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cochrane-simplification-train-200

cochrane-simplification-train-200

We included two trials involving 754 participants. One new trial of 660 participants showed the same success rate of vacuum procedure of 98.2% by both methods (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.98 to 1.02). The two included trials showed significant reductions in the time between applying the vacuum cup and delivery, (one trial (74 women): mean difference (MD) -6.10 minutes, 95% CI -8.83 to -3.37 and the other trial (660 women): with median difference -4.4 minutes, 95% CI -4.8 to -4.0). The two included trials showed no significant difference in detachment rate (RR 0.85, 95% CI 0.38 to 1.86, 2 studies, 754 women), no significant difference in Apgar score below seven at one minute (RR 1.04, 95% CI 0.51 to 2.09) and five minutes (RR 1.00, 95% CI 0.29 to 3.42), no significant differences in scalp abrasions or lacerations, cephalhematoma, subgaleal hemorrhage and hyperbilirubinemia. There were no significant differences between the two methods in all secondary outcomes. The rapid negative pressure application for vacuum assisted vaginal birth reduces duration of the procedure whilst there is no evidence of differences in maternal and neonatal outcomes. Rapid method of negative application should be recommended for vacuum extraction assisted vaginal delivery.

Two good quality randomized controlled trials involving 754 women were identified. Rapid negative pressure application reduced the duration of the procedure without any evidence of differences in outcomes for the mother or infant. Rapid method of negative pressure application should be recommended for vacuum extraction assisted vaginal delivery.

10.1002/14651858.CD006636.pub3

cochrane-simplification-train-201

cochrane-simplification-train-201

We identified five randomised, double-blind studies with 1501 participants, but only four had been published and had relevant outcome data. These four studies were of high quality, although two of the studies were small. Both ibuprofen 200 mg + caffeine 100 mg and ibuprofen 100 mg + caffeine 100 mg produced significantly more participants than placebo who achieved at least 50% of maximum pain relief over six hours, and both doses significantly reduced remedication rates (moderate quality evidence). For at least 50% of maximum pain relief, the NNT was 2.1 (95% confidence interval 1.8 to 2.5) for ibuprofen 200 mg + caffeine 100 mg (four studies, 334 participants) and 2.4 (1.9 to 3.1) for ibuprofen 100 mg + caffeine 100 mg (two studies, 200 participants) (moderate quality evidence). These values were close to those predicted by published models for combination analgesics in acute pain, and were supported by low (good) NNT values for prevention of remedication. Adverse event rates were low, and no sensible analysis was possible. For ibuprofen 200 mg + caffeine 100 mg particularly, the low NNT value is among the lowest (best) values for analgesics in this pain model. The combination is not commonly available, but can be probably be achieved by taking a single 200 mg ibuprofen tablet with a cup of modestly strong coffee or caffeine tablets. In principle, this can deliver good analgesia at lower doses of ibuprofen.

We searched up to 1 February 2015 and found four studies with a maximum of 334 participants with information for analysis. Ibuprofen 200 mg plus caffeine 100 mg provided effective pain relief for 6 in 10 (59%) participants, compared with 1 in 10 (11%) participants with placebo (moderate quality evidence). Adverse events occurred at similar rates with the ibuprofen plus caffeine combination and placebo in these single dose studies (low quality evidence). No serious adverse events or withdrawals due to adverse events occurred with the combination. The combination of ibuprofen 200 mg + caffeine 100 mg is not commonly available, but can probably be achieved by taking a single 200 mg ibuprofen tablet with a cup of modestly strong coffee. Common sources of caffeine include not only caffeine tablets (100 mg is sufficient), but coffee (100 mg to 150 mg per mug or cup with a volume of about 240 mL or 8 fl oz, or a double espresso), but also tea (75 mg per mug), cola drinks (up to 40 mg per drink), energy drinks (approximately 80 mg per drink), plain chocolate (up to 50 mg per bar), and caffeine tablets (100 mg per tablet). Some people may get good levels of pain relief with a lower dose of ibuprofen when the ibuprofen is combined with caffeine.

10.1002/14651858.CD011509.pub2

cochrane-simplification-train-202

cochrane-simplification-train-202

One single-centred trial (46 participants) was identified comparing a topical steroid (betamethasone) given as nasal drops to placebo. Treatment was given twice daily for six weeks; 22 participants received the active drug. Subjective symptom scores, change in polyp size, and side effects were assessed. There was no difference in nasal symptom scores between the treatment and placebo groups. Betamethasone was effective in reducing the size of polyps, but was associated with increased reports of mild side effects, nasal bleeding and discomfort. Risk of bias was high since over 50% of people enrolled did not complete the study. Follow-up of participants was short (six weeks) also reducing the significance of the results for clinical practice. This review suggests topical steroids for nasal polyposis in people with cystic fibrosis have no demonstrable effect on subjective nasal symptom scores. They have some effect in reducing the size of the polyps, but due to the small sample size, poor completion rates and lack of follow-up, the trial is at high risk of bias and evidence for efficacy is limited. Overall there is no clear evidence for using topical steroids in people with cystic fibrosis and nasal polyposis. A well-designed randomised controlled trial of adequate power and long-term follow-up is needed. Validated measures of symptoms and physical findings should be performed and quality of life issues addressed.

Our search found one trial with 46 adult volunteers with cystic fibrosis which compared nasal drops containing a steroid (betamethasone) to identical drops containing no active treatment. Two drops were applied directly to polyps twice a day for six weeks. Volunteers were put into the different treatment groups at random and a total of 22 volunteers received the steroid drops and 24 received the dummy treatment. The trial measured each person's perception of their symptom scores, but found no difference to the scores whether volunteers were using the steroid drops or the dummy treatment. The trial also measured the change in polyp size and found that they shrank. There were no major side effects linked to using betamethasone, and only three volunteers reported increased nose bleeds and discomfort. The small number of volunteers in this trial means the calculations and results should be regarded with some caution. More trials are needed to confirm the findings and these trials should report on measures of symptoms and quality of life issues. We think that volunteers had a truly equal chance of being put in either the steroid group or the control group and wouldn't have known which treatment they were receiving, so these issues would not have influenced the results in any way. However, over 50% of people enrolled did not complete the study and the reasons for dropping out were not very clearly explained. We think it is important to take this fact into account when considering the trial results. Also, the trial only followed the volunteers for six weeks, which is a short time when evaluating a treatment that could be needed for the rest of a person's life.

10.1002/14651858.CD008253.pub4

cochrane-simplification-train-203

cochrane-simplification-train-203

Of the 83 studies identified, 15 studies which included 487 participants, met the inclusion criteria. The numbers in each study ranged from nine up to 72 participants; two studies were in adults, seven were in children and adolescents and six studies included all age ranges. Four studies of hospitalised participants lasted less than one month and 11 studies were outpatient-based, lasting between two months and three years. The studies included participants with a wide range of disease severity and employed differing levels of supervision with a mixture of types of training. There was also wide variation in the quality of the included studies. This systematic review shows very low- to low-quality evidence from both short- and long-term studies that in people with cystic fibrosis aerobic or anaerobic physical exercise training (or a combination of both) has a positive effect on aerobic exercise capacity, pulmonary function and health-related quality of life. No study reported on mortality; two studies reported on adverse events (moderate-quality evidence); one of each study reported on pulmonary exacerbations (low-quality evidence) and diabetic control (very low-quality evidence). Although improvements were not consistent between studies and ranged from no effects to clearly positive effects, the most consistent effects of the heterogeneous exercise training modalities and durations were found for maximal aerobic exercise capacity (in four out of seven studies) with unclear effects on forced expiratory volume in one second (in two out of 11 studies) and health-related quality of life (in two out of seven studies). Evidence about the efficacy of physical exercise training in cystic fibrosis from 15 small studies with low to moderate methodological quality is limited. Exercise training is already part of regular outpatient care offered to most people with cystic fibrosis, and since there is some evidence for beneficial effects on aerobic fitness and no negative side effects exist, there is no reason to actively discourage this. The benefits from including physical exercise training in an individual's regular care may be influenced by the type and duration of the training programme. High-quality randomised controlled trials are needed to comprehensively assess the benefits of exercise programmes in people with cystic fibrosis and the relative benefits of the addition of aerobic versus anaerobic versus a combination of both types of physical exercise training to the care of people with cystic fibrosis.

This review includes 15 studies with a total of 487 people with CF; the numbers in each study ranged from just nine people up to 72 people in the largest study. Two studies were in adults, seven were in children and adolescents and six studies included all age ranges. Four studies lasted less than one month and took place while the participants were in hospital; 11 studies were outpatient-based and lasted from two months up to three years. The studies included people with a wide range of severity of CF lung disease. There were differing levels of supervision in the studies and a mixture of types of training. The outcome most often reported in the studies was the change in lung function; other commonly reported outcomes included peak oxygen consumption, health-related quality of life, change in muscle strength and change in body composition (e.g. muscle and fat). Due to different study designs (type of exercise training, duration, etc.), we could not combine results from different studies. The short-term studies did not show differences between treatments. The longer studies showed that physical exercise training can improve aerobic capacity, there were some improvements in lung function and health-related quality of life, but these were not consistent across all studies. No study reported the number of deaths; two studies reported on side effects; one study reported on pulmonary exacerbations and another on diabetic control. We included a number of small studies and thought the quality of these studies was moderate at best (only for side effects). Overall, there was only low- to very low-quality evidence that aerobic or anaerobic physical exercise training (or a combination of both) has a positive effect on aerobic exercise capacity, pulmonary function and health-related quality of life in people with CF. In four of the studies the participant characteristics at the start of the studies were different between groups, despite being put into the different treatment groups at random. It is not possible for people not to know which treatment group they are in when comparing exercise training to no exercise. However, we do not think the fact that people knew which treatment they were receiving would affect the results for lung function as long as the assessments were done properly. In contrast, there may be bias when the people assessing an individual's cardiopulmonary fitness are not blinded to which group the volunteer is in. In less than half of the included studies, the investigators tried to prevent the outcome assessors from knowing which groups the participants were in; and in only one study was the lead researcher blinded. The studies did not routinely measure health-related quality of life and where it was measured, different measurement tools were used. Selective reporting of results maybe an issue, especially as most of the included studies were not listed in trial registries, which give advance details of the outcomes being measured. We are uncertain about the effects and further better quality studies will likely change these findings.

10.1002/14651858.CD002768.pub4

cochrane-simplification-train-204

cochrane-simplification-train-204

We identified six RCTs with a total of 218 participants randomised, one trial awaiting classification and five ongoing trials. All trials were conducted in participants at high risk of CVD, two trials examined CoQ10 supplementation alone and four examined CoQ10 supplementation in patients on statin therapy; we analysed these separately. All six trials were small-scale, recruiting between 20 and 52 participants; one trial was at high risk of bias for incomplete outcome data and one for selective reporting; all studies were unclear in the method of allocation and therefore for selection bias. The dose of CoQ10 varied between 100 mg/day and 200 mg/day and the duration of the interventions was similar at around three months. No studies reported mortality or non-fatal cardiovascular events. None of the included studies provided data on adverse events. Two trials examined the effect of CoQ10 on blood pressure. For systolic blood pressure we did not perform a meta-analysis due to significant heterogeneity. In one trial CoQ10 supplementation had no effect on systolic blood pressure (mean difference (MD) -1.90 mmHg, 95% confidence interval (CI) -13.17 to 9.37, 51 patients randomised). In the other trial there was a statistically significant reduction in systolic blood pressure (MD -15.00 mmHg, 95% CI -19.06 to -10.94, 20 patients randomised). For diastolic blood pressure we performed a random-effects meta-analysis, which showed no evidence of effect of CoQ10 supplementation when these two small trials were pooled (MD -1.62 mmHg, 95% CI -5.2 to 1.96). One trial (51 patients randomised) looked at the effect of CoQ10 on lipid levels. The trial showed no evidence of effect of CoQ10 supplementation on total cholesterol (MD 0.30 mmol/L, 95% CI -0.10 to 0.70), high-density lipoprotein (HDL)-cholesterol (MD 0.02 mmol/L, 95% CI -0.13 to 0.17) or triglycerides (MD 0.05 mmol/L, 95% CI -0.42 to 0.52). Of the four trials that investigated CoQ10 supplementation in patients on statin therapy, three of them showed that simultaneous administration of CoQ10 did not significantly influence lipid levels or systolic blood pressure levels between the two groups. The fourth trial showed a significant increase in the change in total and low-density lipoprotein (LDL)-cholesterol at three months across the four arms of the trial (α-tocopherol, CoQ10, CoQ10 + α-tocopherol and placebo), however the way in which the data were presented meant that we were unable to determine if there was any significant difference between the CoQ10 only and placebo arms. In contrast, there was no significant difference in the change in HDL-cholesterol and triglycerides after three months between the four arms of the trial. There are very few studies to date examining CoQ10 for the primary prevention of CVD. The results from the ongoing studies will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution and further high quality trials with longer-term follow-up are needed to determine the effects on cardiovascular events.

This review therefore assessed the effectiveness of CoQ10 supplementation for CVD prevention. We included trials administering CoQ10 as a single supplement in healthy adults or those at high risk of CVD (but without a diagnosis of CVD) and measuring cardiovascular events or major CVD risk factors, such as blood pressure and lipid levels. We found six completed randomised controlled trials with a total of 218 participants randomised. All were conducted in participants at high risk of CVD. Two examined CoQ10 supplementation alone and four examined CoQ10 supplementation in patients on statin therapy. The trials were small and short-term, none measured cardiovascular events or adverse events, and we regarded two of the six trials as being at high risk of bias. Very few small trials contributed to the analyses and no conclusions can be drawn at this time. We also identified five ongoing trials and the results from these will add to the evidence base in due course. More longer-term trials are needed to determine the effect of CoQ10 on cardiovascular events.

10.1002/14651858.CD010405.pub2

cochrane-simplification-train-205

cochrane-simplification-train-205

Eight studies involving 262 participants were included in the review. Participants had stable asthma, with severity ranging from mild to severe. All studies were randomised trials, three studies had high withdrawal rates. Participants were between five to 18 years of age, and in seven studies swimming training varied from 30 to 90 minutes, two to three times a week, over six to 12 weeks. The programme in one study gave 30 minutes training six times per week. The comparison was usual care in seven studies and golf in one study. Chlorination status of swimming pool was unknown for four studies. Two studies used non-chlorinated pools, one study used an indoor chlorinated pool and one study used a chlorinated but well-ventilated pool. No statistically significant effects were seen in studies comparing swimming training with usual care or another physical activity for the primary outcomes; quality of life, asthma control, asthma exacerbations or use of corticosteroids for asthma. Swimming training had a clinically meaningful effect on exercise capacity compared with usual care, measured as maximal oxygen consumption during a maximum effort exercise test (VO2 max) (two studies, n = 32), with a mean increase of 9.67 mL/kg/min; 95% confidence interval (CI) 5.84 to 13.51. A difference of equivalent magnitude was found when other measures of exercise capacity were also pooled (four studies, n = 74), giving a standardised mean difference (SMD) 1.34; 95% CI 0.82 to 1.86. Swimming training was associated with small increases in resting lung function parameters of varying statistical significance; mean difference (MD) for FEV1 % predicted 8.07; 95% CI 3.59 to 12.54. In sensitivity analyses, by risk of attrition bias or use of imputed standard deviations, there were no important changes on effect sizes. Unknown chlorination status of pools limited subgroup analyses. Based on limited data, there were no adverse effects on asthma control or occurrence of exacerbations. This review indicates that swimming training is well-tolerated in children and adolescents with stable asthma, and increases lung function (moderate strength evidence) and cardio-pulmonary fitness (high strength evidence). There was no evidence that swimming training caused adverse effects on asthma control in young people 18 years and under with stable asthma of any severity. However whether swimming is better than other forms of physical activity cannot be determined from this review. Further adequately powered trials with longer follow-up periods are needed to better assess the long-term benefits of swimming.

We reviewed a total of eight studies involving 262 participants between the ages of five and 18 years with well-controlled asthma. They underwent swimming training varying from 30 to 90 minutes two to three times a week over six to 12 weeks in seven studies, and in one study training lasted 30 minutes six times per week. This review found that for swimming training compared to control (either usual care or another physical activity), there were improvements in resting lung function tests, but no effects were found on quality of life, control of asthma symptoms or asthma exacerbations. Physical fitness increased with swimming training compared with usual care. There were few reported adverse asthmatic events in swimming training participants during the programmes. The relatively small number of studies and participants limits this review’s ability to measure some outcomes that are of interest, particularly the impact on quality of life and  asthma exacerbations. In summary, swimming training is well-tolerated in children and adolescents with stable asthma, and increases physical fitness and lung function. However, whether swimming is better and/or safer than other forms of physical activity cannot be determined from this review. Further studies with longer follow-up periods may help us understand any long-term benefits of swimming.

10.1002/14651858.CD009607.pub2

cochrane-simplification-train-206

cochrane-simplification-train-206

Only one small study (n = 44) fulfilled the inclusion criteria. Results suggested that cell salvage did not affect mortality overall (death rates were 67% (14/21 participants) in the cell salvage group and 65% (15/23) in the control group) (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.31 to 3.72). For individuals with abdominal injury, mortality was also similar in both groups (OR 0.48, 95% CI 0.11 to 2.10). Less donor blood was needed for transfusion within the first 24 hours postinjury in the cell salvage group compared with the control group (mean difference (MD) -4.70 units, 95% CI -8.09 to -1.31). Adverse events, notably postoperative sepsis, did not differ between groups (OR 0.54, 95% CI 0.11 to 2.55). Cost did not notably differ between groups (MD -177.81, 95% CI -452.85 to 97.23, measured in GBP in 2002). Evidence for the use of cell salvage in individuals undergoing abdominal or thoracic trauma surgery remains equivocal. Large, multicentre, methodologically rigorous trials are needed to assess the relative efficacy, safety and cost-effectiveness of cell salvage in different surgical procedures in the emergency context.

We identified one randomised controlled trial, which involved people with a penetrating injury to the chest. In this study, 44 people (mostly male and with similar characteristics in terms of type of injury) were given either their own reprocessed blood (through cell salvage) or standard care using donated blood. The study was conducted at a hospital in Johannesburg, South Africa in 2002. Results indicated no important differences between the two groups of participants with regard to survival, postoperative infection, or cost. There was a reduction in the amount of banked blood (blood that has been donated and stored) required for transfusion within the first 24 hours following injury among people receiving cell salvage. Data on other adverse events were not reported. We believe that larger, multicentre, methodologically rigorous trials are needed to assess the relative efficacy, safety and cost-effectiveness of cell salvage in trauma surgery and other surgical procedures. The quality of the one study identified was high, but the number of participants was not large. No firm conclusions can be drawn as to the safety and effectiveness of cell salvage in individuals undergoing abdominal or thoracic trauma surgery.

10.1002/14651858.CD007379.pub2

cochrane-simplification-train-207

cochrane-simplification-train-207

Nineteen randomised studies (2728 participants) of concurrent chemoradiotherapy versus radiotherapy alone were included. Chemoradiotherapy significantly reduced overall risk of death (HR 0.71, 95% CI 0.64 to 0.80; I2 0%; 1607 participants) and overall progression-free survival at any site (HR 0.69, 95% CI 0.58 to 0.81; I2 45%; 1145 participants). Incidence of acute oesophagitis, neutropenia and anaemia were significantly increased with concurrent chemoradiation. Six trials (1024 patients) of concurrent versus sequential chemoradiation were included. A significant benefit of concurrent treatment was shown in overall survival (HR 0.74, 95% CI 0.62 to 0.89; I2 0%; 702 participants). This represented a 10% absolute survival benefit at 2 years. More treatment-related deaths (4% vs 2%) were reported in the concurrent arm without statistical significance (RR 2.02, 95% CI 0.90 to 4.52; I2 0%; 950 participants). There was increased severe oesophagitis with concurrent treatment (RR 4.96, 95%CI 2.17 to 11.37; I2 66%; 947 participants). This update of the review published in 2004 incorporates additional trials and more mature data. It demonstrates the benefit of concurrent chemoradiation over radiotherapy alone or sequential chemoradiotherapy. Patient selection is an important consideration in view of the added toxicity of concurrent treatment. Uncertainty remains as to how far this is purely due to a radiosensitising effect and whether similar benefits could be achieved by using modern radiotherapy techniques and more dose intensive accelerated and/ or hyperfractionated radiotherapy regimens.

A total of twenty-five randomised studies (including 3752 patients) were included in this updated review: nineteen trials (2728 patients) comparing concurrent chemoradiotherapy with radiotherapy alone and six trials (1024 patients) comparing concurrent with sequential chemoradiotherapy. Both comparisons demonstrated significant reduction in risk of death with use of concurrent chemoradiation, with an associated increase in incidence of acute oesophagitis.

10.1002/14651858.CD002140.pub3

cochrane-simplification-train-208

cochrane-simplification-train-208

This systematic review now has 21 included studies (four of which we added in the 2016 update), two studies awaiting assessment, and 47 excluded studies. In total, data for meta-analyses were available in 21 trials (n = 6218 women), of which only four reported live births. UGET was associated with an increased chance of a live birth/ongoing pregnancy compared with CTET (OR 1.47, 95% CI 1.30 to 1.65; 13 trials; n = 5859 women; I2 = 74%; low-quality evidence). Sensitivity analysis by including only trials with low risk of selection bias or by using a random-effects model did not alter the effect. We estimate that for women with a chance of a live birth/ongoing pregnancy of 23% using CTET, this would increase to between 28% and 33% using UGET. We considered the quality of the evidence using GRADE methodology to be low. UGET was associated with an increase in the chance of a clinical pregnancy (OR 1.31, 95% CI 1.17 to 1.45; 20 trials; n = 6711 women; I2 = 42%; moderate-quality evidence). We identified no differences between groups for the incidence of adverse events including multiple pregnancy, ectopic pregnancy, or miscarriage. These events were relatively rare, and sample sizes limited the ability to detect such differences. The evidence suggests ultrasound guidance improves the chance of live birth/ongoing and clinical pregnancies compared with clinical touch, without increasing the chance of multiple pregnancy, ectopic pregnancy, or miscarriage. Methodological limitations included: only four studies reporting details of both computerised randomisation techniques and adequate allocation concealment, only four studies reported on the outcome of live birth, and none of the nine studies that reported on ongoing pregnancy reported on live birth, suggesting possible reporting bias. Adequate reporting of randomisation and allocation concealment will improve the quality of future studies. The primary outcome measure of future studies should be the reporting of live births per woman randomised.

