a higher rate of sleepiness/drowsiness than the active comparators (OR 1.74, 95% CI 0.86 to 3.53). There was, however, a high risk of bias in the included studies. The included studies did not report on all the outcomes that were pre-specified in the protocol for this review. Even though more effective than placebo, due to the high risk of bias of the included studies, the small number of studies and the overall small sample size, it is not possible to recommend hydroxyzine as a reliable first-line treatment in GAD.

This review shows that hydroxyzine is better than placebo in terms of anxiety symptoms in individuals with generalised anxiety disorder (GAD). Too few data were available to be able to draw any conclusions about the efficacy and tolerability of hydroxyzine compared with benzodiazepines and buspirone. Given the robust evidence for the efficacy of antidepressants for GAD, these findings suggest that hydroxyzine should not be recommended as first-line treatment GAD.

10.1002/14651858.CD006815.pub2

cochrane-simplification-train-2997

cochrane-simplification-train-2997

Fifty-two studies met our inclusion criteria, randomly assigning 5077 participants to comparisons of interest. Most studies were double-blind and placebo-controlled, but studies varied in duration from one day to three years. Most participants had mild or intermittent asthma, often with co-morbid allergic rhinitis. Eighteen studies recruited only adults, 25 recruited only children and several recruited both or did not specify (n = 9). With the exception of adverse events, reporting of outcomes of interest to this review was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence. Allocation procedures generally were not well described, about a quarter of the studies were at high risk of bias for performance or detection bias or both and participant attrition was high or unknown in around half of the studies. One short study reported exacerbations requiring a hospital visit and observed no adverse events. Five studies reported quality of life, but the data were not suitable for meta-analysis. Serious adverse events were infrequent, and analysis using risk differences suggests that no more than 1 in 100 are likely to suffer a serious adverse event as a result of treatment with SLIT (RD 0.0012, 95% confidence interval (CI) -0.0077 to 0.0102; participants = 2560; studies = 22; moderate-quality evidence). Within secondary outcomes, wide but varied reporting of largely unvalidated asthma symptom and medication scores precluded meaningful meta-analysis; a general trend suggested SLIT benefit over placebo, but variation in scales meant that results were difficult to interpret. Changes in inhaled corticosteroid use in micrograms per day (MD 35.10 mcg/d, 95% CI -50.21 to 120.42; low-quality evidence), exacerbations requiring oral steroids (studies = 2; no events) and bronchial provocation (SMD 0.69, 95% CI -0.04 to 1.43; very low-quality evidence) were not often reported. This led to many imprecise estimates with wide confidence intervals that included the possibility of both benefit and harm from SLIT. More people taking SLIT had adverse events of any kind compared with control (OR 1.70, 95% CI 1.21 to 2.38; low-quality evidence; participants = 1755; studies = 19), but events were usually reported to be transient and mild. Lack of data prevented most of the planned subgroup and sensitivity analyses. Lack of data for important outcomes such as exacerbations and quality of life and use of different unvalidated symptom and medication scores have limited our ability to draw a clinically useful conclusion. Further research using validated scales and important outcomes for patients and decision makers is needed so that SLIT can be properly assessed as clinical treatment for asthma. Very few serious adverse events have been reported, but most studies have included patients with intermittent or mild asthma, so we cannot comment on the safety of SLIT for those with moderate or severe asthma. SLIT is associated with increased risk of all adverse events.

We included 52 studies involving 5077 people. These studies lasted between one day and three years. Most of the people included in the studies had mild asthma. Both males and females were included, and about half of the studies included only children. Most studies involved people with house dust mites or pollen allergy. The evidence presented here is current to 25 March 2015. Very few studies recorded the number of people who had asthma attacks leading to a hospital visit or the need for additional medication, so we do not know if SLIT reduces asthma attacks, possibly because most of the patients included in these studies had mild asthma. A few studies reported quality of life, but they used different scales, so we could not really tell if SLIT had a positive effect. Some studies reported that people taking SLIT had fewer asthma symptoms and had a reduced need for asthma medication compared with controls, but studies measured this in different ways, some of which may not be accurate. People receiving SLIT were no more or less likely to experience serious unwanted side effects, but these were generally very rare. We are not confident that this finding would apply to people with more severe asthma. People receiving SLIT were more likely to experience any unwanted side effect, but many of these were mild. Guidelines for asthma treatment suggest that SLIT should be used only for people with asthma that is difficult to control with standard treatments. However, many of the studies in this review included people with mild asthma, so trials looking at the effects of SLIT for people with more severe asthma are needed. It would be helpful if these studies used standard scales to report their findings, so that results can be combined in the future. The evidence presented in this review is generally of moderate or low quality, and very few studies have reported outcomes that are important to people with asthma, such as asthma attacks and quality of life. Most studies did not clearly explain how investigators decided which people would receive SLIT and which individuals would receive placebo or normal care, and in some studies, both participants and trial organisers knew which treatment they were getting. This may have affected the results.