We found 21 randomised controlled trials that compared UGET with clinical touch in a total of 6218 women. The evidence is current to May 2015. Live birth/ongoing pregnancies were increased for the ultrasound-guided group compared with the clinical touch group, based on low-quality evidence. We estimate that for women with a chance of a live birth/ongoing pregnancy of 23% using clinical touch, this would increase to between 28% and 33% using UGET. Data for live birth should be interpreted carefully, as differences between the studies make drawing a conclusion difficult. The evidence suggests that in studies that used the same brand of transfer catheter in both the ultrasound-guided and the clinical touch groups, ultrasound guidance was linked to an increase in the chance of a live birth. There was no evidence that the risk of harm using UGET, including miscarriage, ectopic pregnancies, and multiple pregnancies, is any different than when clinical touch is used to guide the embryo transfer. The quality of the evidence for live birth/ongoing pregnancy was low due to poor reporting of study methods and inconsistency in trial results.

10.1002/14651858.CD006107.pub4

cochrane-simplification-train-209

cochrane-simplification-train-209

We included six relevant trials undertaken between 1969 and 1980. We found no significant difference in death (n = 175, 1 RCT, RR in the longer term 0.42, CI 0.10 to 1.83, very low quality evidence). In the long term, there was no difference in improvement of mental state (n = 61, 1 RCT, RR 3.39, CI 0.76 to 15.02, very low quality evidence). There was no difference in readmission to hospital (n = 651, 4 RCTs, RR by the long term 1.26, CI 1.00 to 1.57, low quality evidence). Data for leaving the study prematurely by the longer term showed no difference (n = 229, 2 RCTs, (RR 0.77, CI 0.34 to 1.77, low quality evidence). There was a significant difference favouring short stay (P = 0.01) in numbers of participants with delayed discharge from hospital exceeding the time planned in study (n = 404, 3 RCTs, RR in the longer term 0.54, CI 0.33 to 0.88, low quality evidence). There was no difference in numbers of participants lost to follow-up (n = 404, 3 RCTs, RR by the longer term 1.07, CI 0.70 to 1.62, low quality evidence). Finally, there was a significant difference favouring short-stay hospitalisation for social functioning, including unemployment, unable to housekeep, or unknown employment status (n = 330, 2 RCTs, RR by longer term 0.61, CI 0.50 to 0.76, very low quality evidence). The effects of hospital care and the length of stay is important for mental health policy. We found limited low and very low quality data which were all over 30 years old. Outcomes from these studies do suggest that a planned short-stay policy does not encourage a 'revolving door' pattern of admission and disjointed care for people with serious mental illness. More large, well-designed and reported trials are justified especially where a short-stay policy is not routine care.

The review aims to determine what length of stay in hospital is the most helpful and is now based on a 2012 search. Six randomised trials are included that compare short stay in hospital with either long stay in hospital or standard care. No differences were found between groups in readmission to hospital, mental state, leaving the study early, risk of death and people lost to follow-up. There was a significant difference favouring short-stay hospitalisation for social functioning. There was limited information that suggested that short-stay hospitalisation does not encourage a ‘revolving door’ pattern of admission to hospital and disjointed or poor care. This should reassure people with mental illness coming into hospital that a short stay (of less than 28 days) means they are no more likely to be readmitted, to leave hospital abruptly, or to lose contact with services after leaving hospital than if they received long-stay care. Short-stay patients are also more likely to leave hospital on their planned discharge date and possibly have a greater chance of finding employment. For psychiatrists, policy makers and health professionals it is important to know that short-stay hospitalisation does not lead to a ‘revolving door’ pattern of admission to hospital and poor or fragmented care. However, all evidence in this review was rated by the review authors to be low quality. More large, well-designed and well-reported trials are justified that focus on important outcomes such as death, self-harm, harm to others, employment, criminal behaviour, mental state, satisfaction with treatment and services, homelessness, social or family relationships and costs. This plain language summary has been written by a consumer Benjamin Gray, Service User and Service User Expert, Rethink Mental Illness.

10.1002/14651858.CD000384.pub3

cochrane-simplification-train-210

cochrane-simplification-train-210

Four trials met the inclusion criteria, with a total of 3198 children under five years of age, and were conducted in Afghanistan, Spain, and the USA. Prevalence of vitamin D deficiency varied widely in these populations (range: 73.1% in Afghanistan, 10 to 12% in USA, and 6.2% in Spain). The included trials evaluated mortality (two trials), pneumonia incidence (two trials), diarrhoea incidence (two trials), hospitalization (two trials), and mean serum vitamin D concentrations (four trials). We do not know whether vitamin D supplementation impacts on all-cause mortality because this outcome was underpowered due to few events (risk ratio (RR) 1.43, 95% confidence interval (CI) 0.54 to 3.74; one trial, 3046 participants, low quality evidence). For pneumonia, episodes of 'radiologically confirmed' first or only episode of pneumonia were little different in the supplemented and unsupplemented group (Rate Ratio: 1.06, 95% confidence interval (CI) 0.89 to 1.26; two trials, 3134 participants, moderate quality evidence), and similarly for children with confirmed or unconfirmed pneumonia (RR 0.95, 95% CI 0.87 to 1.04; one trial, 3046 participants). In these two trials there were no obvious differences between supplemented and unsupplemented children regarding episodes of diarrhoea. In the single large trial from Afghanistan, the trial authors reported that vitamin D supplementation was associated with an increase in repeat episodes of pneumonia confirmed by chest radiograph (RR 1.69, 95% CI 1.28 to 2.21; one trial, 3046 participants), but not reflected in the outcome of confirmed or unconfirmed pneumonia (RR 1.06, 95% CI 1.00 to 1.13; one trial, 3046 participants). For hospital admission measured in one small trial, there was no difference detected (RR 0.86, 95% CI 0.20 to 3.62; one trial, 88 participants; very low quality evidence). The mean serum vitamin D concentrations were higher in supplemented compared to unsupplemented children at the end of supplementation (MD 7.72 ng/mL, 95% CI 0.50 to 14.93; four trials, 266 participants, low quality evidence). These results were driven primarily by two smaller trials with large magnitudes of effect. In the other two bigger trials, serum vitamin D concentrations were elevated in the intervention group for most of the trial duration but not at the end of supplementation. This may be due to time elapsed at measurement from the last dose, incomplete compliance, or increased need of vitamin D with infant age. We did not find any trial that reported on the incidence of TB, malaria or febrile illness, duration of pneumonia, duration of diarrhoea, severity of infection, and cause-specific mortality (due to TB, diarrhoea, or malaria). Evidence from one large trial did not demonstrate benefit of vitamin D supplementation on the incidence of pneumonia or diarrhoea in children under five years. To our knowledge, trials that evaluated supplementation for preventing other infections, including TB and malaria, have not been performed.

The review authors examined the available evidence up to 17 June 2016, and included four trials with a total of 3198 children under five years of age. The included trials were conducted in Afghanistan, Spain and the USA. The review did not detect an effect of vitamin D supplementation on death (low quality evidence); the occurrence of the first or only episode of pneumonia; or on children with pneumonia, irrespective of whether this had been confirmed by hospital tests (moderate quality evidence). Limited evidence showed that there was no obvious difference in the first or repeat episodes of diarrhoea between supplemented and unsupplemented children. We do not know about whether Vitamin D influences hospital admissions as there was only one small study measuring this (very low quality evidence). The mean serum vitamin D concentrations were higher in the supplemented versus unsupplemented children at the end of supplementation period (low quality evidence). One large trial from Afghanistan showed an increase in repeat episodes of confirmed pneumonia but not on confirmed and unconfirmed pneumonia. None of the included trials reported on TB or malaria as outcomes. One large trial has not demonstrated an effect of vitamin D on death or respiratory infections in children under five years of age. We did not find trials evaluating Vitamin D supplementation to prevent other infections such as TB and malaria.

10.1002/14651858.CD008824.pub2

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Twenty one randomised trials with a total of 1371 children met the inclusion criteria. Sample sizes were generally small. All studies but one investigated children with functional faecal incontinence. Interventions varied amongst trials and few outcomes were shared by trials addressing the same comparisons. Combined results of nine trials showed higher rather than lower rates of persisting symptoms of faecal incontinence up to 12 months when biofeedback was added to conventional treatment (OR 1.11 CI 95% 0.78 to 1.58). This result was consistent with that of two trials with longer follow-up (OR 1.31 CI 95% 0.80 to 2.15). In one trial the adjunct of anorectal manometry to conventional treatment did not result in higher success rates in chronically constipated children (OR 1.40 95% CI 0.72 to 2.73 at 24 months). In one small trial the adjunct of behaviour modification to laxative therapy was associated with a significant reduction in children's soiling episodes at both the three month (OR 0.14 CI 95% 0.04 to 0.51) and the 12 month assessment (OR 0.20 CI 95% 0.06 to 0.65). There is no evidence that biofeedback training adds any benefit to conventional treatment in the management of functional faecal incontinence in children. There was not enough evidence on which to assess the effects of biofeedback for the management of organic faecal incontinence. There is some evidence that behavioural interventions plus laxative therapy, rather than laxative therapy alone, improves continence in children with functional faecal incontinence associated with constipation.

This review identified 21 studies with a total of 1371 children. Behavioural interventions when used together with laxative therapy may improve continence in children with non-organic faecal incontinence and constipation whilst biofeedback does not add any long-term benefit. Children who received biofeedback treatment had not always been evaluated beforehand for the suitability of the treatment. There was not enough evidence to assess the effects of biofeedback in children with organic faecal incontinence.

10.1002/14651858.CD002240.pub4

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We identified three eligible RCTs and five CTs, including participants aged 11 to 14 years, who were non-smokers at baseline. Of the eight trials identified, six had analyzable data relevant for this review, which contributed to meta-analyses (7275 participants in total: 4003 intervention; 3272 control; 2484 participants after adjusting for clustering). All except one of the studies tested the 'Smokefree Class Competition' (SFC), which has been widely implemented throughout Europe. In this competition, classes with youth generally between the ages of 11 and 14 years commit to being smoke-free for a six-month period, and report their smoking status regularly. If 90% or more of the class are non-smokers at the end of the six months, the class goes into a competition to win prizes. The one study that was not a trial of the SFC was a controlled trial in which schools in two communities were assigned to the intervention, with schools in a third community acting as controls. Students in the intervention community with lower smoking rates at the end of the project (one school year) received rewards. Most studies resulted in statistically non-significant results. Only one study of the SFC reported a significant effect of the competition on the prevention of smoking at the longest follow-up. However, this study was at risk of multiple biases, and when we calculated the adjusted risk ratio (RR) we no longer detected a statistically significant difference. The pooled RR for the more robust RCTs (3 studies, n = 3056 participants/1107 adjusted for clustering) suggests that there is no statistically significant effect of incentives, in the form of the SFC, to prevent smoking initiation among children and adolescents in the long term (RR 1.00, 95% confidence interval (CI) 0.84 to 1.19). Pooled results from the non-randomized trials also did not detect a significant effect of the SFC, and we were unable to extract data on our outcome of interest from the one trial that did not study the SFC. There is little robust evidence to suggest that unintended consequences (such as making false claims about their smoking status and bullying of smoking students) are consistently associated with such interventions, although this has not been the focus of much research. There was insufficient information to assess the dose-response relationship or to report costs of incentives for preventing smoking uptake. We judged the included RCTs to be at unclear risk of bias, and the non-RCTs to be at high risk of bias. Using GRADE, we rated the overall quality of the evidence for our primary outcome as 'low' (for RCTs) and 'very low' (for non-RCTs), because of imprecision (all studies had wide confidence intervals), and for the risks of bias identified. We further downgraded the non-RCT evidence, due to issues with the non-RCT study design, likely to introduce further bias. The very limited evidence currently available suggests that incentive programmes do not prevent smoking initiation among youth. However, there are relatively few published studies and these are of variable quality. In addition, trials included in the meta-analyses were all studies of the SFC, which distributed small to moderately-sized prizes to whole classes, usually through a lottery system. It is therefore possible that other incentive programmes could be more successful at preventing smoking uptake in young people. Future studies might investigate the efficacy of a wider range of incentives, including those given to individual participants to prevent smoking uptake, whilst considering both the effect of incentives on smoking initiation and the progression to smoking. It would be useful if incentives were evaluated in varying populations from different socioeconomic and ethnic backgrounds, and if intervention components were described in detail.

This is an update of a previous review. The first version was published in 2012 and included seven studies. For this update we searched for new studies in December 2016 and found one. This review now includes eight trials. Seven of these were trials of the 'Smokefree Class Competition' (SFC), which has been widely used throughout Europe. In this competition, classes (generally between the ages of 11 and 14 years) promise to be smoke-free for a six-month period. They report regularly on their smoking status, and if 90% or more of the class are non-smokers at the end of the six months, the class goes into a competition to win prizes. In the one trial that did not test the SFC, classes with the smallest percentage of students smoking at the school year's end were given rewards. We assessed the results from seven trials of SFC and found that the competition did not have a significant impact on whether or not young people started smoking. As there was only one trial that was not of the SFC, we concluded that we do not have enough information to evaluate whether this programme was effective in preventing young people from starting to smoke. Potential negative effects of the SFC have not been widely researched, but the available data suggest that the SFC programme does not have any significant negative effects. We judged the overall quality of evidence to be low or very low, because it is based on a small number of studies, with imprecise effects and with a high or uncertain risk of bias.

10.1002/14651858.CD008645.pub3

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Three randomized controlled trials were identified. One was of good methodological quality (Markowitz 2000). This study looked at the use of 6-mercaptopurine (6-MP) as a steroid sparing agent. No difference in linear growth was observed between the intervention and placebo groups, although the total steroid dose received over the 18 month follow up period was reduced in the group receiving 6-MP. The two remaining randomized controlled trials (Sanderson 1987; Thomas 1993a) consider the use of enteral feeding versus corticosteroids for induction of remission, with height velocity standard deviation score at 6 months as an outcome measure. Although of less rigorous methodological quality, the results of these studies are discussed in detail in the review. In both studies height velocity standard deviation scores were significantly increased in the enteral feeding group compared with the corticosteroid group. In addition to these randomized controlled trials, a body of lower quality evidence does exist relevant to two other important interventions; the use of supplemental enteral nutrition (Morin 1980; Belli 1988; Israel 1995) and the judicious use of surgical interventions in pre-pubertal children with refractory disease (Alperstein 1985; Lipson 1990; McLain 1990). Newer treatments, such as infliximab, are now becoming more widely used and may offer advantages in promoting growth. These effects are as yet unstudied. This review highlights the need for large, multi centre studies of the different treatment options in paediatric Crohn's disease and the importance of standardised measurements of growth, such as height velocity standard deviation scores and height standard deviation scores as outcome measures.

The aim of this review was to evaluate the effectiveness of various treatments for growth failure in childhood Crohn's disease. Three randomized controlled trials were identified. One trial did not show any benefit for linear growth with 6-mercaptopurine treatment compared to placebo among children being treated with steroids. The other two trials looked at nutritional treatment (elemental feedings) versus steroids (prednisolone). Both trials showed a statistically significant benefit for height velocity standard deviation scores with nutritional treatment. However, these results need to be confirmed by large, multi-centre, randomized controlled trials of therapeutic interventions in pre-pubertal children with Crohn's disease. These trials should use growth as an outcome measure. In conclusion, more research is needed to identify effective treatments for growth failure in childhood Crohn's disease.

10.1002/14651858.CD003873.pub2

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This review included 18 double-blind placebo-controlled trials with a total of 2456 participants. Five trials were assessed at unclear risk of bias, thirteen at high risk, and none at low risk of bias. Compared to placebo, antibiotics probably reduce the risk of infection in patients undergoing third molar extraction(s) by approximately 70% (RR 0.29 (95% CI 0.16 to 0.50) P < 0.0001, 1523 participants, moderate quality evidence) which means that 12 people (range 10-17) need to be treated with antibiotics to prevent one infection following extraction of impacted wisdom teeth. There is evidence that antibiotics may reduce the risk of dry socket by 38% (RR 0.62 (95% CI 0.41 to 0.95) P = 0.03, 1429 participants, moderate quality evidence) which means that 38 people (range 24-250) need to take antibiotics to prevent one case of dry socket following extraction of impacted wisdom teeth. There is also some evidence that patients who have prophylactic antibiotics may have less pain (MD -8.17 (95% CI -11.90 to -4.45) P < 0.0001, 372 participants, moderate quality evidence ) overall 7 days after the extraction compared to those receiving placebo, which may be a direct result of the lower risk of infection. There is no evidence of a difference between antibiotics and placebo in the outcomes of fever (RR 0.34, 95% CI 0.06 to 1.99), swelling (RR 0.92, 95% CI 0.65 to 1.30) or trismus (RR 0.84, 95% CI 0.42 to 1.71) 7 days after tooth extraction. Antibiotics are associated with an increase in generally mild and transient adverse effects compared to placebo (RR 1.98 (95% CI 1.10 to 3.59) P = 0.02) which means that for every 21 people (range 8-200) who receive antibiotics, an adverse effect is likely. Although general dentists perform dental extractions because of severe dental caries or periodontal infection, there were no trials identified which evaluated the role of antibiotic prophylaxis in this group of patients in this setting. All of the trials included in this review included healthy patients undergoing extraction of impacted third molars, often performed by oral surgeons. There is evidence that prophylactic antibiotics reduce the risk of infection, dry socket and pain following third molar extraction and result in an increase in mild and transient adverse effects. It is unclear whether the evidence in this review is generalisable to those with concomitant illnesses or immunodeficiency, or those undergoing the extraction of teeth due to severe caries or periodontitis. However, patients at a higher risk of infection are more likely to benefit from prophylactic antibiotics, because infections in this group are likely to be more frequent, associated with complications and be more difficult to treat. Due to the increasing prevalence of bacteria which are resistant to treatment by currently available antibiotics, clinicians should consider carefully whether treating 12 healthy patients with antibiotics to prevent one infection is likely to do more harm than good.

This review looks at whether antibiotics, given to dental patients as part of their treatment, prevent infection after tooth extraction. There were 18 studies considered, with a total of 2456 participants who received either antibiotics (of different kinds and dosages) or placebo, immediately before and/or just after tooth extraction. There were concerns about aspects of the design and reporting of all the studies. In all of the studies healthy people had extractions of impacted wisdom teeth done by oral surgeons. This review provides evidence that antibiotics administered just before and/or just after surgery reduce the risk of infection, pain and dry socket after wisdom teeth are removed by oral surgeons, but that using antibiotics also causes more (generally brief and minor) side effects for these patients. Additionally, there was no evidence that antibiotics prevent fever, swelling or problems with restricted mouth opening in patients who have had wisdom teeth removed. There was no evidence to judge the effects of preventative antibiotics for extractions of severely decayed teeth, teeth in diseased gums, or extractions in patients who are sick or have low immunity to infection. Undertaking research in these groups of people may not be possible or ethical. However, it is likely that in situations where patients are at a higher risk of infection that preventative antibiotics may be beneficial, because infections in this group are likely to be more frequent and more difficult to treat. Another concern, which cannot be assessed by clinical trials, is that widespread use of antibiotics by people who do not have an infection is likely to contribute to the development of bacterial resistance. The conclusion of this review is that antibiotics given to healthy people to prevent infections, may cause more harm than benefit to both the individual patients and the population as a whole.

10.1002/14651858.CD003811.pub2

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We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. When we updated the searches in 2012 we found no additional trials. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi2 = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054). In patients already diagnosed with clinically probable or definite ALS, creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALSFRS-R progression or percent predicted FVC progression.

However, human trials have shown mixed results thus far. Therefore, we systematically reviewed all available clinical trial evidence as of July 2012 to determine if creatine benefits or harms people with ALS/MND. This review included three well-designed clinical trials involving a total of 386 participants receiving either creatine or placebo. Overall, creatine was well-tolerated with no serious side effects. Using various statistical methods, we found that creatine at a dose of 5 to 10 g per day did not improve ALS survival or slow ALS progression in any meaningful way. There was a hint that creatine may slightly worsen breathing ability, but this may have just been misleading statistical variability.

10.1002/14651858.CD005225.pub3

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Twenty-two small trials involving 2676 people were included. One trial was placebo controlled, 18 compared two or more drug treatments, three compared treatment regimens, and one compared different drug vehicles. Fewer treatment failures occurred by day seven with oral ivermectin compared with placebo in one small trial (55 participants). Topical permethrin appeared more effective than oral ivermectin (140 participants, 2 trials), topical crotamiton (194 participants, 2 trials), and topical lindane (753 participants, 5 trials). Permethrin also appeared more effective in reducing itch persistence than either crotamiton (94 participants, 1 trial) or lindane (490 participants, 2 trials). No difference was detected between permethrin (a synthetic pyrethroid) and a natural pyrethrin-based topical treatment (40 participants, 1 trial), and between permethrin and benzyl benzoate (53 participants, 1 trial), however both these trials were small. No significant difference was detected in the number of treatment failures between crotamiton and lindane (100 participants, 1 trial), lindane and sulfur (68 participants, 1 trial), benzyl benzoate and sulfur (158 participants, 1 trial), and benzyl benzoate and natural synergized pyrethrins (240 participants, 1 trial); all were topical treatments. No trials of malathion were identified. No serious adverse events were reported. A number of trials reported skin reactions in participants randomized to topical treatments. There were occasional reports of headache, abdominal pain, diarrhoea, vomiting, and hypotension. Topical permethrin appears to be the most effective treatment for scabies. Ivermectin appears to be an effective oral treatment. More research is needed on the effectiveness of malathion, particularly when compared to permethrin, and on the management of scabies in an institutional setting and at a community level.

The review of trials attempted to cover all these. The authors identified 22 small trials involving 2676 people, with 19 of the trials taking place in resource-poor countries. Permethrin appeared to be the most effective topical treatment for scabies, and ivermectin appeared to be an effective oral treatment. However, ivermectin is unlicensed for this indication in many countries. Adverse events such as rash, vomiting, and abdominal pain were reported, but the trials were too small to properly assess serious but rare potential adverse effects. No trials of herbal or traditional medicines were identified for inclusion.

10.1002/14651858.CD000320.pub2

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Thirteen trials recruiting 34,980 women were included in the systematic review. Risk of bias was low for allocation concealment and selective reporting, unclear for random sequence generation and incomplete outcome data and high for blinding of both outcome assessment and participants and personnel. There was no difference in antenatal, obstetric and neonatal outcome or morbidity in screened versus control groups. Routine late pregnancy ultrasound was not associated with improvements in overall perinatal mortality. There is little information on long-term substantive outcomes such as neurodevelopment. There is a lack of data on maternal psychological effects. Overall, the evidence for the primary outcomes of perinatal mortality, preterm birth less than 37 weeks, induction of labour and caesarean section were assessed to be of moderate or high quality with GRADE software. There was no association between ultrasound in late pregnancy and perinatal mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.67 to 1.54; participants = 30,675; studies = eight; I² = 29%), preterm birth less than 37 weeks (RR 0.96, 95% CI 0.85 to 1.08; participants = 17,151; studies = two; I² = 0%), induction of labour (RR 0.93, 95% CI 0.81 to 1.07; participants = 22,663; studies = six; I² = 78%), or caesarean section (RR 1.03, 95% CI 0.92 to 1.15; participants = 27,461; studies = six; I² = 54%). Three additional primary outcomes chosen for the 'Summary of findings' table were preterm birth less than 34 weeks, maternal psychological effects and neurodevelopment at age two. Because none of the included studies reported these outcomes, they were not assessed for quality with GRADE software. Based on existing evidence, routine late pregnancy ultrasound in low-risk or unselected populations does not confer benefit on mother or baby. There was no difference in the primary outcomes of perinatal mortality, preterm birth less than 37 weeks, caesarean section rates, and induction of labour rates if ultrasound in late pregnancy was performed routinely versus not performed routinely. Meanwhile, data were lacking for the other primary outcomes: preterm birth less than 34 weeks, maternal psychological effects, and neurodevelopment at age two, reflecting a paucity of research covering these outcomes. These outcomes may warrant future research.

The ultrasound scan protocols in each trial varied, as did the reasons for ultrasound scans after 24 weeks' gestation. The influence of first and second trimester ultrasounds is difficult to disentangle, and assessment of most measures at late pregnancy is based on gestational reference data, which rely on accurate gestational dating in early pregnancy. Trials were undertaken over a period of time covering early introduction into clinical practice to widespread use, during which time how to assess fetal size and well being ultrasonographically were still being debated. As ultrasound technology continues to advance and become more accessible, it is important to maintain a clear idea of its relevance. Ultrasound, being a clinical investigation, may be used to detect abnormality without the impact of such detection on clinical outcomes being full assessed. Exposure of the expectant mother to uncertainty and possible anxiety about the health of her baby has implications that may be far reaching. In addition, little is known about how the baby that was compromised in the uterus develops after birth and in the first years of life.

10.1002/14651858.CD001451.pub4

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Eleven RCTs involving 808 participants met the inclusion criteria. The methodological quality of the included studies was variable and most of the predefined outcomes were reported by only one or two studies, therefore the quality of the evidence was low. Five studies with a total of 405 patients reported the incidence of DVT. In the CPM group (205 patients) 36 developed DVT (18%) compared to 29 (15%) in the control group (200 patients). The results of the meta-analysis showed no evidence that CPM had any effect on preventing VTE after TKA (RR 1.22, 95% CI 0.84 to 1.79). One trial (150 participants) did not find PE in any of the patients during hospitalisation or in the subsequent three months. PE was not reported in the other included studies. None of the trials reported deaths among the included participants. There is not enough evidence from the available RCTs to conclude that CPM reduces VTE after TKA. We cannot assess the effect of CPM on mortality because no such events occurred amongst the participants of these trials. The quality of the evidence was low. The results are supported by only a small number of studies, most of which are of low to moderate quality.

We included 11 trials involving 808 participants in our review. The methodological quality of the included studies was variable and the quality of the evidence was low because the outcomes of interest were only reported by one or two studies. Sensitive methods such as venography or sonography were not always used to diagnose DVT and the CPM was applied differently across studies, varying in range of motion, duration of CPM per day and the number of days after the surgery. The incidence of DVT or VTE was not clearly different in the CPM group compared with the control group of participants. This review did not find enough evidence from randomised controlled trials to conclude that CPM reduces VTE.

10.1002/14651858.CD008207.pub3

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For TTP, we found six RCTs (331 participants) evaluating PE with FFP as the control. Interventions tested included antiplatelet therapy (APT) plus PE with FFP, FFP transfusion and PE with cryosupernatant plasma (CSP). Two studies compared plasma infusion (PI) to PE with FFP and showed a significant increase in failure of remission at two weeks (RR 1.48, 95% 1.12 to 1.96) and all-cause mortality (RR 1.91, 95% 1.09 to 3.33) in the PI group. Seven RCTs were undertaken in children with HUS. None of the assessed interventions used (FFP transfusion, heparin with or without urokinase or dipyridamole, shiga toxin binding protein and steroids) were superior to supportive therapy alone, for all-cause mortality, neurological/extrarenal events, renal biopsy changes, proteinuria or hypertension at the last follow-up visit. Bleeding was significantly higher in those receiving anticoagulation therapy compared to supportive therapy alone (RR 25.89, 95% CI 3.67 to 182.83). PE with FFP is still the most effective treatment available for TTP. For patients with HUS, supportive therapy including dialysis is still the most effective treatment. All studies in HUS have been conducted in the diarrhoeal form of the disease. There were no RCTs evaluating the effectiveness of any interventions on patients with atypical HUS who have a more chronic and relapsing course.

This review also showed that in patients with typical or diarrhoea associated haemolytic uraemic syndrome, there are no interventions that are superior to supportive therapy which includes control of fluid and electrolyte imbalance, use of dialysis if required, control of hypertension and blood transfusion as required.

10.1002/14651858.CD003595.pub2

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Nine randomised clinical trials with 879 participants fulfilled our inclusion criteria. All trials were at high risk of bias, and we rated the evidence as low to very low quality. All of the included trials compared combined external beam radiotherapy plus chemoembolisation versus chemoembolisation alone in people with unresectable hepatocellular carcinoma; moreover, three of the trials compared external beam radiotherapy alone versus chemoembolisation alone. All trials were conducted in China. The median age in most of the included trials was around 52 years, and most trial participants were male. The median follow-up duration ranged from one to three years. None of the trials reported data on cancer-related mortality, quality of life, serious adverse events, or time to progression of the tumour. For the comparison of radiotherapy plus chemoembolisation versus chemoembolisation alone, the risk ratio for one-year all-cause mortality was 0.51 (95% confidence interval (CI) 0.41 to 0.62; P < 0.001; 9 trials; low-quality evidence); for complete response rate was 2.14 (95% CI 1.47 to 3.13; P < 0.001; 7 trials; low-quality evidence); and for overall response rate defined as complete response plus partial response was 1.58 (95% CI 1.40 to 1.78; P < 0.001; 7 trials; low-quality evidence), all in favour of combined treatment with external beam radiotherapy plus transarterial chemoembolisation and seemingly supported by our Trial Sequential Analysis. Additionally, the combined treatment was associated with a higher risk of elevated total bilirubin and elevated alanine aminotransferase. The risk ratio for the risk of elevated alanine aminotransferase was 1.41 (95% CI 1.08 to 1.84; P = 0.01; very low-quality evidence), while for elevated total bilirubin it was 2.69 (95% CI 1.34 to 5.40; P = 0.005; very low-quality evidence). For the comparison of radiotherapy versus chemoembolisation, the risk ratio for one-year all-cause mortality was 1.21 (95% CI 0.97 to 1.50; 3 trials; I2 = 0%; very low-quality evidence) which was not supported by our Trial Sequential Analysis. In addition, we found seven ongoing randomised clinical trials evaluating different external beam radiotherapy techniques for people with unresectable hepatocellular carcinoma. We found very low- and low-quality evidence suggesting that combined external beam radiotherapy and chemoembolisation may be associated with lower mortality and increased complete and overall response rates, despite an increased toxicity as expressed by a higher rise of bilirubin and alanine aminotransferase. A high risk of systematic errors (bias) as well as imprecision and inconsistency suggest that these findings should be considered cautiously and that high-quality trials are needed to assess further the role of external beam radiotherapy for unresectable hepatocellular carcinoma.

We searched the medical literature for randomised clinical trials (where people are allocated at random to one of two or more treatment groups) in order to perform an analysis of the role of radiotherapy administered externally for advanced liver cancer. We found nine randomised clinical trials including a total of 879 people with advanced liver cancer. All of the included trials were conducted in China. The average age in most of the included studies was around 52 years, and most trial participants were male. The average follow-up duration ranged from one to three years. All trials were at high risk of bias, and we rated the evidence as low to very low quality. Most of the included trials compared combined radiotherapy and chemoembolisation versus chemoembolisation alone. We also identified seven ongoing randomised clinical trials. The evidence is current to October 2016. When compared with chemoembolisation alone, combined radiotherapy plus chemoembolisation may be associated with fewer deaths and more tumour size reduction, despite being associated with an increased risk for non-life-threatening adverse effects such as a higher rise of bilirubin and alanine aminotransferase. Combined radiotherapy and chemoembolisation may be associated with fewer deaths and increased overall response, but also an increased risk of adverse effects, when compared with chemoembolisation alone. The low quality of evidence suggests that these results should be considered cautiously and that high-quality randomised trials should be performed to assess further the role of external beam radiotherapy for unresectable hepatocellular carcinoma.

10.1002/14651858.CD011314.pub2

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We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high-dose versus low-dose coenzyme Q10 and vitamin E (the trialists considered the low-dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion. In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co-operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant-treated and the placebo groups (mean difference 0.79 points, 95% confidence interval -1.97 to 3.55 points; low-quality evidence). The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End-diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low. There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year-long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis. Low-quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low-quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low-quality evidence, serious and non-serious adverse events were rare in both antioxidant and placebo groups. No non-antioxidant agents have been investigated in RCTs of 12 months' duration.

We decided to review clinical trials that had participants who took antioxidants for at least 12 months, as Friedreich ataxia is a slowly progressing condition. A wide search of the medical literature found four randomised controlled trials, but only two of them had published results in medical journals. One trial, involving 28 participants, compared idebenone to a placebo. The other, involving 44 participants, compared high-dose and very low-dose combined coenzyme Q10 and vitamin E. The two unpublished trials studied pioglitazone in 40 participants and idebenone in 232 participants, but we had no data. According to low quality evidence from two small published trials included in the review, antioxidants did not improve neurological symptoms in Friedreich ataxia. An additional large, unpublished study of idebenone reportedly found no benefit from idebenone for heart or neurological symptoms, but data are not available for checking and analysis. When published this trial will very likely influence our quality assessments and conclusions. Although some measures of heart wall thickness and mass decreased in the smaller of the two published trials, the quality of this evidence was low or very low and the importance of these findings is not clear. . Numbers of serious or non-serious adverse events were low and similar with antioxidants and placebo. The only serious adverse event that required withdrawal of an antioxidant was increased bowel frequency in one person receiving coenzyme Q with vitamin E. The evidence in the review is up to date to February 2016.

10.1002/14651858.CD007791.pub4

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We included nine RCTs (1242 participants and 426 surrogate decision-makers) in this review. The meta-analysis included seven studies (876 participants). Participants' mean ages ranged from 62 to 82 years, and 53% to 100% of the studies' participants were men. All included studies took place in the US or the UK. Only one study reported concordance between participants' preferences and end-of-life care, and it enrolled people with heart failure or renal disease. Owing to one study with small sample size, the effects of ACP on concordance between participants' preferences and end-of-life care were uncertain (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.91 to 1.55; participants = 110; studies = 1; very low-quality evidence). It corresponded to an assumed risk of 625 per 1000 participants receiving usual care and a corresponding risk of 744 per 1000 (95% CI 569 to 969) for ACP. There was no evidence of a difference in quality of life between groups (standardised mean difference (SMD) 0.06, 95% CI –0.26 to 0.38; participants = 156; studies = 3; low-quality evidence). However, one study, which was not included in the meta-analysis, showed that the quality of life score improved by 14.86 points in the ACP group compared with 11.80 points in the usual care group. Completion of documentation by medical staff regarding discussions with participants about ACP processes may have increased (RR 1.68. 95% CI 1.23 to 2.29; participants = 92; studies = 2; low-quality evidence). This corresponded to an assumed risk of 489 per 1000 participants with usual care and a corresponding risk of 822 per 1000 (95% CI 602 to 1000) for ACP. One study, which was not included in the meta-analysis, also showed that ACP helped to improve documentation of the ACP process (hazard ratio (HR) 2.87, 95% CI 1.09 to 7.59; participants = 232). Three studies reported that implementation of ACP led to an improvement of participants' depression (SMD –0.58, 95% CI –0.82 to –0.34; participants = 278; studies = 3; low-quality evidence). We were uncertain about the effects of ACP on the quality of communication when compared to the usual care group (MD –0.40, 95% CI –1.61 to 0.81; participants = 9; studies = 1; very low-quality evidence). We also noted an increase in all-cause mortality in the ACP group (RR 1.32, 95% CI 1.04 to 1.67; participants = 795; studies = 5). The studies did not report participants' satisfaction with care/treatment and caregivers' satisfaction with care/treatment. ACP may help to increase documentation by medical staff regarding discussions with participants about ACP processes, and may improve an individual's depression. However, the quality of the evidence about these outcomes was low. The quality of the evidence for each outcome was low to very low due to the small number of studies and participants included in this review. Additionally, the follow-up periods and types of ACP intervention were varied. Therefore, further studies are needed to explore the effects of ACP that consider these differences carefully.

In October 2019, we searched for studies assessing the effects of ACP in people with heart failure. We included studies that delivered ACP, which included different methods such as discussion and consideration of individuals' values and preferences on future care and medical treatment compared to usual care strategies. This review included nine studies involving 1242 participants and 426 families/carers. Data from seven studies (876 participants) showed that ACP may increase completion of documentation by medical staff regarding discussions with participants about ACP processes and may improve depression of participants. All-cause mortality might be increased in participants receiving ACP. The effects of ACP on quality of life remained uncertain due to the inclusion of small studies in our meta-analysis. This is further illustrated by the fact that only one study reported whether the received end-of-life care met participants' preferences. Similarly, only one study reported the quality of communication during ACP between participants and healthcare providers. Therefore, the effects of ACP on whether end-of-life care met participants' preferences and on quality of communication were uncertain. None of the studies evaluated satisfaction with care. The quality of evidence was low/very low. Since the number of studies and patients in this review was small, the effects of ACP were limited. There is clearly a need for high-quality evidence from large studies to fully explore the effects of ACP for people with heart failure, in particular their quality of life and whether end-of-life care received after ACP actually meet their preferences.

10.1002/14651858.CD013022.pub2

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We included eight RCTs (702 women at high risk of developing OHSS). The quality of evidence was low or very low. The main limitations were failure to report live birth, risk of bias due to lack of information about study methods, and imprecision due to low event rates and lack of data. Four of the studies were published only as abstracts, and provided limited data. Coasting versus no coasting Rates of OHSS were lower in the coasting group (OR 0.11, 95% CI 0.05 to 0.24; I² = 0%, two RCTs; 207 women; low-quality evidence), suggesting that if 45% of women developed moderate or severe OHSS without coasting, between 4% and 17% of women would develop it with coasting. There were too few data to determine whether there was a difference between the groups in rates of live birth (OR 0.48, 95% CI 0.14 to 1.62; one RCT; 68 women; very low-quality evidence), clinical pregnancy (OR 0.82, 95% CI 0.46 to 1.44; I² = 0%; two RCTs; 207 women; low-quality evidence), multiple pregnancy (OR 0.31, 95% CI 0.12 to 0.81; one RCT; 139 women; low-quality evidence), or miscarriage (OR 0.85, 95% CI 0.25 to 2.86; I² = 0%; two RCTs; 207 women; very low-quality evidence). Coasting versus EUFA There were too few data to determine whether there was a difference between the groups in rates of OHSS (OR 0.98, 95% CI 0.34 to 2.85; I² = 0%; 2 RCTs; 83 women; very low-quality evidence), or clinical pregnancy (OR 0.67, 95% CI 0.25 to 1.79; I² = 0%; 2 RCTs; 83 women; very low-quality evidence); no studies reported live birth, multiple pregnancy, or miscarriage. Coasting versus antagonist One RCT (190 women) reported this comparison, and no events of OHSS occurred in either arm. There were too few data to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.74, 95% CI 0.42 to 1.31; one RCT; 190 women; low-quality evidence), or multiple pregnancy rates (OR 1.00, 95% CI 0.43 to 2.32; one RCT; 98 women; very low-quality evidence); the study did not report live birth or miscarriage. Coasting versus FSH co-trigger Rates of OHSS were higher in the coasting group (OR 43.74, 95% CI 2.54 to 754.58; one RCT; 102 women; very low-quality evidence), with 15 events in the coasting arm and none in the FSH co-trigger arm. There were too few data to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.92, 95% CI 0.43 to 2.10; one RCT; 102 women; low-quality evidence). This study did not report data suitable for analysis on live birth, multiple pregnancy, or miscarriage, but stated that there was no significant difference between the groups. Coasting versus cabergoline There were too few data to determine whether there was a difference between the groups in rates of OHSS (OR 1.98, 95% CI 0.09 to 5.68; P = 0.20; I² = 72%; two RCTs; 120 women; very low-quality evidence), with 11 events in the coasting arm and six in the cabergoline arm. The evidence suggested that coasting was associated with lower rates of clinical pregnancy (OR 0.38, 95% CI 0.16 to 0.88; P = 0.02; I² =0%; two RCTs; 120 women; very low-quality evidence), but there were only 33 events altogether. These studies did not report data suitable for analysis on live birth, multiple pregnancy, or miscarriage. There was low-quality evidence to suggest that coasting reduced rates of moderate or severe OHSS more than no coasting. There was no evidence to suggest that coasting was more beneficial than other interventions, except that there was very low-quality evidence from a single small study to suggest that using FSH co-trigger at the time of HCG administration may be better at reducing the risk of OHSS than coasting. There were too few data to determine clearly whether there was a difference between the groups for any other outcomes.

Eight randomised controlled trials (702 women) were identified that compared withholding gonadotrophins (coasting) with another intervention to prevent ovarian hyperstimulation syndrome. The other interventions included no coasting, early unilateral follicular aspiration (taking follicles from one ovary 10 to 12 hours after the administration of human chorionic gonadotrophin (hCG)), gonadotrophin-releasing hormone (GnRH) antagonist (drugs that block the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH), and FSH co-trigger (extra dose of FSH given at the same time as the hCG). There was low-quality evidence to suggest that coasting reduced rates of moderate or severe OHSS more than no coasting. There was no evidence to suggest that coasting was more beneficial than other interventions, except that there was very low-quality evidence from a single small study to suggest that using FSH co-trigger at the time of HCG administration may be better at reducing the risk of OHSS than coasting. There were too few data to determine clearly whether there was a difference between the groups for any other outcomes. The quality of evidence was low or very low. The main limitations were failure to report live birth, risk of bias due to lack of information about study methods, and imprecision due to low event rates and lack of data. Four of the studies were published only as abstracts, and provided limited data.

10.1002/14651858.CD002811.pub4

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We found no randomised clinical trials comparing cryotherapy versus no intervention or versus systemic treatments; however, we identified one randomised clinical trial comparing cryotherapy with conventional surgery. The trial was conducted in Ukraine. The trial included 123 participants with solitary, or multiple unilobar or bilobar liver metastases; 63 participants received cryotherapy and 60 received conventional surgery. There were 36 women and 87 men. The primary sites for the metastases were colon and rectum (66.6%), stomach (7.3%), breast (6.5%), skin (4.9%), ovaries (4.1%), uterus (3.3%), kidney (3.3%), intestines (1.6%), pancreas (1.6%), and unknown (0.8%). The trial was not reported sufficiently enough to assess the risk of bias of the randomisation process, allocation concealment, or presence of blinding. It was also not possible to assess incomplete outcome data and selective outcome reporting bias. The certainty of evidence was low because of risk of bias and imprecision. The participants were followed for up to 10 years (minimum five months). The trial reported that the mortality at 10 years was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group. The calculated by us relative risk (RR) with 95% Confidence Interval (CI) was: RR 0.88, 95% CI 0.77 to 1.02. We judged the evidence as low-certainty evidence. Regarding adverse events and complications, separately and in total, our calculation showed no evidence of a difference in recurrence of the malignancy in the liver: 86% (54/63) of the participants in the cryotherapy group and 95% (57/60) of the participants in the conventional surgery group developed a new malignancy (RR 0.90, 95% CI 0.80 to 1.01; low-certainty evidence). The frequency of reported complications was similar between the cryotherapy group and the conventional surgery group, except for postoperative pain. Both insignificant and pronounced pain were reported to be more common in the cryotherapy group while intense pain was reported to be more common in the conventional surgery group. However, the authors did not report whether there was any evidence of a difference. There were no intervention-related mortality or bile leakages. We identified no evidence for health-related quality of life, cancer mortality, or time to progression of liver metastases. The study reported tumour response in terms of the carcinoembryonic antigen level in 69% of participants, and reported results in the form of a graph for 30% of participants. The carcinoembryonic antigen level was lower in the cryotherapy group, and decreased to normal values faster in comparison with the control group (P < 0.05). Funding: the trial did not provide information on funding. The evidence for the effectiveness of cryotherapy versus conventional surgery in people with liver metastases is of low certainty. We are uncertain about our estimate and cannot determine whether cryotherapy compared with conventional surgery is beneficial or harmful. We found no evidence for the benefits or harms of cryotherapy compared with no intervention, or versus systemic treatments.