10.1002/14651858.CD011293.pub2

cochrane-simplification-train-2998

cochrane-simplification-train-2998

We included nine reviews investigating TENS use in people with defined chronic pain or in people with chronic conditions associated with ongoing pain. One review investigating TENS for phantom or stump-associated pain in people following amputation did not have any included studies. We therefore extracted data from eight reviews which represented 51 TENS-related RCTs representing 2895 TENS-comparison participants entered into the studies. The included reviews followed consistent methods and achieved overall high scores on the AMSTAR checklist. The evidence reported within each review was consistently rated as very low quality. Using review authors' assessment of risk of bias, there were significant methodological limitations in included studies; and for all reviews, sample sizes were consistently small (the majority of studies included fewer than 50 participants per group). Six of the eight reviews presented a narrative synthesis of included studies. Two reviews reported a pooled analysis. Primary and secondary outcomes One review reported a beneficial effect of TENS versus sham therapy at reducing pain intensity on a 0 to 10 scale (MD −1.58, 95% CI −2.08 to −1.09, P < 0.001, I² = 29%, P = 0.22, 5 studies, 207 participants). However the quality of the evidence was very low due to significant methodological limitations and imprecision. A second review investigating pain intensity performed a pooled analysis by combining studies that compared TENS to sham with studies that compared TENS to no intervention (SMD −0.85, 95% CI −1.36 to −0.34, P = 0.001, I² = 83%, P < 0.001). This pooled analysis was judged as offering very low quality evidence due to significant methodological limitations, large between-trial heterogeneity and imprecision. We considered the approach of combining sham and no intervention data to be problematic since we would predict these different comparisons may be estimating different true effects. All remaining reviews also reported pain intensity as an outcome measure; however the data were presented in narrative review form only. Due to methodological limitation and lack of useable data, we were unable to offer any meaningful report on the remaining primary outcome regarding nature/incidence of adverse effects, nor for the remaining secondary outcomes: disability, health-related quality of life, analgesic medication use and participant global impression of change for any comparisons. We found the included reviews had a number of inconsistencies when evaluating the evidence from TENS studies. Approaches to assessing risk of bias around the participant, personnel and outcome-assessor blinding were perhaps the most obvious area of difference across included reviews. We also found wide variability in terms of primary and secondary outcome measures, and inclusion/exclusion criteria for studies varied with respect to including studies which assessed immediate effects of single interventions. We found the methodological quality of the reviews was good, but quality of the evidence within them was very low. We were therefore unable to conclude with any confidence that, in people with chronic pain, TENS is harmful, or beneficial for pain control, disability, health-related quality of life, use of pain relieving medicines, or global impression of change. We make recommendations with respect to future TENS study designs which may meaningfully reduce the uncertainty relating to the effectiveness of this treatment in people with chronic pain.

As of November 2018, we found nine reviews eligible for inclusion. Seven reviews specifically investigated TENS for the treatment of pain/function in a variety of chronic conditions in adults. We also included one review investigating a range of electrotherapy modalities for neck pain and one review examining non-pharmacological interventions in people with spinal cord injury. Both of these reviews included studies investigating TENS. Though the included reviews were of high quality, we found the quality of the evidence presented within the reviews to be very low. We are unable to confidently state whether TENS is effective in relieving pain in people with chronic pain. This is due to the very low quality of the evidence, and the overall small numbers of participants included in studies in the reviews. Issues with quality, study size and lack of data meant we were unable to draw any conclusion on TENS-associated harms or side-effects or the effect of TENS on disability, health-related quality of life, use of pain-relieving medicines or people's impression of how much TENS changed their condition.