We last searched for evidence in June 2018. We included only one trial conducted in Ukraine, and participants' primary cancer was colorectal (bowel) cancer in 66% of instances, but there were also people with stomach, breast, skin, and other tumours. All of them had cancer spread to the liver. In this trial, 123 participants were allocated at random to receive either cryotherapy (63 people) or conventional surgery (affected parts of the liver were removed; 60 people). The trial did not provide information on funding. The trial was at high risk of bias. The participants were followed for up to 10 years (minimum five months). The trial reported that the mortality at 10 years was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group. We judged the evidence as low-certainty evidence. We found no evidence of a difference in proportion of participants with recurrence of the malignancy in the liver: 86% (54/63) of the participants in the cryotherapy group and 95% (57/60) of the participants in the conventional surgery group developed a new malignancy (low-certainty evidence). The frequency of reported complications was similar between the cryotherapy group and the conventional surgery group, except for postoperative pain. Both insignificant and pronounced pain were reported to be more common in the cryotherapy group while intense pain was reported to be more common in the conventional surgery group. However, it was not reported whether there was any evidence of a difference. The frequency of unwanted effects (adverse events or complications) was mostly similar in both groups, but pain intensity and frequency seemed to differ between the groups. There were no intervention-related mortality or bile leakages. The trial did not provide data on quality of life; cancer mortality, and time to progression of liver metastases. The evidence for the effectiveness of cryotherapy versus conventional surgery in people with liver metastases is of low certainty. We are uncertain about our estimate and cannot determine whether cryotherapy compared with conventional surgery is beneficial or harmful. We found no evidence for the benefits or harms of cryotherapy compared with no intervention, or versus systemic treatments.

10.1002/14651858.CD009058.pub3

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The review included five studies with 430 participants. Studies varied in the preparations of valproate, mean doses (480 mg/day to 1000 mg/day), duration of treatment (three weeks to six weeks), and outcome measures used. The studies were generally well conducted although some methodological information was missing and one study was at high risk of attrition bias. The quality of evidence related to our primary efficacy outcome of agitation varied from moderate to very low. We found moderate-quality evidence from two studies that measured behaviour with the total Brief Psychiatric Rating Scale (BPRS) score (range 0 to 108) and with the BPRS agitation factor (range 0 to 18). They found that there was probably little or no effect of valproate treatment over six weeks (total BPRS: mean difference (MD) 0.23, 95% confidence interval (CI) –2.14 to 2.59; 202 participants, 2 studies; BPRS agitation factor: MD –0.67, 95% CI –1.49 to 0.15; 202 participants, 2 studies). Very low-quality evidence from three studies which measured agitation with the Cohen-Mansfield Agitation Index (CMAI) were consistent with a lack of effect of valproate treatment on agitation. There was variable quality evidence on other behaviour outcomes reported in single studies of no difference between groups or a benefit for the placebo group. Three studies, which measured cognitive function using the Mini-Mental State Examination (MMSE), found little or no effect of valproate over six weeks, but we were uncertain about this result because the quality of the evidence was very low. Two studies that assessed functional ability using the Physical Self-Maintenance Scale (PSMS) (range 6 to 30) found that there was probably slightly worse function in the valproate-treated group, which was of uncertain clinical importance (MD 1.19, 95% CI 0.40 to 1.98; 203 participants, 2 studies; moderate-quality evidence). Analysis of adverse effects and serious adverse events (SAE) indicated a higher incidence in valproate-treated participants. A meta-analysis of three studies showed that there may have been a higher rate of adverse effects among valproate-treated participants than among controls (odds ratio (OR) 2.02, 95% CI 1.30 to 3.14; 381 participants, 3 studies, low-quality evidence). Pooled analysis of the number of SAE for the two studies that reported such data indicated that participants treated with valproate preparations were more likely to experience SAEs (OR 4.77, 95% CI 1.00 to 22.74; 228 participants, 2 studies), but the very low quality of the data made it difficult to draw any firm conclusions regarding SAEs. Individual adverse events that were more frequent in the valproate-treated group included sedation, gastrointestinal symptoms (nausea, vomiting, and diarrhoea), and urinary tract infections. This updated review corroborates earlier findings that valproate preparations are probably ineffective in treating agitation in people with dementia, but are associated with a higher rate of adverse effects, and possibly of SAEs. On the basis of this evidence, valproate therapy cannot be recommended for management of agitation in dementia. Further research may not be justified, particularly in light of the increased risk of adverse effects in this often frail group of people. Research would be better focused on effective non-pharmacological interventions for this patient group, or, for those situations where medication may be needed, further investigation of how to use other medications as effectively and safely as possible.

Studies measured agitated behaviour with various scales and the reliability of the evidence for the different scales ranged from moderate to very low. Overall, we found no evidence that valproate preparations improved behaviour, or specifically, agitated behaviour. We found that valproate preparations probably had little or no effect on participants' ability to perform daily activities. We could not be sure whether they had an effect on cognition (thinking and remembering) because the reliability of the evidence was very low. We found low-reliability evidence from three studies that participants taking valproate may be more likely than those taking placebo to experience harmful effects. We could not be as certain about differences in serious harms, such as serious illness or admission to hospital, but data from two studies suggested that these may be more common in the participants taking valproate. Some of the side effects associated with valproate were sleepiness, feeling sick, being sick, watery stools, and urinary tract infections. We only identified five relatively small studies for inclusion in this review. They varied in their methods, type of medicine and its dose, duration of treatment, and scales used to make measurements. This limited our ability to pool data across studies. However, we could be moderately confident in the conclusion that valproate preparations do not improve agitated behaviour in dementia. They may also be associated with harmful effects.

10.1002/14651858.CD003945.pub4

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One new study was identified for this 2018 update, bringing the total number of included studies to two and the total number of participants to 451. Both trials discharged patients randomised to the outpatient group within 36 hours of initial triage and both followed participants for 90 days. One study compared the same treatment regimens in both outpatient and inpatient groups, and the other study used different treatment regimes. There was no clear difference in treatment effect for the outcomes of short-term mortality (30 days) (RR 0.33, 95% CI 0.01 to 7.98, P = 0.49; low-quality evidence), long-term mortality (90 days) (RR 0.98, 95% CI 0.06 to 15.58, P = 0.99, low-quality evidence), major bleeding at 14 days (RR 4.91, 95% CI 0.24 to 101.57, P = 0.30; low-quality evidence) and at 90 days (RR 6.88, 95% CI 0.36 to 132.14, P = 0.20; low-quality evidence), minor bleeding (RR 1.08, 95% CI 0.07 to 16.79; P = 0.96, low-quality evidence), recurrent PE within 90 days (RR 2.95, 95% CI 0.12 to 71.85, P = 0.51, low-quality evidence), and participant satisfaction (RR 0.97, 95% CI 0.90 to 1.04, P = 0.39; moderate-quality evidence). We downgraded the quality of the evidence because the CIs were wide and included treatment effects in both directions, the sample sizes and numbers of events were small, and because the effect of missing data and the absence of publication bias could not be verified. PE-related mortality, and adverse effects such as haemodynamic instability and compliance, were not assessed by the included studies. Currently, only low-quality evidence is available from two published randomised controlled trials on outpatient versus inpatient treatment in low-risk patients with acute PE. The studies did not provide evidence of any clear difference between the interventions in overall mortality, bleeding and recurrence of PE.

We searched scientific databases for clinical trials of low-risk adults (aged 18 years and over) allocated to home (outpatient) management or hospital (inpatient) management of acute PE. The evidence is current to March 2018. We included two studies, which included a total of 453 people. We are uncertain whether, compared with inpatient treatment, outpatient treatment has an important effect on number of deaths, bleeding, recurrence of PE, and patient satisfaction because the results were imprecise and the studies did not report side effects such as haemodynamic instability (where drugs or procedures are needed to maintain a stable blood pressure), and compliance (how well people follow medical advice). The evidence from the included studies was of low quality because of imprecision in the results. This was due to there being only small numbers of people in the studies (and small numbers of events), and because we could not confirm the absence of publication bias (reports of studies where no effect was shown might not be published). Therefore, further well-conducted randomised controlled trials (where people are allocated at random to one of two or more treatment groups, one of which is a control treatment) are required before informed practice decisions can be made.

10.1002/14651858.CD010019.pub3

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Five studies were included with a total of 176 participants (71 people participated in water-based exercise training and 54 in land-based exercise training; 51 completed no exercise training). All studies compared supervised water-based exercise training versus land-based exercise training and/or no exercise training in people with COPD (with average forced expiratory volume in one second (FEV1) %predicted ranging from 39% to 62%). Sample sizes ranged from 11 to 53 participants. The exercise training programmes lasted from four to 12 weeks, and the mean age of participants ranged from 57 to 73 years. A moderate risk of bias was due to lack of reporting of randomisation, allocation and blinding procedures in some studies, as well as small sample sizes. Compared with no exercise, water-based exercise training improved the six-minute walk distance (mean difference (MD) 62 metres; 95% confidence interval (CI) 44 to 80 metres; three studies; 99 participants; moderate quality evidence), the incremental shuttle walk distance (MD 50 metres; 95% CI 20 to 80 metres; one study; 30 participants; high quality evidence) and the endurance shuttle walk distance (MD 371 metres; 95% CI 121 to 621 metres; one study; 30 participants; high quality evidence). Quality of life was also improved after water-based exercise training compared with no exercise (standardised mean difference (SMD) -0.97, 95% CI -0.37 to -1.57; two studies; 49 participants; low quality evidence). Compared with land-based exercise training, water-based exercise training did not significantly change the six-minute walk distance (MD 11 metres; 95% CI -11 to 33 metres; three studies; 62 participants; moderate quality evidence) or the incremental shuttle walk distance (MD 9 metres; 95% CI -15 to 34 metres; two studies; 59 participants; low quality evidence). However, the endurance shuttle walk distance improved following water-based exercise training compared with land-based exercise training (MD 313 metres; 95% CI 232 to 394 metres; two studies; 59 participants; moderate quality evidence). No significant differences were found between water-based exercise training and land-based exercise training for quality of life, as measured by the St George's Respiratory Questionnaire or by three of four domains of the Chronic Respiratory Disease Questionnaire (CRDQ); however, the fatigue domain of the CRDQ showed a statistically significant difference in favour of water-based exercise (MD -3.00; 95% CI -5.26 to -0.74; one study; 30 participants). Only one study reported long-term outcomes after water-based exercise training for quality of life and body composition, and no significant change was observed between baseline results and six-month follow-up results. One minor adverse event was reported for water-based exercise training (based on reporting from two studies; 20 participants). Impact of disease severity could not be examined because data were insufficient. There is limited quality evidence that water-based exercise training is safe and improves exercise capacity and quality of life in people with COPD immediately after training. There is limited quality evidence that water-based exercise training offers advantages over land-based exercise training in improving endurance exercise capacity, but we remain uncertain as to whether it leads to better quality of life. Little evidence exists examining the long-term effect of water-based exercise training.

Five studies were identified up to August 2013. These studies included a total of 176 participants, with 71 people participating in water-based exercise training, 54 people participating in land-based exercise training and 51 people completing no exercise training. The average age of participants ranged from 57 to 73 years. The water-based exercise training programmes varied from four to 12 weeks in duration with attendance two to three times a week for between 35 and 90 minutes. The water-based exercises were designed to be as similar as possible to the exercises conducted in the land-based exercise sessions. The most common types of exercises were walking and cycling-type movements in the water, as well as strength training, most often using floats to increase the intensity. Participants who completed a water-based exercise training programme could walk an average of 371 metres farther than those who completed no exercise training and 313 metres farther than those who completed land-based exercise training. Quality of life also improved in participants who completed water-based exercise training, and significantly better quality of life was reported in these participants compared with those who completed no exercise training. Little information was provided to show whether these effects last for a long time after training has ceased. The effect that severity of COPD may have on benefits of water-based exercise training needs further examination. Two studies reported on adverse events; one minor adverse event was documented (from 20 people participating in water-based exercise training). The quality of evidence contributing to these results was generally low to moderate. This was mainly a result of poor study design and not enough data.

10.1002/14651858.CD008290.pub2

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We included nine short-term RCTs (duration 12 weeks or less) in the analysis (345 participants; age range 18 to 76 years). Participants were exposed to a variety of traumas, ranging from assault, traffic accidents and work accidents to cardiac surgery and septic shock. Seven studies were conducted at single centres. The seven RCTs included four hydrocortisone studies, three propranolol studies (of which one study had a third arm investigating gabapentin), and single trials of escitalopram and temazepam. Outcome assessment measures included the Clinician-Administered PTSD Scale (CAPS), the 36-Item Short-Form Health Survey (SF-36) and the Center for Epidemiological Studies – Depression Scale (CES-D). In four trials with 165 participants there was moderate quality evidence for the efficacy of hydrocortisone in preventing the onset of PTSD (risk ratio (RR) 0.17; 95% confidence interval (CI) 0.05 to 0.56; P value = 0.004), indicating that between seven and 13 patients would need to be treated with this agent in order to prevent the onset of PTSD in one patient. There was low quality evidence for preventing the onset of PTSD in three trials with 118 participants treated with propranolol (RR 0.62; 95% CI 0.24 to 1.59; P value = 0.32). Drop-outs due to treatment-emergent side effects, where reported, were low for all of the agents tested. Three of the four RCTs of hydrocortisone reported that medication was more effective than placebo in reducing PTSD symptoms after a median of 4.5 months after the event. None of the single trials of escitalopram, temazepam and gabapentin demonstrated evidence that medication was superior to placebo in preventing the onset of PTSD. Seven of the included RCTs were at a high risk of bias. Differential drop-outs between groups undermined the results of three studies, while one study failed to describe how the allocation of medication was concealed. Other forms of bias that might have influenced study results included possible confounding through group differences in concurrent medication and termination of the study based on treatment response. There is moderate quality evidence for the efficacy of hydrocortisone for the prevention of PTSD development in adults. We found no evidence to support the efficacy of propranolol, escitalopram, temazepam and gabapentin in preventing PTSD onset. The findings, however, are based on a few small studies with multiple limitations. Further research is necessary in order to determine the efficacy of pharmacotherapy in preventing PTSD and to identify potential moderators of treatment effect.

There was moderate quality evidence that hydrocortisone (a steroid medication) prevented PTSD. There was moderate quality evidence that hydrocortisone reduced the severity of PTSD symptoms. There was no evidence that propranolol (a beta-blocker), escitalopram (a type of antidepressant), temazepam (a tranquillizer) or gabapentin (an anticonvulsant) prevented PTSD. All medications were acceptable, with low numbers of people dropping out due to side effects; however not all studies provided information on this. The review authors do not feel there is sufficient evidence yet to recommend any medication as a preventative treatment for PTSD. The review authors recommend that future high quality research is needed to provide stronger evidence for the effectiveness of medications in preventing PTSD.

10.1002/14651858.CD006239.pub2

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Nineteen studies involving 1120 women were eligible for inclusion. Antibiotic versus antibiotic (10 trials, 430 women): During active prophylaxis the rate range of microbiological recurrence patient-year (MRPY) was 0 to 0.9 person-year in the antibiotic group against 0.8 to 3.6 with placebo. The RR of having one microbiological recurrence (MR) was 0.21 (95% CI 0.13 to 0.34), favouring antibiotic and the NNT was 1.85. For clinical recurrences (CRPY) the RR was 0.15 (95% CI 0.08 to 0.28). The NNT was 1.85. The RR of having one MR after prophylaxis was 0.82 (95% CI 0.44 to 1.53). The RR for severe side effects was 1.58 (95% CI 0.47 to 5.28) and for other side effects the RR was 1.78 (CI 1.06 to 3.00) favouring placebo. Side effects included vaginal and oral candidiasis and gastrointestinal symptoms. Antibiotic versus antibiotic (eight trials, 513 women): These trials were not pooled. Weekly perfloxacin was more effective than monthly. The RR for MR was 0.31(95% CI 0.19 to 0.52). There was no significant difference in MR between continuous daily and postcoital ciprofloxacin. Continuous antibiotic prophylaxis for 6-12 months reduced the rate of UTI during prophylaxis when compared to placebo. After prophylaxis two studies showed no difference between groups. There were more adverse events in the antibiotic group. One RCT compared postcoital versus continuous daily ciprofloxacin and found no significant difference in rates of UTIs, suggesting that postcoital treatment could be offered to woman who have UTI associated with sexual intercourse.

The review found that non-pregnant women who had two or more UTIs in the past year had less chance of having a further UTI if given a six to 12 month treatment with antibiotics. The most commonly reported side effects are digestive problems, skin rash and vaginal irritation. More research is needed determine the optimal duration for antibiotic treatment.

10.1002/14651858.CD001209.pub2

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Six RCT's (n=483), with 8-16 weeks follow-up, met our inclusion criteria. Meta-analysis of five trials (n=425) with adequate data indicated that potassium supplementation compared to control resulted in a large but statistically non-significant reductions in SBP (mean difference: -11.2, 95% CI: -25.2 to 2.7) and DBP (mean difference: -5.0, 95% CI: -12.5 to 2.4). The substantial heterogeneity between trials was not explained by potassium dose, quality of trials or baseline blood pressure. Excluding one trial in an African population with very high baseline blood pressure resulted in smaller overall reductions in blood pressure (SBP mean difference: -3.9, 95% CI: -8.6 to 0.8; DBP mean difference: -1.5, 95% CI: -6.2 to 3.1). Further sensitivity analysis restricted to two high quality trials (n=138) also found non-significant reductions in blood pressure (SBP mean difference: -7.1, 95% CI: -19.9 to 5.7; DBP mean difference: -5.5, 95% CI: -14.5 to 3.5). Potassium supplementation has no statistically significant effect on blood pressure. Due to small number of participants in the two high quality trials, the short duration of follow-up, and the unexplained heterogeneity between trials, the evidence about the effect of potassium supplementation on blood pressure is not conclusive. Further high quality RCTs of longer duration are required to clarify whether potassium supplementation can reduce blood pressure and improve health outcomes.

Most included trials were of poor quality, so their results may not be reliable. The trials were not long enough or large enough to measure whether potassium supplements reduce the risk of death, heart attack or stroke, which may be caused by high blood pressure. The studies reporting adverse effects did not find any serious side effects from taking potassium supplements. This review does not confirm whether potassium supplements can lower high blood pressure and therefore does not recommend them for treating hypertension. More trials enrolling a large number of participants with long periods of follow-up are necessary to know whether or not potassium supplements can lower high blood pressure.

10.1002/14651858.CD004641.pub2

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No additional trials could be included in this update. One trial at low risk of bias evaluating oral penicillin in combination with analgesics versus placebo with analgesics, involving 40 participants was included in a former update of the review. The certainty of the evidence was rated low for the different outcomes. Our primary outcome was patient-reported pain (intensity/duration) and pain relief. There was a close parallel distribution of the pain ratings in both the intervention (median 6.0, interquartile range (IQR) 10.5), and for placebo (median 6.0, IQR 9.5) over the seven-day study period. There was insufficient evidence to claim or refute a benefit for penicillin for pain intensity. There was no significant difference in the mean total number of ibuprofen tablets over the study period: 9.20 (standard deviation (SD) 6.02) in the penicillin group versus 9.60 (SD 6.34) in the placebo group; mean difference -0.40 (95% confidence interval (CI) -4.23 to 3.43; P = 0.84). This applied equally for the mean total number of Tylenol tablets: 6.90 (SD 6.87) used in the penicillin group versus 4.45 (SD 4.82) in the placebo group; mean difference 2.45 (95% CI -1.23 to 6.13; P = 0.19). Our secondary outcome on reporting of adverse events was not addressed in this study. This Cochrane Review which was based on one low-powered small sample trial assessed as at low risk of bias, illustrates that there is insufficient evidence to determine whether antibiotics reduce pain or not compared to not having antibiotics. The results of this review confirm the necessity for further larger sample and methodologically sound trials that can provide additional evidence as to whether antibiotics, prescribed in the preoperative phase, can affect treatment outcomes for irreversible pulpitis.

The evidence on which this review is based was current as of 18 February 2019. One study involving 40 people with irreversible pulpitis (nerve damage) was included. There were two groups of 20 people, one group was treated with penicillin 500 mg, the other with placebo (no active ingredient) every six hours over a seven-day period. In addition, all of the participants received painkillers (ibuprofen and paracetamol (acetaminophen) combined with codeine).Key resultsAntibiotics do not appear to significantly reduce toothache caused by irreversible pulpitis. Furthermore, there was no difference in the total number of ibuprofen or Tylenol tablets used over the study period between both groups. The administration of penicillin does not significantly reduce the pain perception, the percussion (tapping on the tooth) perception, or the quantity of pain medication required by people with irreversible pulpitis. There was no reporting on adverse events or reactions. This was a study with a small number of participants and the certainty of the evidence for the different outcomes was rated as low. There is currently insufficient evidence to be able to decide if antibiotics help for this condition. This review highlights the need for more and better quality studies on the use of antibiotics for irreversible pulpitis.

10.1002/14651858.CD004969.pub5

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Information on cognitive function at the start of a study was available on 4080 participants randomised in three trials. Cognitive function data were available on 3536 participants at final follow-up. In two studies participants received gel capsules containing either omega-3 PUFA (the intervention) or olive or sunflower oil (placebo) for six or 24 months. In one study, participants received margarine spread for 40 months; the margarine for the intervention group contained omega-3 PUFA. Two studies had cognitive health as their primary outcome; one study of cardiovascular disease included cognitive health as an additional outcome. None of the studies examined the effect of omega-3 PUFA on incident dementia. In two studies involving 3221 participants there was no difference between the omega-3 and placebo group in mini-mental state examination score at final follow-up (following 24 or 40 months of intervention); MD -0.07 (95% CI -0.25 to 0.10). In two studies involving 1043 participants, other tests of cognitive function such as word learning, digit span and verbal fluency showed no beneficial effect of omega-3 PUFA supplementation. Participants in both the intervention and control groups experienced either small or no cognitive declines during the studies. The main reported side-effect of omega-3 PUFA supplementation was mild gastrointestinal problems. Overall, minor adverse events were reported by fewer than 15% of participants, and reports were balanced between intervention groups. Adherence to the intervention was on average over 90% among people who completed the trials. All three studies included in this review are of high methodological quality. Direct evidence on the effect of omega-3 PUFA on incident dementia is lacking. The available trials showed no benefit of omega-3 PUFA supplementation on cognitive function in cognitively healthy older people. Omega-3 PUFA supplementation is generally well tolerated with the most commonly reported side-effect being mild gastrointestinal problems. Further studies of longer duration are required. Longer-term studies may identify greater change in cognitive function in study participants which may enhance the ability to detect the possible effects of omega-3 PUFA supplementation in preventing cognitive decline in older people.

The authors of this review included studies where healthy participants over the age of 60 years who were cognitively healthy at the start of the study were randomly assigned to receive extra omega-3 PUFA in their diet or a placebo (such as olive oil). The main outcomes of interest were new cases of dementia diagnosed during the study period, cognitive decline, side-effects, and adherence to the intervention. The authors included three randomised controlled trials involving 3536 participants. In two studies participants were randomly assigned to receive gel capsules containing omega-3 PUFA or olive or sunflower oil for six or 24 months. In the third study, participants were randomly assigned to receive tubs of margarine spread for 40 months (regular margarine versus margarine fortified with omega-3 PUFA). None of the studies examined the effect of omega-3 PUFA on new dementia cases over the study period. In two studies involving 3221 participants there was no difference between the omega-3 PUFA and placebo group in mini-mental state examination score at final follow-up. In two studies (1043 participants), other tests of cognitive function such as word learning, digit span and verbal fluency showed no beneficial effect of omega-3 PUFA supplementation. Participants in both the intervention and control groups experienced little or no cognitive decline during the studies. The main reported side-effect of omega-3 PUFA supplementation was mild gastrointestinal problems, but overall minor symptoms were reported by fewer than 15% of participants, and people in the control group were just as likely to report symptoms as those receiving an omega-3 PUFA supplement. Adherence to the supplementation protocol was high in all trials with on average over 90% of supplements being apparently consumed by trial participants. All three studies included in this review were of high methodological quality, and so the findings are unlikely to be due to chance or bias. The results of the available studies show no benefit for cognitive function with omega-3 PUFA supplementation among cognitively healthy older people. Omega-3 PUFA supplements may have other health benefits, and the authors comment that consumption of fish is recommended as part of a healthy diet. Longer studies are required, during which greater changes in cognitive function may occur, to enable researchers to identify possible benefits of omega-3 PUFA in preventing cognitive decline.

10.1002/14651858.CD005379.pub3

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An updated literature search performed in July 2008 did not identify any new trials. Only two randomized controlled trials were identified that satisfied the inclusion criteria. These two trials could not be pooled for analysis because of major differences in design and patient populations. In the first trial, 11 patients received intravenous cyclosporine (4 mg/kg) and 9 received placebo. Two of 11 in the treatment group failed to respond to therapy compared with nine of nine in the placebo group (RR 0.18, 95% CI 0.05 - 0.64). However, 3/11 and 4/9 eventually underwent colectomy in the treatment and placebo groups respectively and follow-up was less than a month. In the second trial 15 patients were treated with intravenous cyclosporine and 15 with intravenous methylprednisolone. Five of 15 patients in the cyclosporine group failed to respond to therapy as compared to 7/15 in the methylprednisolone group (RR 0.71, 95% CI 0.29 - 1.75). After 1 year 7/9 responders in the cyclosporine group were still in remission compared with 4/8 in the steroid group (p > 0.05) and the colectomy rate was similar in both groups. The mean time to response in the cyclosporine group in the 2 trials was short (7 days and 5.2 days). These results should be interpreted with caution given the small numbers of trials and patients evaluated for comparison, and limited follow-up (few weeks in one trial to a year in the other). The precise assessment of the occurrence of adverse events was difficult because the trials described different adverse reactions, which reversed after discontinuation of cyclosporine. There was no evidence in the trials reviewed that cyclosporine was more effective than standard treatment for preventing colectomy but this effect cannot be excluded due to the small sample size and rarity of this outcome. Additional limitations of current research include lack of data on quality of life, costs and long-term results of cyclosporine therapy. There is limited evidence that cyclosporine is more effective than standard treatment alone for severe ulcerative colitis. The relatively quick response makes the short-term use of cyclosporine potentially attractive, but the long-term benefit is unclear, when adverse events such as cyclosporine-induced nephrotoxicity may become more obvious. There is a need for additional research on quality of life, costs and long-term results from cyclosporine therapy in severe ulcerative colitis.

The aim of this review was to assess the effectiveness of CsA for severe UC. The literature search identified 36 studies. Only 2 studies were of high methodological quality and both support the use of CsA in UC patients with a severe attack. However, both studies were small (involving only 50 patients altogether) and limited in the length of follow-up (from a few weeks up to a year). There is limited evidence that cyclosporine is more effective than standard treatment for severe ulcerative colitis. The conclusion of the review is that while the data concerning the use of CsA in severe UC are encouraging, more studies are needed.

10.1002/14651858.CD004277.pub2

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Ten trials met the inclusion criteria. PEDro quality ratings ranged from 6/10 to 10/10. Concentration of BoNT-A ranged from 50U/1.0ml to 200U/1.0ml saline with doses of 0.5U to 16U/kg body weight and total doses of 220 to 410 Units (Botox®). A combination of BoNT-A and occupational therapy is more effective than occupational therapy alone in reducing impairment, improving activity level outcomes and goal achievement, but not for improving quality of life or perceived self-competence. When compared with placebo or no treatment, there is moderate evidence that BoNT-A alone is not effective. This systematic review found high level evidence supporting the use of BoNT-A as an adjunct to managing the upper limb in children with spastic CP. BoNT-A should not be used in isolation but should be accompanied by planned occupational therapy. Further research is essential to identify children most likely to respond to BoNT-A injections, monitor longitudinal outcomes, determine timing and effect of repeated injections and the most effective dosage, dilution and volume schedules. The most effective adjunct therapies including frequency and intensity of delivery also requires investigation.

This review demonstrated improvements on a range of measures with the combined treatment. In the absence of significant side effects, injection of BoNT-A has been identified as a safe and effective treatment for upper limb spasticity when used in combination with occupational therapy in children with cerebral palsy.

10.1002/14651858.CD003469.pub4

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We included three trials examining pulmonary exacerbations (171 participants) and two trials examining long-term therapy (85 participants). We regarded the most important outcomes as quality of life and lung function. The analysis did not identify any statistically significant difference between oral anti-pseudomonal antibiotics and other treatments for these outcome measures for either pulmonary exacerbations or long-term treatment. One of the included trials reported significantly better lung function when treating a pulmonary exacerbation with ciprofloxacin when compared with intravenous treatment; however, our analysis did not confirm this finding. We found no evidence of difference between oral anti-pseudomonal antibiotics and other treatments regarding adverse events or development of antibiotic resistance, but trials were not adequately powered to detect this. None of the studies had a low risk of bias from blinding which may have an impact particularly on subjective outcomes such as quality of life. The risk of bias for other criteria could not be clearly stated across the studies. We found no conclusive evidence that an oral anti-pseudomonal antibiotic regimen is more or less effective than an alternative treatment for either pulmonary exacerbations or long-term treatment of chronic infection with P. aeruginosa. Until results of adequately-powered future trials are available, treatment needs to be selected on a pragmatic basis, based upon any available non-randomised evidence, the clinical circumstances of the individual, the known effectiveness of drugs against local strains and upon individual preference.

We included five trials with 256 participants. Three trials included people experiencing a flare up of disease (171 participants) and two trials looked at long-term therapy (85 participants). We found no conclusive evidence to show that oral antibiotics were more or less effective than an alternative treatment for either flare ups of disease or long-term treatment of chronic infection with Pseudomonas aeruginosa. One of the trials with volunteers being treated for a flare up of disease reported significantly better lung function when using ciprofloxacin compared with intravenous treatment; but we did not agree with this finding when we analysed the same data. We did not find any evidence of differences between oral antibiotics and other treatments in terms of adverse events or the development of antibiotic resistance, but we do note that the trials were not designed to detect such differences. Until the results of large trials are available, people should choose their treatment on a practical basis, basing decisions on any available evidence, their clinical circumstances, the known effectiveness of drugs against local strains of the bug and individual preference. The evidence we found was limited. The trials were very different in terms of design, drugs used, length of treatment and follow up and the outcomes measured. We judged the trials to be at different risks of bias, but we did not think any of them had a low risk of bias from blinding, which might affect the results of subjective outcomes like quality of life.

10.1002/14651858.CD005405.pub4

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We identified six randomised controlled trials including a total of 262 participants. Four studies were conducted with primary school or kindergarten teachers, one with student teachers and one with telemarketers. Three studies found similar self-reported vocal symptoms between those who attended direct voice training and those who were in a no intervention control group (standardised mean difference (SMD) 0.27; 95% CI -0.12 to 0.66). Two studies found similar self-reported vocal symptoms between those who attended indirect voice training and those who were in a no intervention control group (SMD 0.44; 95% CI -0.03 to 0.92). One study found similar scores on the Voice Handicap Index for those who had direct and indirect voice training combined and for those who had no intervention. Two studies compared a combination of direct and indirect voice training with indirect voice training only. Both studies found similar scores for self-reported phonation difficulty (mean difference -5.55; 95% CI -23.75 to 12.66) in both groups. The evidence for all comparisons was rated as low quality. No work-directed studies were found. No studies evaluated the effectiveness of prevention in terms of sick leave or number of diagnosed voice disorders. We found no evidence that either direct or indirect voice training or the two combined are effective in improving self-reported vocal functioning when compared to no intervention. The current practice of giving training to at-risk populations for preventing the development of voice disorders is therefore not supported by definitive evidence of effectiveness. Larger and methodologically better trials are needed with outcome measures that better reflect the aims of interventions.

We conducted a systematic search of the literature on preventing voice disorders in adults. We then appraised the quality of the studies found and combined their results. We found six studies which met our inclusion criteria. Four were conducted with teachers, one with student teachers and one with telemarketers. We found no evidence that either direct or indirect voice training nor the two combined are effective in improving vocal functioning when measured using self-reported outcomes and when compared to no intervention. All the included studies were small and of low methodological quality. Given the extent of the problem and the widespread use of voice training, further research is warranted.

10.1002/14651858.CD006372.pub2

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We included 11 trials involving 904 adults, published between 1990 and 2014. Eight studies were conducted in the USA, and one each in Canada, Spain and Turkey. Sample sizes ranged from 20 to 154 participants aged between 18 and 85 years old. The proportion of female participants varied between 52% and 100%. The duration of follow-up in the studies varied from seven days to 12 months. The exercise type most prescribed for the intervention was aerobic (walking in 70% of the studies, or bicycle riding or treadmill) at least five times a week. Duration was 30 to 45 minutes at moderate intensity. Participants were supervised in 90% of the studies. For four of the primary outcomes the results did not differ significantly and all were low-quality evidence (number of ARI episodes per person per year, rate ratio 0.91 (95% confidence interval (CI) 0.59 to 1.42); proportion of participants who experienced at least one ARI over the study period, risk ratio 0.76 (95% CI 0.57 to 1.01); severity of ARI symptoms, mean difference (MD) -110 (95% CI -324 to 104); and number of symptom days in the follow-up period, MD -2.1 days (95% CI -4.4 to 0.3)). However, one primary outcome, the number of symptom days per episode of illness, was reduced in those participants who exercised (MD -1.1 day, 95% CI -1.7 to -0.5, moderate-quality evidence). We found no significant differences for the secondary outcomes (laboratory parameters (blood lymphocytes, salivary secretory immunoglobulin and neutrophils); quality of life outcomes; cost-effectiveness and exercise-related injuries). There was good adherence to the intervention with no difference between the exercise and non-exercise groups. We rated the quality of evidence for the primary outcomes as low for most outcomes using the GRADE criteria: allocation concealment was not reported and there was a lack of blinding; in addition, there was imprecision (the CI is very wide because of a small number of participants) and inconsistency, which may be due to differences in study design. We cannot determine whether exercise is effective at altering the occurrence, severity or duration of acute respiratory infections. One analysis of four trials suggests that the number of days of illness per episode of infection might be reduced by exercise. The small size of the studies, risk of bias and heterogeneous populations trialled all contribute to the uncertainty. Larger studies, with less risk of bias from patient selection, blinding of outcomes assessors, reporting of all outcomes measured and with registration of study protocols, are required to settle the question.

A search of the major databases to July 2014 found 11 trials involving 904 participants between the ages of 18 and 85 years old, which tested the effect of exercise on acute respiratory infection symptoms. Exercise was supervised and prescribed at least five times a week, with 30 to 45 minutes of moderate-intensity activities in most studies. The number of acute respiratory infections per person per year and the severity of these symptoms were similar in the exercising and non-exercising groups. Similarly, the number of people experiencing at least one acute respiratory infection and the number of symptom days in the follow-up period were similar among people who did or did not exercise. One analysis of four trials suggested that the number of days of illness per episode of infection might be reduced by exercise. The quality of the trials was poor, which means that there might be benefit or even harm attributable to exercise. We need further studies with fewer potential biases to understand whether exercise is able to reduce the occurrence, severity or duration of acute respiratory infections.

10.1002/14651858.CD010596.pub2

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We were able to include six studies (586 participants). Non-standard care consisted solely of another type of exercise programme. All outcomes were short term (less than six months). There was a clear difference in the outcome leaving the study early (6 RCTs, n=586, RR 0.64 CI 0.49 to 0.83, medium quality evidence) in favour of the yoga group. There were no clear differences between groups for the remaining outcomes. These included mental state (improvement in Positive and Negative Syndrome Scale, 1 RCT, n=84, RR 0.81 CI 0.62 to 1.07, low quality evidence), social functioning (improvement in Social Occupational Functioning Scale, 1 RCT, n=84, RR 0.90 CI 0.78 to 1.04, low quality evidence), quality of life (mental health) (average change 36-Item Short Form Survey (SF-36) quality-of-life sub-scale, 1 RCT, n=69, MD -5.30 CI -17.78 to 7.18, low quality evidence), physical health, (average change WHOQOL-BREF physical-health sub-scale, 1 RCT, n=69, MD 9.22 CI -0.42 to 18.86, low quality evidence). Only one study reported adverse effects, finding no incidence of adverse events in either treatment group. There were a considerable number of missing outcomes, which included relapse, change in cognition, costs of care, effect on standard care, service intervention, disability, and activities of daily living. We found minimal differences between yoga and non-standard care, the latter consisting of another exercise comparator, which could be broadly considered aerobic exercise. Outcomes were largely based on single studies with limited sample sizes and short-term follow-up. Overall, many outcomes were not reported and evidence presented in this review is of low to moderate quality - too weak to indicate that yoga is superior or inferior to non-standard care control for management of people with schizophrenia.

We ran electronic searches for trials (latest search was in March 2017) for trials that randomised people with schizophrenia to receive yoga or another add-on treatment. One thousand and thirty four records were found and checked by the review authors. Six trials with 586 participants met the review requirements and provided useable data. Other add-on treatments consisted of other forms of exercise only. There is little evidence currently available, is low quality, and suggests that yoga is no more effective than other add-on treatments for schizophrenia. Current evidence from randomised controlled trials shows yoga is no more effective than other add on treatments for schizophrenia, but the only available comparators to yoga were other forms of exercise. The evidence is weak as the number of studies available was small, and only short-term follow-up was reported. More, larger, and long-term trials that compare yoga with other alternatives to exercise are therefore necessary.

10.1002/14651858.CD012052.pub2

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Five small heterogeneous randomised controlled trials, all at high risk of performance bias and most at risk of at least one other type of bias, were included. These involved approximately 200 participants with a diagnosis of patellofemoral pain syndrome. All compared taping versus control (no or placebo taping) and all included one or more co-interventions given to both taping and control group participants; this was prescribed exercise in four trials. The intensity and length of treatment was very varied: for example, length of treatment ranged from one week in one trial to three months in another. A meta-analysis of the visual analogue scale (VAS) pain data (scale 0 to 10: worst pain), measured in different ways, from four trials (data from 161 knees), found no statistically or clinically significant difference between taping and non taping in pain at the end of the treatment programmes (mean difference (MD) -0.15; 95% confidence interval (CI) -1.15 to 0.85; random-effects model used given the significant heterogeneity (P < 0.0001)). Data for other outcomes measuring function and activities of daily living were from single trials only and gave contradictory results. The currently available evidence from trials reporting clinically relevant outcomes is low quality and insufficient to draw conclusions on the effects of taping, whether used on its own or as part of a treatment programme. Further research involving large, preferably multi-centre, good quality and well reported randomised controlled trials that measure clinically important outcomes and long-term results is warranted. Before this, consensus is required on the diagnosis of patellofemoral pain syndrome, the standardisation of outcome measurement and an acceptable approach for patellar taping.

The review found five trials, involving around 200 participants with this condition, which compared the clinical use of taping with no taping. All five studies differed from each other in terms of the type of participants (one trial involved army recruits), length and schedule of the treatment programme and assessment of outcome. In four trials, participants of both taping and no or placebo taping groups were prescribed exercises. In part because both the therapist and the patient knew whether they were getting taping, some caution was necessary in interpreting the study results. Pooled results from four trials (161 knees) for the level of pain at the end of the treatment programme (ranging for one week to three months) showed no difference between those given taping and those not. Data for other outcomes measuring function and activities of daily living were from single trials only and gave different results. The review concluded that the currently available evidence from trials reporting clinically relevant outcomes is and low quality and insufficient to draw conclusions on the effects of taping. However, before further trials are conducted, some consensus is required to establish the typical patients, taping technique and the best way of measuring outcome.

10.1002/14651858.CD006717.pub2

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19 publications describing 10 trials of adults were included in the review. Studies that compared reduced dose (mean 60% reduction) ICS/LABA combination to a fixed moderate/high dose ICS found no significant difference in severe exacerbations requiring oral corticosteroids (RR 1.0, 95%CI 0.76 to 1.32), withdrawal due to worsening asthma (RR 0.82, 95%CI 0.5 to 1.35) or airway inflammation. There were also significant improvements in FEV1 (change from baseline WMD 0.10, 95%CI 0.07 to 0.12), morning & evening PEF and percent rescue free days with LABA. Two studies provided outcomes for a reduced/tapering ICS dose comparison. More participants receiving the LABA/reduced ICS combination achieved a reduction in ICS dose reaching significance in one study. A significant reduction of 253 mcg BDP was achieved in one study. In adults with asthma, using moderate to high maintenance doses of ICS, the addition of LABA has an ICS-sparing effect. The addition of LABA permits more participants on minimum maintenance ICS to reduce ICS. The precise magnitude of the ICS dose reduction requires further study.

This review compared reduced dose (mean 60% reduction in inhaled steroid) ICS/LABA combination to either a fixed moderate/high dose ICS or a reduced/tapering ICS dose. In adults with asthma, who use moderate to high maintenance doses of ICS, the addition of LABA has an ICS-sparing effect. LABA permit a reduction of 37% (253 mcg BDP) in subjects on minimum maintenance ICS and up to 60% (300 mcg FP) in subjects on maintenance ICS without deterioration in asthma control.

10.1002/14651858.CD005076.pub2

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Twenty-one RCTs were included, with a total of 2538 participants randomised to low GI intervention (1288) or high GI (1250). All 21 included studies reported the effect of low GI diets on risk factors for cardiovascular disease, including blood lipids and blood pressure. Twenty RCTs (18 of which were newly included in this version of the review) included primary prevention populations (healthy individuals or those at high risk of CVD, with mean age range from 19 to 69 years) and one RCT was in those diagnosed with pre-existing CVD (a secondary prevention population, with mean age 26.9 years). Most of the studies did not have an intervention duration of longer than six months. Difference in GI intake between comparison groups varied widely from 0.6 to 42. None of the included studies reported the effect of low GI dietary intake on cardiovascular mortality and cardiovascular events such as fatal and nonfatal myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, and stroke. The unclear risk of bias of most of the included studies makes overall interpretation of the data difficult. Only two of the included studies (38 participants) reported on adverse effects and did not observe any harms (low-quality evidence). There is currently no evidence available regarding the effect of low GI diets on cardiovascular disease events. Moreover, there is currently no convincing evidence that low GI diets have a clear beneficial effect on blood lipids or blood pressure parameters.

In this review update, we examined 21 randomised studies that assessed the effects of low GI diets compared to diets with a similar composition but a higher GI on cardiovascular disease events and levels of cholesterol in the blood or blood pressure (major risk factors for cardiovascular disease, such as heart attacks or stroke). Studies were included up to July 2016. Participants were adults with a mean age of between 19 and 69 years. In most studies, participants had cardiovascular risk factors such as overweight or obesity or abnormal blood fat levels, and one study included participants with existing heart disease. The diets were followed for at least 12 weeks but most studies had unclear of bias and some of the compared diets only had small differences in GI. Cardiovascular disease events were not reported and no evidence of differences in effects of the diets on blood cholesterol and blood pressure were seen. Most studies did not report harms but the two that did found no harmful effects of the diets, however the evidence was poor. There was insufficient evidence from randomised controlled trials to recommend consumption of low GI diets for the purpose of improving blood lipids or blood pressure.

10.1002/14651858.CD004467.pub3

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We identified a total of 556 records, of which 486 records were excluded on the basis of title and abstract. We retrieved the remaining 70 references in full to determine eligibility. No studies fulfilled the inclusion criteria of this review, and thus we found no evidence to support or oppose the use of codeine or derivatives as antitussive agents for chronic cough in children. While chronic cough is not the same as acute cough, systematic reviews on the use of codeine efficacy for acute cough in children conclude an overall lack of evidence to support or oppose the use of over-the-counter cough and cold medications containing codeine (or derivatives) for treatment of acute cough in children. The lack of sufficient evidence to support the use of these medications has been consistently reaffirmed by medical experts in international chronic cough guidelines and by governing medical and pharmaceutical authorities in the USA, Europe, Canada, New Zealand, and Australia. Due to the lack of sufficient evidence to support efficacy, and the known risks associated with use - in particular the increased risks for children - these medications are now not recommended for children less than 12 years of age and children between 12 to 18 years with respiratory conditions. This review has highlighted the absence of any randomised controlled trials evaluating codeine-based medications in the treatment of childhood chronic cough. Given the potential adverse events of respiratory suppression and opioid toxicity, national therapeutic regulatory authorities recommend the contraindication of access to codeine in children less than 12 years of age. We suggest that clinical practice adhere to clinical practice guidelines and thus refrain from using codeine or its derivatives to treat cough in children. Aetiological-based management practices continue to be advocated for children with chronic cough.