10.1002/14651858.CD011890.pub3

cochrane-simplification-train-2999

cochrane-simplification-train-2999

We included 13 RCTs involving a total of 7292 participants, both children (n = 6402) and adults (n = 890). Nine studies were conducted in middle-income countries, three studies in high-income countries, and only one study in a low-income country. Five studies did not report methods of randomisation, and one study failed to conceal the allocations. Eleven studies did not blind participants, and six studies did not blind outcome assessments. Two studies had high attrition rates, and one study selectively reported the results. Three studies were funded by pharmaceutical companies. Paralytic poliomyelitis. No study reported data on this outcome. Seroconversion rates. These were significantly higher for all three types of wild poliovirus for children given intramuscular full-dose IPV after a single primary dose and two primary doses, but only significantly higher for type two wild poliovirus given intramuscularly after three primary doses: • dose one (six studies): poliovirus type 1 (odds ratio (OR) 0.30, 95% confidence interval (CI) 0.22 to 0.41; 2570 children); poliovirus type 2 (OR 0.43, 95% CI 0.31 to 0.60; 2567 children); poliovirus type 3 (OR 0.19, 95% CI 0.12 to 0.30; 2571 children); • dose two (three studies): poliovirus type 1 (OR 0.23, 95% CI 0.16 to 0.33; 981 children); poliovirus type 2 (OR 0.41, 95% CI 0.28 to 0.60; 853 children); and poliovirus type 3 (OR 0.12, 95% CI 0.07 to 0.22; 855 children); and • dose three (three studies): poliovirus type 1 (OR 0.45, 95% CI 0.07 to 3.15; 973 children); poliovirus type 2 (OR 0.34, 95% CI 0.19 to 0.63; 973 children); and poliovirus type 3 (OR 0.18, 95% CI 0.01 to 2.58; 973 children). Using the GRADE approach, we rated the certainty of the evidence as low or very low for seroconversion rate (after a single, two, or three primary doses) for all three poliovirus types due to significant risk of bias, heterogeneity, and indirectness in applicability/generalisability. Geometric mean titres. No study reported mean antibody titres. Median antibody titres were higher for intramuscular full-dose IPV (7 studies with 4887 children); although these studies also reported a rise in antibody titres in the intradermal group, none reported the duration for which the titres remained high. Any vaccine-related adverse event. Five studies (2217 children) reported more adverse events, such as fever and redness, in the intradermal group, whilst two studies (1904 children) reported more adverse events in the intramuscular group. There is low- and very low-certainty evidence that intramuscular full-dose IPV may result in a slight increase in seroconversion rates for all three types of wild poliovirus, compared with intradermal fractional-dose IPV. We are uncertain whether intradermal fractional-dose (one-fifth) IPV has better protective effects and causes fewer adverse events in children than intramuscular full-dose IPV.

The database searches, up-to-date to February 2019, found 13 randomised controlled trials (a type of experiment in which participants are randomly assigned to one of two or more treatment groups). Three studies comprised 890 adult participants; a further 10 studies comprised 6402 infants and children. Nine studies were conducted in middle-income countries; three studies in high-income countries; and one study in a low-income country. The studies had a duration of 2 to 19 months. Three studies were supported financially by drug companies, and three studies received the vaccines from the pharmaceutical company. There is overall limited confidence in the quality of the included studies since, for example, in most trials the recipient or assessor (or both) were aware of the vaccine being given. The review included 13 studies with a total of 7292 participants (6402 children and 890 adults). Where possible, we combined the results of similar studies in a meta-analysis (a statistical method of combining the results of multiple single studies to calculate an overall effect). There are three types of wild poliovirus: types 1, 2, and 3. We found that the number of antibody responses to the vaccine (measured using something called seroconversion rates) in children was higher in the group that received the vaccine by intramuscular injection compared to the group that had a similar number of injections given intradermally, after one single dose (6 studies, 2571 children) and two doses (3 studies, 981 children) for all three types of poliovirus, and after three doses for type 2 poliovirus (3 studies, 973 children). The vaccines produce antibodies against all three types of poliovirus. The quantity of antibodies produced by the vaccines (measured as geometric median titres) was higher in children receiving a full dose of IPV via intramuscular route for all three types of poliovirus (7 studies, 4887 children). Five studies (2217 children) reported more adverse events, such as fever and redness, in the intradermal group, whilst two studies (1904 children) reported more adverse events in the intramuscular group. None of the included studies reported data on the occurrence of paralytic poliomyelitis. Based on the evidence, intramuscular full-dose IPV may result in a slight increase in seroconversion rates for all three types of wild poliovirus when compared with intradermal fractional-dose IPV. We are uncertain if a fractional dose of IPV given intradermally is better than a full dose of IPV given intramuscularly at producing antibodies for all three types of poliovirus or reducing adverse effects.

10.1002/14651858.CD011780.pub2