We searched for any randomised controlled trial comparing either codeine (or medications produced from codeine) versus placebo in the treatment of chronic cough (4 weeks or longer) in children aged 18 years and younger. The search identified 556 records. We reviewed and assessed all of these against predetermined inclusion/exclusion criteria. We found no eligible studies to include in this review. However, our search did find studies that investigated codeine (or medications produced from codeine) in the treatment of acute cough (two weeks or less) in children. Another Cochrane review specifically for children with acute cough evaluated these studies and found no evidence to support or oppose use of codeine (or medications produced from codeine). This overall lack of evidence is consistent with international chronic cough guidelines, which recommend treating the cause of the cough. Due to the known risks associated with use, in particular the increased risks for children, governing bodies in the USA, Europe, Canada, New Zealand, and Australia have stated these medications are now not recommended for children younger than 12 years of age and children between 12 to 18 years with respiratory conditions. Given the lack of supporting trials, the findings from trials of acute cough in children, and the known harmful side effects, we have concluded that codeine-based medications cannot be recommended in children with chronic cough. We found no studies and hence there is no quality of evidence.

10.1002/14651858.CD011914.pub2

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Two studies compared corticosteroids to placebo and six studies compared corticosteroids to 5-ASA. Corticosteroids were found to be significantly more effective than placebo at inducing remission in CD (RR 1.99; 95% CI 1.51 to 2.64; P < 0.00001). Corticosteroids were found to be more effective than 5-ASA at inducing remission in studies with long follow-up duration (i.e. > 15 weeks; RR 1.65; 95% CI 1.33 to 2.03; P < 0.00001). Corticosteroids induced adverse events in a higher proportion of patients than placebo (RR 4.89; 95% CI 1.98 to 12.07; P = 0.0006), or low-dose 5-ASA (RR 2.38; 95% CI 1.34 to 4.25; P = 0.003). No difference existed in the proportion of patients experiencing adverse events when steroids were compared to high-dose 5-ASA. Steroids did not induce more study withdrawals due to adverse events than either placebo or 5-ASA. Corticosteroids are effective for induction of remission in patients with CD, particularly when used for more than 15 weeks. Although corticosteroids cause more adverse events than either placebo or low-dose 5-ASA, these adverse events did not lead to increased study withdrawal in the included studies. Further information is required to determine the optimal duration of treatment and tapering protocol to maximize the efficacy of treatment with corticosteroids. Additionally, further study is required to determine whether corticosteroids are more effective in patients with certain phenotypes or when administered intravenously.

Controlled clinical studies that evaluated the effect of systemic corticosteroids to induce remission in Crohn's disease were reviewed. For inclusion in this analysis, studies could compare any form of corticosteroid that is systemically absorbed (e.g. prednisone, prednisolone, 6-methylprednisolone or hydrocortisone) to either placebo (fake medicine) or 5-aminosalicylates (e.g. mesalazine, mesalamine or sulfasalazine). Corticosteroids were found to be more effective than either placebo or 5-aminosalicylates at inducing remission in Crohn's disease. Although corticosteroids caused side effects more often in patients compared with placebo and 5-aminosalicylates, these side effects were not serious enough to cause withdrawal from the studies reviewed. In summary, corticosteroids are effective at inducing remission in patients with Crohn's disease. While they cause frequent side effects, these side effects were relatively minor in the reviewed studies, some of which followed patients for up to 24 weeks.

10.1002/14651858.CD006792.pub2

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We identified a total of 13 randomized trials involving 2362 participants. Ten trials (2122 participants) reported sufficient detail on survival to be included in a meta-analysis for the primary outcome. Preoperative chemotherapy improves overall survival (HR 0.88, 95% confidence interval (CI) 0.80 to 0.96) and is associated with a significantly higher rate of complete (R0) resection (RR 1.11, 95% CI 1.03 to 1.19). No evidence suggests that the overall rate of resection (RR 0.96, 95% CI 0.92 to 1.01), tumor recurrence (RR 0.81, 95% CI 0.54 to 1.22) or nonfatal complications (RR 0.90; 95% CI 0.76 to 1.06) was different for preoperative chemotherapy compared with surgery alone. Trials reported risks of toxicity with chemotherapy that ranged from 11% to 90%. In summary, preoperative chemotherapy plus surgery offers a survival advantage compared with surgery alone for patients with resectable thoracic esophageal cancer, but the evidence is of moderate quality. Some evidence of toxicity and preoperative mortality have been associated with chemotherapy.

This review included information from 13 randomized studies and combined results from 2122 patients to answer our question regarding survival. This review of 13 trials, including patients with esophageal cancer of any cell type, found some evidence that cisplatin-based chemotherapy may help them to live longer. However, chemotherapy may introduce side effects. This review used information from randomized studies that is considered to represent the highest quality of evidence.

10.1002/14651858.CD001556.pub3

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Twenty-one RCTs were identified that involved non-surgical management of chronic pelvic pain: 13 trials were included in the review, and eight were excluded. The studies included a total of 750 women—406 women in the intervention groups and 344 in the control groups. Included studies had high attrition rates, and investigators often did not blind adequately or did not clearly describe randomisation procedures. Medical treatment versus placebo Progestogen (medroxyprogesterone acetate (MPA)) was more effective than placebo at the end of treatment in terms of the number of women achieving a greater than 50% reduction in visual analogue scale (VAS) pain score immediately after treatment (Peto OR 3.00, 95% CI 1.70 to 5.31, two studies, n = 204, I2 = 22%, moderate-quality evidence). Evidence of benefit was maintained up to nine months after treatment (Peto OR 2.09, 95% CI 1.18 to 3.71, two studies, n = 204, I2 = 0%, moderate-quality evidence). Women treated with progestogen reported more adverse effects (e.g. weight gain, bloatedness) than those given placebo (high-quality evidence). The estimated effect of lofexidine on pain outcomes when compared with placebo was compatible with benefit and harm (Peto OR 0.42, 95% CI 0.11 to 1.61, one study, 39 women, low-quality evidence). Women in the lofexidine group reported more adverse effects (including drowsiness and dry mouth) than women given placebo (moderate-quality evidence). Head-to-head comparisons of medical treatments Head-to-head comparisons showed that women taking goserelin had greater improvement in pelvic pain score (MD 3, 95% CI 2.08 to 3.92, one study, n = 47, moderate-quality evidence) at one year than those taking progestogen. Women taking gabapentin had a lower VAS pain score than those taking amytriptyline (MD -1.50, 95% CI -2.06 to -0.94, n = 40, low-quality evidence). Study authors reported that no statistically significant difference was observed in the rate of adverse effects among women taking gabapentin compared with women given amytriptyline. The study comparing goserelin versus progestogen did not report on adverse effects. Psychological treatment Women who underwent reassurance ultrasound scans and received counselling were more likely to report improved pain than those treated with a standard 'wait and see' policy (Peto OR 6.77, 95% CI 2.83 to 16.19, n = 90, low-quality evidence). Significantly more women who had writing therapy as a disclosure reported improvement in pain than those in the non-disclosure group (Peto OR 4.47, 95% CI 1.41 to 14.13, n = 48, very low-quality evidence). No difference between groups in pain outcomes was noted when other psychological therapies were compared with standard care or placebo (quality of evidence ranged from very low to low). Studies did not report on adverse effects. Complementary therapy Distension of painful pelvic structures was more effective for pain when compared with counselling (MD 35.8, 95% CI 23.08 to 48.52 on a zero to 100 scale, one study, n = 48, moderate-quality evidence). No difference in pain levels was observed when magnetic therapy was compared with use of a control magnet (very low-quality evidence). Studies did not report on adverse effects. The results of studies examining psychological and complementary therapies could not be combined to yield meaningful results. Evidence of moderate quality supports progestogen as an option for chronic pelvic pain, with efficacy reported during treatment. In practice, this option may be most acceptable among women unconcerned about progestogenic adverse effects (e.g. weight gain, bloatedness—the most common adverse effects). Although some evidence suggests possible benefit of goserelin when compared with progestogen, gabapentin as compared with amytriptyline, ultrasound versus 'wait and see' and writing therapy versus non-disclosure, the quality of evidence is generally low, and evidence is drawn from single studies. Given the prevalence and healthcare costs associated with chronic pelvic pain in women, RCTs of other medical, lifestyle and psychological interventions are urgently required.

Twenty-one randomised controlled studies were identified, of which 13 were included. Eight studies were excluded. The studies included a total of 750 women—406 women in the intervention groups and 344 women in the control groups. The interventions assessed included medical treatment and psychological, cognitive, behavioural, complementary and physical therapies. The evidence is current to February 2014. The review concludes that evidence shows improvement of pain in women given a high dose of progestogen (50 mg medroxyprogesterone acetate) immediately post-treatment and for up to nine months after treatment. However, progestogen was associated with adverse effects such as weight gain and bloating. Women who underwent reassurance ultrasound scans and who received counselling were more likely to report improved pain than those whose treatment involved a 'wait and see' policy. Some evidence of benefit was seen with writing disclosure therapy and with distension of painful pelvic structures. No good evidence of benefit was noted with other interventions when compared with standard care or placebo. The quality of the evidence was low or moderate for most comparisons, and in most cases evidence was derived from single small studies. Moreover, we were unable to draw meaningful conclusions on quality of life and physical and functional outcomes because of the large variation in outcome measures used by the included studies. Many interventions identified in this review involved only single studies with small sample sizes. Additional studies will be required in the future to replicate results obtained with the use of specific medical interventions.

10.1002/14651858.CD008797.pub2

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A single study was included for analysis in this review. This study compared the use of telemedicine (Baby Carelink) for parents and families of infants in the NICU with a control group without access to this programme and assessed the length of hospital stay for the infants and family satisfaction in multiple components of infant care. The study shows no difference in the length of hospital stay (average length of stay: telemedicine group: 68.5 days (standard deviation (SD) 28.3 days), control group: 70.6 days (SD 35.6 days), MD -2.10 days (95% confidence interval: -18.85 to 14.65 days). There was insufficient information for further analysis of measures of family satisfaction. There is insufficient evidence to support or refute the use of telemedicine technology to support the parents of high-risk newborn infants receiving intensive care. Clinical trials are needed to assess the application of telemedicine to support parents and families of infants in NICU with length of hospital stay and their perception of NICU care as the major outcomes.

This review identified one trial which did not show that telemedicine alters the time these infants stay in hospital. However, there was some imprecision of the published data in this study that makes it difficult to make firm recommendations either way with telemedicine.

10.1002/14651858.CD006818.pub2

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We pooled data from 14 trials of 1109 participants in a meta-analysis. Moderate quality evidence suggests that post-pyloric feeding is associated with low rates of pneumonia compared with gastric tube feeding (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.51 to 0.84). Low-quality evidence shows an increase in the percentage of total nutrient delivered to the patient by post-pyloric feeding (mean difference (MD) 7.8%, 95% CI 1.43 to 14.18). Evidence of moderate quality revealed no differences in duration of mechanical ventilation or in mortality. Intensive care unit (ICU) length of stay was similar between the two groups. The effect on the time required to achieve the full nutrition target was uncertain (MD -1.99 hours 95% CI -10.97 to 6.99) (very low-quality evidence). We found no evidence suggesting an increase in the rate of complications during insertion or maintenance of the tube in the post-pyloric group (RR 0.51, 95% CI 0.19 to 1.364; RR1.63, 95% CI 0.93 to 2.86, respectively); evidence was assessed as being of low quality for both. Risk of bias was generally low in most studies, and review authors expressed concern regarding lack of blinding of the caregiver in most trials. We found moderate-quality evidence of a 30% lower rate of pneumonia associated with post-pyloric feeding and low-quality evidence suggesting an increase in the amount of nutrition delivered to these participants. We do not have sufficient evidence to show that other clinically important outcomes such as duration of mechanical ventilation, mortality and length of stay were affected by the site of tube feeding. Low-quality evidence suggests that insertion of a post-pyloric feeding tube appears to be safe and was not associated with increased complications when compared with gastric tube insertion. Placement of the post-pyloric tube can present challenges; the procedure is technically difficult, requiring expertise and sophisticated radiological or endoscopic assistance. We recommend that use of a post-pyloric feeding tube may be preferred for ICU patients for whom placement of the post-pyloric feeding tube is feasible. Findings of this review preclude recommendations regarding the best method for placing the post-pyloric feeding tube. The clinician is left with this decision, which should be based on the policies of institutional facilities and should be made on a case-by-case basis. Protocols and training for bedside placement by physicians or nurses should be evaluated.

We searched the databases until October 2013 and identified 14 studies (randomized controlled trials) with a total of 1109 participants. We reran the search on 4 February 2015 and will deal with the one study of interest when we update the review. We investigated the benefits of post-pyloric tube feeding for reducing the rate of pneumonia, decreasing the number of days that a person needs to be dependent on a breathing machine, increasing the percentage of nutrients that can be provided to the participant and reducing the number of deaths. We also investigated potential complications that may occur during insertion of the tube, such as bleeding from the gastrointestinal tract, and complications arising during maintenance of the tube, such as the need to replace the tube. We found that post-pyloric feeding appeared to reduce the rate of pneumonia and increase the amount of nutrition delivered to the patient. Its use did not result in fewer days that a person needed to be dependent on a breathing machine nor in fewer deaths. The target amount of feeding for a person fed with a post-pyloric tube was reached without delay. Insertion of a post-pyloric feeding tube appears safe and did not increase the likelihood of complications. We found evidence of moderate quality for the outcomes of rate of pneumonia, duration of dependency on a breathing machine and rate of death, mainly because identified studies were poorly conducted. With regard to the total quantity of nutrients that can be delivered to patients and complications related to insertion and maintenance of the tube, the quality of evidence was assessed as low. Evidence for the time required to reach the target amount of feeding was very low in that results were not similar across studies and study design issues hindered assessment. We recommend that a post-pyloric feeding tube should be used routinely for all ICU patients, when this approach is feasible.

10.1002/14651858.CD008875.pub2

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We included 12 RCTs (1128 participants). All studies but three recruited fewer than 100 participants. Participants had a diagnosis of alcohol dependence according the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or the International Classification of Diseases (ICD)-10 criteria who were currently drinking. The mean age of participants was 48 years, and there were more men (69%), than women. All studies compared baclofen to placebo, except for one study that evaluated baclofen versus acamprosate. The included studies considered baclofen at different doses (range 10 mg a day to 150 mg a day). In all but one of the studies, participants in both the baclofen and placebo groups received psychosocial treatment or counselling of various intensity. We judged most of the studies at low risk of selection, performance, detection (subjective outcome), attrition and reporting bias. We did not find any difference between baclofen and placebo for the primary outcomes: relapse-return to any drinking (RR 0.88, 95% CI 0.74 to 1.04; 5 studies, 781 participants, moderate certainty evidence); frequency of use by percentage of days abstinent (MD 0.39, 95% CI -11.51 to 12.29; 6 studies, 465 participants, low certainty evidence) and frequency of use by percentage of heavy drinking days at the end of treatment (MD 0.25, 95% CI -1.25 to 1.76; 3 studies, 186 participants, moderate certainty evidence); number of participants with at least one adverse event (RR 1.04, 95% CI 0.99 to 1.10; 4 studies, 430 participants, high certainty evidence); the dropout rate at the end of treatment (RR 0.98, 95% CI 0.77 to 1.26, 8 studies, 977 participants, high certainty evidence) and dropout due to adverse events (RR 1.11, 95% CI 0.59 to 2.07; 7 studies, 913 participants, high certainty evidence). We found evidence that baclofen increases amount of use (drink per drinking days), (MD 1.55, 95% CI 1.32 to 1.77; 2 studies, 72 participants, low certainty evidence). Among secondary outcomes, there was no difference on craving (MD 1.38, 95% CI -1.28 to 4.03, 5 studies, 469 participants), and anxiety (SMD 0.07, 95% CI -0.14 to 0.28; 5 trials, 509 participants). We found that baclofen increased depression (SMD 0.27, 95% CI 0.05 to 0.48; 3 studies, 387 participants). Concerning the specific adverse events we found that baclofen increased: vertigo (RR 2.16, 95% CI 1.24 to 3.74; 7 studies, 858 participants), somnolence/sedation (RR 1.48, 95%CI 1.11 to 1.96; 8 studies, 946 participants), paraesthesia (RR 4.28, 95% CI 2.11 to 8.67; 4 studies, 593 participants), and muscle spasms/rigidity (RR 1.94, 95%CI 1.08 to 3.48; 3 studies, 551 participants). For all the other adverse events we did not find significant differences between baclofen and placebo. For the comparison baclofen versus acamprosate, we were only able to extract data for one outcome, craving. For this outcome, we found that baclofen increased craving compared with acamprosate (MD 14.62, 95% CI 12.72 to 16.52; 1 study, 49 participants). None of the primary or secondary outcomes of the review showed evidence of a difference between baclofen and placebo. The high heterogeneity among primary studies results limits the interpretation of the summary estimate, the identification of moderators and mediators of baclofen's effects on alcohol use remains a challenge for further research. Even though some results from RCTs are promising, current evidence remains uncertain regarding the use of baclofen as a first-line treatment for people with AUDs.

We found 12 randomised controlled trials (studies where people were allocated at random to one of two or more treatment or control groups), with 1128 participants. On average, the interventions lasted about five months, while investigators followed up participants from between 4 to 52 months. Five studies took place in the USA and one each in Australia, France, Germany, India, Israel, Italy, and the Netherlands. The studies considered baclofen at different doses (ranging from 10 mg a day to 150 mg a day), and in some cases, the doses were increased during the treatment. None of the studies added other drugs or other treatments to the baclofen treatment. All the studies compared baclofen to placebo, except for one study that compared baclofen to acamprosate at a dose of 666.66 mg three times a day for three months. Compared with placebo, baclofen makes little or no difference to participants who dropped out from treatment, dropped out due to adverse events (side effects), or the number of participants with at least one adverse event. Baclofen probably makes little difference to the number of participants who start drinking again, nor to how much or how often they drink. Baclofen may make little or no difference in the percentage of days people remain alcohol-free. Baclofen may increase the amount of use measured by number of drinks per drinking days. We found that baclofen increased adverse events like depression, vertigo, somnolence, numbness and muscle rigidity but we did not find significant differences between baclofen and placebo for other adverse events. The certainty of evidence (how much we can be confident that the evidence is reliable) was high for results about the number of participants with at least one adverse event, and about people dropping out of the studies for any reason or dropping out due to adverse events. The certainty of the evidence was moderate for results about people returning to any drinking and how many heavy drinking days they had. It was low for results about drink per drinking days and percentage of days of abstinence.

10.1002/14651858.CD012557.pub2

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Our search resulted in 1663 potentially relevant references, of which we included three trials with 14 publications, assessing 398 patients. Overall, we judged the quality of the trials as moderate. The trials were all reported as randomised controlled and open-label. We included two RCTs assessing the effect of HDCT followed by ASCT compared with conventional chemotherapy in a meta-analysis. The number of studies was very low, therefore, the quantification of heterogeneity was not reliable. We included one further RCT (one assessing additional SHDCT followed by ASCT versus HDCT followed by ASCT), which was not compatible with our meta-analysis. For this trial, we performed further analyses. Two trials showed a non-statistically significant trend that HDCT followed by ASCT compared to conventional chemotherapy increases OS (HR 0.67; 95% CI 0.41 to 1.07; P value = 0.10, 157 patients, moderate quality of evidence). However, the increase in PFS was statistically significant for people treated with HDCT followed by ASCT (HR 0.55; 95% CI 0.35 to 0.86; P value = 0.009, 157 patients, moderate quality of evidence). Adverse events were reported in one trial only and did not differ statistically significant between the treatment arms. We were not able to draw conclusions regarding treatment-related mortality (TRM) because of insufficient evidence (RR 0.61; 95% CI 0.16 to 2.22; P value = 0.45, 157 patients, moderate quality of evidence). For the second comparison, SHDCT plus HDCT followed by ASCT versus HDCT followed by ASCT there was no difference between the treatment arms regarding OS (HR 0.93; 95% CI 0.5 to 1.74; P value = 0.816, three-year OS: 80% SHDCT versus 87% HDCT, 241 patients), or PFS (HR 0.87; 95% CI 0.58 to 1.30; P value = 0.505, 241 patients). Seven patients died in the SHDCT arm and one in the HDCT arm due to increased toxicity of the treatment. Adverse events were increased with SHDCT plus HDCT followed by ASCT after two cycles of dexamethasone plus high-dose cytarabine plus cisplatin (DHAP) (88% SHDCT versus 45% HDCT, 223 patients, P value < 0.00001). Overall, more statistically significant World Health Organization (WHO) grade 3/4 infections occurred with SHDCT (48% SHDCT versus 33% HDCT; P value = 0.002, 223 patients). The currently available evidence suggests a PFS benefit for patients with relapsed or refractory HL after first-line therapy, who are treated with HDCT followed by ASCT compared to patients treated with conventional chemotherapy. In addition, data showes a positive trend regarding OS, but more trials are needed to detect a significant effect. Intensifying the HDCT regime before HDCT followed by ASCT did not show a difference as compared to HDCT followed by ASCT, but was associated with increased adverse events.

Both trials assessing HDCT followed by ASCT versus conventional chemotherapy showed no significant improvement in overall survival, however progression-free survival was significantly improved with HDCT followed by ASCT. Only one trial reported adverse events and showed no difference between the treatment arms. The other trial was prematurely closed as patients refused randomisation and requested ASCT. Only one trial evaluated the effect of SHDCT before HDCT plus ASCT, compared to HDCT plus ASCT. Overall survival and progression-free survival were similar in both arms. However, after three years, there was a negative trend for the SHDCT arm regarding mortality as well as significantly increased adverse events. In summary, the currently available evidence suggests a benefit for patients with relapsed HL treated with HDCT followed by ASCT compared to conventional chemotherapy.

10.1002/14651858.CD009411.pub2

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Seven clinical studies totalling 12,223 participants with COPD were included in the review. The studies used similar designs and were generally of good methodological quality. Inclusion criteria for RCTs were similar across the included studies, although studies varied in terms of smoking history and COPD severity of participants. They compared tiotropium (which was delivered by HandiHaler in all studies) with salmeterol (four studies, 8936 participants), formoterol (one study, 431 participants) and indacaterol (two studies, 2856 participants). All participants were instructed to discontinue anticholinergic or long-acting beta2-agonist bronchodilators during treatment, but could receive inhaled corticosteroids (ICS) at a stable dose. Study duration ranged from 3 to 12 months. We extracted data for 11,223 participants. In general, the treatment groups were well matched at baseline. Overall, the risk of bias across the included RCTs was low. In the analysis of the primary outcomes in this review, a high level of heterogeneity amongst studies meant that we did not pool data for St George's Respiratory Questionnaire quality of life score. Subgroup analyses based on the type of LABA found statistically significant differences among effects on quality of life depending on whether tiotropium was compared with salmeterol, formoterol or indacaterol. Tiotropium reduced the number of participants experiencing one or more exacerbations compared with LABA (odds ratio (OR) 0.86; 95% confidence interval (CI) 0.79 to 0.93). For this outcome, there was no difference seen among the different types of LABA. There was no statistical difference in mortality observed between the treatment groups. For secondary outcomes, tiotropium was associated with a reduction in the number of COPD exacerbations leading to hospitalisation compared with LABA treatment (OR 0.87; 95% 0.77 to 0.99), but not in the overall rate of all-cause hospitalisations. There was no statistically significant difference in forced expiratory volume in one second (FEV1) or symptom score between tiotropium and LABA-treated participants. There was a lower rate of non-fatal serious adverse events recorded with tiotropium compared with LABA (OR 0.88; 95% CI 0.78 to 0.99). The tiotropium group was also associated with a lower rate of study withdrawals (OR 0.89; 95% CI 0.81 to 0.99). We identified six full economic evaluations assessing the cost and cost-effectiveness of tiotropium and salmeterol. The studies were based on an economic model or empirical analysis of clinical data from RCTs. They all looked at maintenance costs and the costs for COPD exacerbations, including respiratory medications and hospitalisations. The setting for the evaluations was primary and secondary care in the UK, Greece, Netherlands, Spain and USA. All the studies estimated tiotropium to be superior to salmeterol based on better clinical outcomes (exacerbations or quality of life) and/or lower total costs. However, the authors of all evaluations reported there was substantial uncertainty around the results. In people with COPD, the evidence is equivocal as to whether or not tiotropium offers greater benefit than LABAs in improving quality of life; however, this is complicated by differences in effect among the LABA types. Tiotropium was more effective than LABAs as a group in preventing COPD exacerbations and disease-related hospitalisations, although there were no statistical differences between groups in overall hospitalisation rates or mortality during the study periods. There were fewer serious adverse events and study withdrawals recorded with tiotropium compared with LABAs. Symptom improvement and changes in lung function were similar between the treatment groups. Given the small number of studies to date, with high levels of heterogeneity among them, one approach may be to give a COPD patient a substantial trial of tiotropium, followed by a LABA (or vice versa), then to continue prescribing the long-acting bronchodilator that the patient prefers. Further studies are needed to compare tiotropium with different LABAs, which are currently ongoing. The available economic evidence indicates that tiotropium may be cost-effective compared with salmeterol in several specific settings, but there is considerable uncertainty around this finding.

Tiotropium is an inhaled medication that helps open the airways (bronchodilator) and is used to manage persistent symptoms of COPD. We found seven studies including 12,223 participants that compared tiotropium with long-acting beta2-agonists (LABAs), which are another type of bronchodilator. This systematic review found that currently there is insufficient evidence to suggest which of these treatments provides greater long-term benefit in quality of life. Furthermore, both treatments had similar effects on symptoms, lung function and death rates. Tiotropium appears better than LABAs in preventing COPD exacerbations (worsening of COPD symptoms) and reducing the number of COPD-related hospitalisations. Furthermore, there were fewer participants during the study period with serious adverse events or who withdrew early from the studies with tiotropium compared with LABA treatment. However, there was no difference in the total number of people who were hospitalised. We found six economic evaluations looking at the cost and effectiveness of tiotropium and the LABA salmeterol that were conducted in the UK, Greece, Netherlands, Spain, or USA. All the studies estimated tiotropium to be better than salmeterol based on medical outcomes (exacerbations or quality of life) and/or lower total costs, including respiratory medications and hospitalisations. However, these results were very uncertain.

10.1002/14651858.CD009157.pub2

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Our searches identified over 1700 records, from which we include 24 completed studies (three RCTs, two of which were eligible for our cessation meta-analysis, and 21 cohort studies). Eleven of these studies are new for this version of the review. We identified 27 ongoing studies. Two RCTs compared EC with placebo (non-nicotine) EC, with a combined sample size of 662 participants. One trial included minimal telephone support and one recruited smokers not intending to quit, and both used early EC models with low nicotine content and poor battery life. We judged the RCTs to be at low risk of bias, but under the GRADE system we rated the overall quality of the evidence for our outcomes as ‘low’ or ‘very low’, because of imprecision due to the small number of trials. A ‘low’ grade means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. A ‘very low’ grade means we are very uncertain about the estimate. Participants using an EC were more likely to have abstained from smoking for at least six months compared with participants using placebo EC (RR 2.29, 95% CI 1.05 to 4.96; placebo 4% versus EC 9%; 2 studies; 662 participants. GRADE: low). The one study that compared EC to nicotine patch found no significant difference in six-month abstinence rates, but the confidence intervals do not rule out a clinically important difference (RR 1.26, 95% CI 0.68 to 2.34; 584 participants. GRADE: very low). Of the included studies, none reported serious adverse events considered related to EC use. The most frequently reported AEs were mouth and throat irritation, most commonly dissipating over time. One RCT provided data on the proportion of participants experiencing any adverse events. The proportion of participants in the study arms experiencing adverse events was similar (ECs vs placebo EC: RR 0.97, 95% CI 0.71 to 1.34 (298 participants); ECs vs patch: RR 0.99, 95% CI 0.81 to 1.22 (456 participants)). The second RCT reported no statistically significant difference in the frequency of AEs at three- or 12-month follow-up between the EC and placebo EC groups, and showed that in all groups the frequency of AEs (with the exception of throat irritation) decreased significantly over time. There is evidence from two trials that ECs help smokers to stop smoking in the long term compared with placebo ECs. However, the small number of trials, low event rates and wide confidence intervals around the estimates mean that our confidence in the result is rated 'low' by GRADE standards. The lack of difference between the effect of ECs compared with nicotine patches found in one trial is uncertain for similar reasons. None of the included studies (short- to mid-term, up to two years) detected serious adverse events considered possibly related to EC use. The most commonly reported adverse effects were irritation of the mouth and throat. The long-term safety of ECs is unknown. In this update, we found a further 15 ongoing RCTs which appear eligible for this review.

This is an update of a previous review. The first review was published in 2014 and included 13 studies. For this update, we searched for studies published up to January 2016 and found 11 new studies. Only two of the included studies are randomized controlled trials and followed participants for at least six months. These provide the best evidence. The remaining 22 studies either did not follow participants for very long or did not put people into treatment groups so could not directly compare ECs with something else. These studies can tell us less about how ECs might help with quitting smoking but can tell us about short-term safety. The two randomized trials, conducted in New Zealand and Italy, compared ECs with and without nicotine. We judged these studies to be at low risk of bias. In one study, people wanted to quit smoking, while in the other study they did not. The trial in people who wanted to quit smoking also compared ECs to nicotine patches. Combined results from two studies, involving 662 people, showed that using an EC containing nicotine increased the chances of stopping smoking in the long term compared to using an EC without nicotine. We could not determine if EC was better than a nicotine patch in helping people stop smoking, because the number of participants in the study was low. More studies are needed to evaluate this effect. The other studies were of lower quality, but they supported these findings. None of the studies found that smokers who used EC short- to mid-term (for two years or less) had an increased health risk compared to smokers who did not use ECs. The quality of the evidence overall is low because it is based on only a small number of studies, although these studies were well conducted. More studies of ECs are needed. Some are already underway.

10.1002/14651858.CD010216.pub3

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We included nine trials with 469 women. A diverse set of medications and regimens were studied in these trials, making the comparisons available for meta-analysis limited. The comparisons draw data from six trials with 383 participants. All trials were relatively small and had several aspects of unclear risk of bias with few of this review's outcomes reported. Due to this, no data from three trials were able to be used despite them meeting inclusion criteria. We carried out four comparisons: isosorbide mononitrate or dinitrate compared with misoprostol; misoprostol compared with placebo; chemical dilation (use of medications) compared with mechanical dilation; and any cervical preparation compared with placebo. None of the included studies reported data on the review's primary outcome: cervical or uterine injury (perforation, laceration, creation of a false passage). No clear difference was shown between isosorbide compounds and misoprostol for the outcome need for manual cervical dilation (average risk ratio (RR) 0.76, 95% confidence interval (CI) 0.10 to 5.64; three trials, 150 women; Tau² = 2.11; I² = 69%), however the data were heterogenous. In terms of adverse effects, misoprostol was associated with more vomiting (RR 0.11, 95% CI 0.01 to 0.85; two trials, 120 women), however there were no clear differences between isosorbide compounds and misoprostol in relation to other reported adverse effects (headache, nausea or hypotension). The dosing regimens differed in terms of dose, number of administrations and route of administration in the different trials. Mechanical (Dilapan-S hygroscopic) dilators performed similarly to chemical dilators in a single trial (65 women) that measured difficulty in cervical dilation, excessive bleeding and adverse effects. Misoprostol was shown to be more effective than placebo for cervical ripening (reduced need for manual cervical dilation) (RR 0.14, 95% CI 0.08 to 0.26; one trial, 120 women), and surgical time was reduced when misoprostol was used (mean difference (MD) -3.15, 95% CI -3.59 to -2.70; one trial, 120 women). However, compared to placebo, misoprostol, was associated with more abdominal pain (RR 29.00, 95% CI 1.77 to 475.35; one trial, 120 women), although no clear differences in the risk of other adverse effects (nausea, vomiting, headache or fever) were observed between groups. There was no clear differences between chemical dilation and mechanical dilators for the outcomes: difficulty in cervical dilation, excessive bleeding or adverse effects. Compared with placebo, any cervical preparation reduced the need for manual cervical dilatation (average RR 0.25, 95% CI 0.07 to 0.89; two trials, 168 women; Tau² = 0.67; I² = 81%), and reduced surgical time (MD -2.55, 95% CI -3.67 to -1.43, two trials, 168 women; Tau² = 0.63; I² = 96%). None of the included trials reported on the review's other secondary outcomes, including: injury to bladder or bowel, miscarriage/preterm birth in a subsequent pregnancy, analgesia use after administration of ripening agent but before surgery, or analgesia use after surgery. This review found no evidence to evaluate cervical ripening prior to first trimester surgical evacuation for miscarriage for reducing the rate of cervical or uterine injury, however, this may be because these outcomes are very rare. Cervical preparation was shown to reduce the need for manual cervical dilatation compared with placebo. Misoprostol and isosorbide mononitrate and dinitrate were similarly effective in ripening the cervix, however there was more vomiting with misoprostol. Mechanical (Dilapan-S hygroscopic) dilators performed similarly to chemical dilators. The nine studies included in this review were small and the methodological quality of the trials was mixed, and for the most part, not well-described; thus any conclusions drawn from the data included in this review must be treated with caution. Consequently, large, high-quality trials are required to determine whether the benefits of this treatment outweigh the risks. Further research should be powered to assess the rate of cervical and uterine injury between interventions. Future research should also guide clinicians in deciding whether the benefits of reduced manual cervical dilatation outweigh the risks of adverse effects associated with these agents (nausea, vomiting, headache, fever, diarrhoea and pain). Women's satisfaction and outcomes of future pregnancies should also be assessed.

Our search for studies (on 30 April 2015) identified nine randomised controlled studies involving 469 women, but only six trials (involving 383 women) contributed data towards this review. The studies included small numbers of women and were not generally of high quality. None of the included studies reported data on cervical or uterine injury, which are rare events. Cervical preparation, either using mechanical or chemical dilation with misoprostol, was shown to reduce the need for manual cervical dilatation and surgical time compared with placebo (two trials, 168 women). Misoprostol was associated with more abdominal pain than placebo but no clear differences were observed in the risk of other adverse effects such as nausea, vomiting, headache or fever. Misoprostol and isosorbide mononitrate and dinitrate were similarly effective in ripening the cervix and reducing the need for manual cervical dilation (three trials, 150 women). Misoprostol caused more vomiting but with no clear differences in other reported adverse effects (headache, nausea or hypotension). The dosing regimens differed in terms of dose, number of administrations and route of administration in the different trials. Mechanical (Dilapan-S hygroscopic) dilators performed similarly to chemical dilators in a single trial (65 women) that measured difficulty in cervical dilation, excessive bleeding and adverse effects. The medications or devices used did reduce the need for manual dilation of the cervix, but were associated with some side effects. These include abdominal pain, nausea, vomiting, fever, headache and diarrhoea. The particular agents that we compared were misoprostol, isosorbide mononitrate, isosorbide dinitrate and Dilapan-S hygroscopic dilators. No agent performed significantly better than another. The nine studies included in this review were small and the methodological quality of the trials was varied. For the most part, the study methods were not well-described; thus any conclusions drawn from the data included in this review must be treated with caution. Large, high-quality trials are required to understand whether easier dilation means there is less risk of injury to the woman's uterus or cervix during the surgery, or if there are any effects on future pregnancies.

10.1002/14651858.CD009954.pub2

cochrane-simplification-train-253

cochrane-simplification-train-253

Seven studies with a total of 578 patients were included in the first comparison: mean percentage of rebleeding in H. pylori eradication therapy group was 2.9%, and in the non-eradication therapy group without subsequent long-term maintenance antisecretory therapy it was 20% (OR 0.17, 95% CI 0.10 to 0.32; there was no statistical evidence of heterogeneity; NNT was 7, 95% CI 5 to 11). Three studies with a total of 470 patients were included in the second comparison: mean percentage of rebleeding in H. pylori eradication therapy group was 1.6%, and in non-eradication therapy group with long-term maintenance antisecretory therapy it was 5.6% (OR 0.24, 95% CI 0.09 to 0.67; heterogeneity was not demonstrated; NNT was 20, 95% CI 12 to 100). Subgroup analyses were carried out to examine the effect of NSAIDS and of excluding H.pylori eradication failures from the analyses. Treatment of H. pylori infection is more effective than antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) in preventing recurrent bleeding from peptic ulcer. All patients with peptic ulcer bleeding should be tested for H. pylori infection, and eradication therapy should be prescribed to H. pylori-positive patients.

The review found that, for people who have had a bleeding peptic ulcer caused by Helicobacter pylori, treatment with antibiotics more effectively prevents gastrointestinal re-bleeding than acid-suppressing drugs. Antibiotics when Helicobacter pylori infection is present are also cheaper and more convenient than long-term acid-suppressing drugs.

10.1002/14651858.CD004062.pub2

cochrane-simplification-train-254

cochrane-simplification-train-254

We included a total of 27 trials, and 26 trials involving 15,858 women provided usable outcome data for analysis. These trials were conducted in 17 different countries: 13 trials were conducted in high-income settings; 13 trials in middle-income settings; and no studies in low-income settings. Women allocated to continuous support were more likely to have a spontaneous vaginal birth (average RR 1.08, 95% confidence interval (CI) 1.04 to 1.12; 21 trials, 14,369 women; low-quality evidence) and less likely to report negative ratings of or feelings about their childbirth experience (average RR 0.69, 95% CI 0.59 to 0.79; 11 trials, 11,133 women; low-quality evidence) and to use any intrapartum analgesia (average RR 0.90, 95% CI 0.84 to 0.96; 15 trials, 12,433 women). In addition, their labours were shorter (MD -0.69 hours, 95% CI -1.04 to -0.34; 13 trials, 5429 women; low-quality evidence), they were less likely to have a caesarean birth (average RR 0.75, 95% CI 0.64 to 0.88; 24 trials, 15,347 women; low-quality evidence) or instrumental vaginal birth (RR 0.90, 95% CI 0.85 to 0.96; 19 trials, 14,118 women), regional analgesia (average RR 0.93, 95% CI 0.88 to 0.99; 9 trials, 11,444 women), or a baby with a low five-minute Apgar score (RR 0.62, 95% CI 0.46 to 0.85; 14 trials, 12,615 women). Data from two trials for postpartum depression were not combined due to differences in women, hospitals and care providers included; both trials found fewer women developed depressive symptomatology if they had been supported in birth, although this may have been a chance result in one of the studies (low-quality evidence). There was no apparent impact on other intrapartum interventions, maternal or neonatal complications, such as admission to special care nursery (average RR 0.97, 95% CI 0.76 to 1.25; 7 trials, 8897 women; low-quality evidence), and exclusive or any breastfeeding at any time point (average RR 1.05, 95% CI 0.96 to 1.16; 4 trials, 5584 women; low-quality evidence). Subgroup analyses suggested that continuous support was most effective at reducing caesarean birth, when the provider was present in a doula role, and in settings in which epidural analgesia was not routinely available. Continuous labour support in settings where women were not permitted to have companions of their choosing with them in labour, was associated with greater likelihood of spontaneous vaginal birth and lower likelihood of a caesarean birth. Subgroup analysis of trials conducted in high-income compared with trials in middle-income countries suggests that continuous labour support offers similar benefits to women and babies for most outcomes, with the exception of caesarean birth, where studies from middle-income countries showed a larger reduction in caesarean birth. No conclusions could be drawn about low-income settings, electronic fetal monitoring, the timing of onset of continuous support or model of support. Risk of bias varied in included studies: no study clearly blinded women and personnel; only one study sufficiently blinded outcome assessors. All other domains were of varying degrees of risk of bias. The quality of evidence was downgraded for lack of blinding in studies and other limitations in study designs, inconsistency, or imprecision of effect estimates. Continuous support during labour may improve outcomes for women and infants, including increased spontaneous vaginal birth, shorter duration of labour, and decreased caesarean birth, instrumental vaginal birth, use of any analgesia, use of regional analgesia, low five-minute Apgar score and negative feelings about childbirth experiences. We found no evidence of harms of continuous labour support. Subgroup analyses should be interpreted with caution, and considered as exploratory and hypothesis-generating, but evidence suggests continuous support with certain provider characteristics, in settings where epidural analgesia was not routinely available, in settings where women were not permitted to have companions of their choosing in labour, and in middle-income country settings, may have a favourable impact on outcomes such as caesarean birth. Future research on continuous support during labour could focus on longer-term outcomes (breastfeeding, mother-infant interactions, postpartum depression, self-esteem, difficulty mothering) and include more woman-centred outcomes in low-income settings.

We found 26 studies that provided data from 17 countries, involving more than 15,000 women in a wide range of settings and circumstances. The continuous support was provided either by hospital staff (such as nurses or midwives), or women who were not hospital employees and had no personal relationship to the labouring woman (such as doulas or women who were provided with a modest amount of guidance on providing support). In other cases, the support came from companions of the woman's choice from her own network (such as her partner, mother, or friend). Women who received continuous labour support may be more likely to give birth 'spontaneously', i.e. give birth vaginally with neither ventouse nor forceps nor caesarean. In addition, women may be less likely to use pain medications or to have a caesarean birth, and may be more likely to be satisfied and have shorter labours. Postpartum depression could be lower in women who were supported in labour, but we cannot be sure of this due to the studies being difficult to compare (they were in different settings, with different people giving support). The babies of women who received continuous support may be less likely to have low five-minute Apgar scores (the score used when babies’ health and well-being are assessed at birth and shortly afterwards). We did not find any difference in the numbers of babies admitted to special care, and there was no difference found in whether the babies were breastfed at age eight weeks. No adverse effects of support were identified. Overall, the quality of the evidence was all low due to limitations in study design and differences between studies. Continuous support in labour may improve a number of outcomes for both mother and baby, and no adverse outcomes have been identified. Continuous support from a person who is present solely to provide support, is not a member of the woman's own network, is experienced in providing labour support, and has at least a modest amount of training (such as a doula), appears beneficial. In comparison with having no companion during labour, support from a chosen family member or friend appears to increase women's satisfaction with their experience. Future research should explore how continuous support can be best provided in different contexts.

10.1002/14651858.CD003766.pub6

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cochrane-simplification-train-255

Twenty-eight trials, involving almost 17,000 women, contributed data to the review. Overall, women who received a psychosocial or psychological intervention were significantly less likely to develop postpartum depression compared with those receiving standard care (average RR 0.78, 95% confidence interval (CI) 0.66 to 0.93; 20 trials, 14,727 women). Several promising interventions include: (1) the provision of intensive, individualised postpartum home visits provided by public health nurses or midwives (RR 0.56, 95% CI 0.43 to 0.73; two trials, 1262 women); (2) lay (peer)-based telephone support (RR 0.54, 95% CI 0.38 to 0.77; one trial, 612 women); and (3) interpersonal psychotherapy (standardised mean difference -0.27, 95% CI -0.52 to -0.01; five trials, 366 women). Professional- and lay-based interventions were both effective in reducing the risk to develop depressive symptomatology. Individually-based interventions reduced depressive symptomatology at final assessment (RR 0.75, 95% CI 0.61 to 0.92; 14 trials, 12,914 women) as did multiple-contact interventions (RR 0.78, 95% CI 0.66 to 0.93; 16 trials, 11,850 women). Interventions that were initiated in the postpartum period also significantly reduced the risk to develop depressive symptomatology (RR 0.73, 95% CI 0.59 to 0.90; 12 trials, 12,786 women). Identifying mothers 'at-risk' assisted the prevention of postpartum depression (RR 0.66, 95% CI 0.50 to 0.88; eight trials, 1853 women). Overall, psychosocial and psychological interventions significantly reduce the number of women who develop postpartum depression. Promising interventions include the provision of intensive, professionally-based postpartum home visits, telephone-based peer support, and interpersonal psychotherapy.

The purpose of this review was to examine the effect of psychosocial and psychological interventions to reduce the risk of postpartum depression compared with usual care. This review includes data from 28 randomised controlled trials involving almost 17,000 women. The preventative interventions evaluated in the included trials were diverse and the end-points differed widely but the methodological quality was good to excellent. A clear beneficial effect in the prevention of postpartum depression was found from a range of psychosocial and psychological interventions. Promising interventions included professionally-based postpartum home visits, lay- or peer-based postpartum telephone support, and interpersonal psychotherapy. Interventions provided by various health professionals and lay individuals were similarly beneficial. Interventions that were individually-based were beneficial as were those that involved multiple contacts. There is also evidence that interventions initiated postnatally assisted in preventing postpartum depression as were those specifically targeting 'at-risk' mothers. Many questions remain unanswered and additional research is needed.

10.1002/14651858.CD001134.pub3

cochrane-simplification-train-256

cochrane-simplification-train-256

Eight studies met the inclusion criteria involving 394 participants with AsPD. Data were available from four studies involving 274 participants with AsPD. No study set out to recruit participants solely on the basis of having AsPD, and in only one study was the sample entirely of AsPD participants. Eight different drugs were examined in eight studies. Study quality was relatively poor. Inadequate reporting meant the data available were generally insufficient to allow any independent statistical analysis. The findings are limited to descriptive summaries based on analyses carried out and reported by the trial investigators. All the available data were derived from unreplicated single reports. Only three drugs (nortriptyline, bromocriptine, phenytoin) were effective compared to placebo in terms of improvement in at least one outcome. Nortriptyline was reported in one study as superior for men with alcohol dependency on mean number of drinking days and on alcohol dependence, but not for severity of alcohol misuse or on the patient's or clinician's rating of drinking. In the same study, both nortriptyline and bromocriptine were reported as superior to placebo on anxiety on one scale but not on another. In one study, phenytoin was reported as superior to placebo on the frequency and intensity of aggressive acts in male prisoners with impulsive (but not premeditated) aggression. In the remaining two studies, both amantadine and desipramine were not superior to placebo for adults with opioid and cocaine dependence, and desipramine was not superior to placebo for men with cocaine dependence. The body of evidence summarised in this review is insufficient to allow any conclusion to be drawn about the use of pharmacological interventions in the treatment of antisocial personality disorder.

We considered eight studies, but none of them recruited participants solely on the basis of having antisocial personality disorder. While most studies included in this review looked at treatments to reduce drug or alcohol misuse in people with antisocial personality disorder, no study focused on treating the disorder itself. Studies varied in terms of choice of outcomes. While some studies reported outcome measures that were originally defined in the review protocol as being of particular importance in this disorder (for example, aggression, social functioning and adverse effects resulting from the use of medication), no study reported on reconviction. In summary, we were unable to draw any firm conclusions from the existing literature.  Nonetheless, there was some evidence that nortriptyline (a drug used to treat depression) could help people with antisocial personality disorder to reduce their misuse of alcohol. There was also some evidence that phenytoin (a drug used to treat epilepsy) could help to reduce the intensity of impulsive aggressive acts in people with antisocial personality disorder. Further research is required to clarify which medications are effective for treating the core features of this disorder. This research is best carried out using carefully designed clinical trials. Such trials should recruit sufficient numbers of people on the basis of having the disorder and use outcome measures that are of particular relevance to this disorder. They should also focus on recently marketed drugs where these have largely replaced older medications (for example, nortriptyline and phenytoin) which are no longer widely used.

10.1002/14651858.CD007667.pub2

cochrane-simplification-train-257

cochrane-simplification-train-257

Thirteen trials with 2197 participants met the inclusion criteria: 11 trials investigated treatment regimens; two investigated prophylaxis regimens. The quality of the trials was variable. For eradicating Bordetella pertussis (B. pertussis) from the nasopharynx, short-term antibiotics (azithromycin for three to five days, or clarithromycin or erythromycin for seven days) were as effective as long-term (erythromycin for 10 to 14 days) (risk ratio (RR) 1.01; 95% confidence interval (CI) 0.98 to 1.04), but had fewer side effects (RR 0.66; 95% CI 0.52 to 0.83). Trimethoprim/sulphamethoxazole for seven days was also effective. Nor were there differences in clinical outcomes or microbiological relapse between short and long-term antibiotics. For preventing infection by treating contacts older than six months of age, antibiotics did not significantly improve clinical symptoms, nor the number of cases developing culture-positive B. pertussis. Side effects were reported with antibiotics and they varied from one antibiotic to another. Although antibiotics were effective in eliminating B. pertussis, they did not alter the subsequent clinical course of the illness. There is insufficient evidence to determine the benefits of prophylactic treatment of pertussis contacts.

Thirteen trials involving 2197 participants were included in this review. We found that several antibiotic treatments were equally effective in eliminating the bacteria infecting patients, but they did not alter the clinical outcome. There was insufficient evidence to decide whether there is benefit for treating healthy contacts. Side effects were reported with antibiotics and they varied from one antibiotic to another. The result of the review should be interpreted with caution since this review is based on a limited number of trials and some of these trials involved small numbers of participants.

10.1002/14651858.CD004404.pub3

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cochrane-simplification-train-258

Two trials with a total of 210 participants were included. Both trials were at some risk of performance bias. One trial had four intervention groups and the other had three. One trial found that foot orthoses when compared with flat insoles (control group) had better results at six weeks in knee pain (participants with global improvement: risk ratio 1.48, 95% confidence interval 1.11 to 1.99), but not at one year follow-up. Participants in the orthoses group reported significantly more minor adverse effects (e.g. rubbing, blistering) compared with the flat insole group (risk ratio 1.87, 95% confidence intervaI 1.21 to 2.91). Both trials in their comparisons of orthoses plus physiotherapy versus physiotherapy alone found no statistically significant differences between the two intervention groups in knee pain or function. Results for knee pain outcomes did not show significant differences between foot orthoses versus physiotherapy. Although participants in the physiotherapy group had consistently better results for the functional index questionnaire, the clinical relevance of these results is uncertain. While not robust, the available evidence does not reveal any clear advantage of foot orthoses over simple insoles or physiotherapy for patellofemoral pain. While foot orthoses may help relieve knee pain over the short term, the benefit may be marginal. Patients treated with orthoses are more likely to complain of mild adverse effects and discomfort.

We included two studies with a total of 210 participants in this review. Both trials were at some risk of bias because not enough care had been taken to ensure that groups received the same treatment other than the interventions being tested. One trial found some benefits from using foot orthoses over simple insoles at six weeks but not at one year. Participants wearing orthoses were, however, more likely to report minor adverse effects (e.g. rubbing, blistering) and discomfort compared with those wearing insoles. There were no important differences in knee pain and function in people given foot orthoses as well as physiotherapy when compared with people given physiotherapy only. Results for knee pain and function did not show important differences between foot orthoses versus physiotherapy. On the basis of the available evidence we do not recommend foot orthoses for adults with pain around the knee cap.

10.1002/14651858.CD008402.pub2

cochrane-simplification-train-259

cochrane-simplification-train-259

Fifty-one studies were included. They used three different models, namely case management, shared care, and interdisciplinary teams. Six additional interventional strategies were used besides these models: (1) patient-held record, (2) telephone follow-up, (3) communication and case discussion between distant healthcare professionals, (4) change in medical record system, (5) care protocols, directives and guidelines, and (6) coordination of assessments and treatment. Based on the median effect size estimates, no significant difference in patient health-related outcomes was found between patients assigned to interventions and those assigned to usual care. A limited number of studies reported psychological health, satisfaction of providers, or process of care measures. However, they could not be regrouped to calculate median effect size estimates because of a high heterogeneity among studies. Results from this Cochrane review do not allow us to conclude on the effectiveness of included interventions to improve continuity of care on patient, healthcare provider or process of care outcomes. Future research should evaluate interventions that target an improvement in continuity as their primary objective and describe these interventions with the categories proposed in this review. Also of importance, continuity measures should be validated with persons with cancer who have been followed in various settings.

Three main models of care (case management, shared care and interdisciplinary team) designed to improve continuity of care were identified in the 51 studies included in this review. We found no standard instruments that allow to specifically measure continuity of care in patients with cancer. According to our analysis, there was no clear evidence that the interventions assessed in this review either improved or worsened patient health-related outcomes. Therefore, our analyses did not allow us to draw firm conclusions on the effectiveness of interventions designed to improve continuity of care in the follow-up of patients with cancer. Few studies reported provider and informal caregiver outcomes, as well as process of care outcomes, so they could not be regrouped for analysis. The main limitations of this review were the various differences between the included studies, especially in their study designs, interventions, participants, patients' phase of care, measured outcomes, healthcare settings, and length of follow-up. More relevant research is needed to sort out which interventions aiming to improve continuity of care in the follow-up of patients with cancer are the most beneficial to improve patient, provider and process of care outcomes. Future research should identify which outcomes are the most sensitive to change and the most meaningful regarding continuity of care. Also, it would be valuable to develop a standardised instrument to measure continuity of care in patients with cancer.

10.1002/14651858.CD007672.pub2

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cochrane-simplification-train-260

Our search identified 8299 articles (excluding duplicates). We examined the titles and abstracts of 1125 articles and the full-text versions of 97 articles. We included seven studies in our review, which reported data from 1491 children; all were conducted in hospital settings. Overall, study quality was moderate. In two studies the presence of chest pain more than doubled the probability of M. pneumoniae. Wheeze was 12% more likely to be absent in children with M. pneumoniae (pooled positive likelihood ratio (LR+) 0.76, 95% CI 0.60 to 0.97; pooled negative likelihood ratio (LR-) 1.12, 95% CI 1.02 to 1.23). Our sensitivity analysis showed that the presence of crepitations was associated with M. pneumoniae, but this finding was of borderline statistical significance (pooled LR+ 1.10, 95% CI 0.99 to 1.23; pooled LR- 0.66, 95% CI 0.46 to 0.96). M. pneumoniae cannot be reliably diagnosed in children and adolescents with community-acquired pneumonia based on clinical symptoms and signs. Although the absence of wheeze is a statistically significant diagnostic indicator, it does not have sufficient diagnostic value to guide empirical macrolide treatment. Data from two studies suggest that the presence of chest pain more than doubles the probability of M. pneumoniae. However, further research is needed to substantiate this finding. More high quality large-scale studies in primary care settings are needed to help develop prediction rules based on epidemiological data as well as clinical and baseline patient characteristics.

This review assesses the value of clinical symptoms and signs in helping doctors and nurses decide whether a child or young person might have a chest infection caused by M. pneumoniae. We analysed data from seven studies including a total of 1491 children, all of which were conducted in hospital settings. We found that the presence of wheeze makes M. pneumoniae slightly less likely and the presence of crepitations (i.e. crackles heard on listening to the chest) makes M. pneumoniae slightly more likely. However, these clinical features are not sufficiently helpful to guide decisions about prescribing antibiotics for possible M. pneumoniae infections. Based on the results of two studies, the presence of chest pain doubles the likelihood of M. pneumoniae. However, further research in this area is needed, particularly in general practice and outpatient populations.

10.1002/14651858.CD009175.pub2

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cochrane-simplification-train-261

Six trials (343 participants) evaluated Eutectic Mixture of Local Anaesthetics (EMLA): lidocaine-prilocaine cream for the pain associated with ulcer debridement. The between-group difference in pain measured on a 100 mm scale was statistically significant in favour of EMLA (MD -20.65, 95% CI -12.19 to -29.11). No significant between-group differences in burning or itching were observed. Two trials (470 participants with venous leg ulcers) evaluated ibuprofen slow-release foam dressings for persistent venous leg ulcer pain. Compared with local best practice, significantly more participants in the ibuprofen dressing group achieved the outcome of >50% of the total maximum pain relief score between day 1 and day 5 than participants in the local best practice group (RR 1.63, 95% CI 1.24 to 2.15). The number needed to treat was 6 (95% CI 4 to 12). In the second trial, compared with an identical non-ibuprofen foam dressing, there was no statistically significant difference in the proportion of participants experiencing slight to complete pain relief on the first evening of treatment.Limited data were available to assess healing rates or adverse events. There is some evidence to suggest that ibuprofen dressings may offer pain relief to people with painful venous leg ulcers. EMLA (5%) appears to provide effective pain relief during the debridement of venous leg ulcers. Further research should consider standardised pain assessment methods and assess both the effect on ulcer healing and the impact of long term use of these treatments.

Two trials tested a dressing containing ibuprofen, however, the pain measures and time frames reported were different. One trial indicated that pain relief achieved over 5 days with ibuprofen dressings could represent a clinically relevant reduction in pain. The other trial found no significant difference in the chance of pain relief, measured on the first night of treatment, for ibuprofen dressings compared with foam dressings. This trial, however, was small and participants were only followed for a few weeks, which may not be long enough to assess whether the dressing affects healing. There was evidence from five trials that a local anaesthetic cream (EMLA 5%) reduces the post-procedural pain of debriding leg ulcers but there was insufficient evidence regarding any side effects of this cream and its impact on healing.

10.1002/14651858.CD001177.pub3

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cochrane-simplification-train-262

We reran the searches and included one new study (100 participants) in this updated review. In total, we included 11 studies with 829 participants, although most analyses were based on data from fewer participants and evidence of low quality. We noted substantial heterogeneity in the included trials. Thus, our results should be read with caution. It was not possible to combine trials for the primary outcome (LOER), but individual trials reported faster induction times (typically 24 to 82 seconds faster, 41 seconds (31.37 to 50.62)) with high initial concentration sevoflurane (six studies, 443 participants, low-quality evidence). Apnoea appeared to be more common in the high initial concentration sevoflurane group (risk ratio (RR) 3.14, 95% confidence interval (CI) 1.72 to 5.7, two studies, 160 participants, low-quality evidence). We found no evidence of differences between the two groups in the incidence of cough (odds ratio (OR) 1.23, 95% CI 0.53 to 2.81, eight studies, 589 participants, low-quality evidence), laryngospasm (OR 1.59, 95% CI 0.16 to 15.9, seven studies, 588 participants, low-quality evidence), breath holding (OR 1.16, 95% CI 0.47 to 2.83, five studies, 389 participants, low-quality evidence), patient movement (RR 1.14, 95% CI 0.69 to 1.89, five studies, 445 participants, low-quality evidence) or bradycardia (OR 0.8, 95% CI 0.22 to 2.88, three studies, 199 participants, low-quality evidence), and the overall incidence of complications was low. A high initial concentration sevoflurane technique probably offers more rapid induction of anaesthesia and a similar rate of complications, except for apnoea, which may be more common with a high initial concentration. However, this conclusion is not definitive because the included studies provided evidence of low quality.

We included in our review 11 randomized controlled trials (829 participants). These trials were conducted between 1997 and 2014 and differed with regard to participants (adults vs children), concentrations of sevoflurane used, addition of nitrous oxide and opioids and other factors. Some elements of the methods suggested low-quality evidence would be obtained. The studies could not always be combined, and study results cannot be stated with certainty. The high initial concentration technique shortened induction time (six studies, 443 participants, low-quality evidence) and led to similar rates of cough (eight studies, 589 participants, low-quality evidence), sudden sustained closure of the vocal cords that prevented breathing (seven studies, 588 participants, low-quality evidence), breath holding (five studies, 389 participants, low-quality evidence), sudden movements (five studies, 445 participants, low-quality evidence) and slow heart rate (three studies, 199 participants, low-quality evidence). The high initial concentration technique showed greater suspension of breathing when compared with the low initial concentration technique (two studies, 160 participants, low-quality evidence). The included studies provided low-quality evidence, and study results should be interpreted with caution. More studies are needed to enable firm conclusions.

10.1002/14651858.CD006837.pub3

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cochrane-simplification-train-263

Five RCTs met our inclusion criteria. Three trials aimed to improve adherence to a specific method of contraception amongst existing or new contraception users by comparing automated text message interventions versus standard care. Two trials aimed to improve both uptake and adherence, not limited to one method, in both users and non-users of contraception. No trials were at low risk of bias in all areas assessed. One trial in the USA reported improved self reported oral contraceptive (OC) continuation at six months from an intervention comprising a range of uni-directional and interactive text messages (RR 1.19, 95% CI 1.05 to 1.35). One trial in Cambodia reported increased self reported use of effective contraception at four months post abortion from an intervention comprising automated interactive voice messages and phone counsellor support (RR 1.39, 95% CI 1.17 to 1.66). One feasibility trial in the USA reported a lower mean number of days between scheduled and completed attendance for the first but not subsequent Depo-Provera appointments using clinic records from an intervention comprising reminders and healthy self management text messages (mean difference (MD) -8.60 days, 95% CI -16.74 to -0.46). Simple text message OC reminders had no effect on missed pills as assessed by electronic medication monitoring in a small trial in the USA (MD 0.5 missed pills, 95% CI -1.08 to 2.08). No effect on self reported contraception use was noted amongst isotretinoin users from an intervention that provided health information via two uni-directional text messages and mail (RR 1.26, 95% CI 0.84 to 1.89). One trial assessed potential adverse effects of the intervention and reported no evidence of road traffic accidents or domestic abuse. Our review provides limited evidence that interventions delivered by mobile phone can improve contraception use. Whilst evidence suggests that a series of interactive voice messages and counsellor support can improve post-abortion contraception, and that a mixture of uni-directional and interactive daily educational text messages can improve OC adherence, the cost-effectiveness and long-term effects of these interventions remain unknown. Further high-quality trials are required to robustly establish the effects of interventions delivered by mobile phone to improve contraception use.

In 2014, we undertook computer searches for randomised trials evaluating mobile phone-based interventions to increase contraception use. We found five trials. Three trials used text messaging to support women in continuing to use a specific method of contraception. Two trials aimed to improve both uptake and continued use of contraception - one with voice and one with text messaging. Our review provides limited evidence that interventions delivered by mobile phone improve contraception use. One trial in the USA reported that women were more likely to continue to take the contraceptive pill from an intervention comprising a range of educational text messages. One trial in Cambodia reported increased use of contraception at four months post abortion from an intervention comprising voice messages and phone counsellor support. Another trial in the USA reported improved attendance for the first but not subsequent contraceptive injection appointments from an intervention comprising reminders and healthy self management text messages. Simple text message contraceptive pill reminders did not reduce missed pills in a small trial in the USA. No difference in contraception use was reported amongst users of isotretinoin (a drug used for acne) from an intervention that provided health information via text messages and mail. In conclusion, evidence indicates that a series of voice messages and counsellor support can improve contraception amongst women seeking abortion services not wanting to get pregnant again at the current time, and data suggest that daily educational text messages can improve continued use of the contraceptive pill. However, the cost value and long-term effectiveness of these interventions remain unknown. More good quality trials are needed to establish the effectiveness of interventions delivered by mobile phone to increase contraception use.

10.1002/14651858.CD011159.pub2

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cochrane-simplification-train-264

Meta-analysis of the 5 cross-over studies found a reduction in SBP of 20.09 mmHg (95%CI:16.58-23.06,p<0.00001) and a 6.75 mmHg (95%CI:4.8-8.69,p<0.00001) reduction in DBP. These results were statistically significant and there was no evidence of heterogeneity between the studies. There may be a dose response effect with spironolactone up to 50 mg/day, but the confidence intervals around the mean end-of-study blood pressure for doses ranging 25-500 mg/day all overlapped. In other words, it appears that doses >50mg/day do not produce further reductions in either SBP or DBP. One cross-over study found that spironolactone 25 mg/day did not statistically significantly change SBP or DBP compared to placebo, SBP: -9.9 (95%CI:-21.15,1.35); DBP -2.34 (95%CI:-7.92,3.06). From the limited available evidence, spironolactone appears to lower blood pressure compared to placebo to a similar degree in patients with primary (essential) hypertension when doses of 100-500 mg/day are given. A dose of 25 mg/day did not statistically significantly reduce systolic or diastolic blood pressure, compared to placebo. Given the lack of a dose-response, coupled with a possible increased risk in adverse events with higher doses, doses of 25 to 100 mg/day are reasonable. There is no evidence of the effect of spironolactone on clinical outcomes in hypertensive patients.

The aim of this review was to determine the extent to which spironolactone reduces blood pressure, the nature of spironolactone’s adverse effect profile, and to determine the clinical impact of its use for hypertension. The search revealed 5 cross-over trials with a total of 137 patients that received both spironolactone followed by placebo or vice verse, in a random order. One other trial was found that randomly gave 42 patients either spironolactone (22 patients) or placebo (20 patients). The daily doses of spironolactone used in these studies ranged from 25-500 mg daily. Studies followed patients for 4 to 8 weeks of therapy. None of the studies reported on the clinical impact of spironolactone (i.e. whether spironolactone reduced heart attacks or strokes compared to placebo). Overall reporting of adverse effects was poor so no conclusions can be drawn about the adverse effect profile. This meta-analysis shows that spironolactone reduces systolic/diastolic blood pressure by approximately 20/7 mm Hg compared to placebo.

10.1002/14651858.CD008169.pub2

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cochrane-simplification-train-265

The review included 26 cluster-randomised/quasi-randomised trials, covering a wide range of interventional packages, including two subsets from three trials. Assessment of risk of bias in these studies suggests concerns regarding insufficient information on sequence generation and regarding failure to adequately address incomplete outcome data, particularly from randomised controlled trials. We incorporated data from these trials using generic inverse variance method in which logarithms of risk ratio (RR) estimates were used along with the standard error of the logarithms of RR estimates. Our review showed a possible effect in terms of a reduction in maternal mortality (RR 0.80; 95% confidence interval (CI) 0.64 to 1.00, random-effects (11 studies, n = 167,311; random-effects, Tau² = 0.03, I² 20%). However, significant reduction was observed in maternal morbidity (average RR 0.75; 95% CI 0.61 to 0.92; four studies, n = 138,290; random-effects, Tau² = 0.02, I² = 28%); neonatal mortality (average RR 0.75; 95% CI 0.67 to 0.83; 21 studies, n = 302,646; random-effects, Tau² = 0.06, I² = 85%) including both early and late mortality; stillbirths (average RR 0.81; 95% CI 0.73 to 0.91; 15 studies, n = 201,181; random-effects, Tau² = 0.03, I² = 66%); and perinatal mortality (average RR 0.78; 95% CI 0.70 to 0.86; 17 studies, n = 282,327; random-effects Tau² = 0.04, I² = 88%) as a consequence of implementation of community-based interventional care packages. Community-based intervention packages also increased the uptake of tetanus immunisation by 5% (average RR 1.05; 95% CI 1.02 to 1.09; seven studies, n = 71,622; random-effects Tau² = 0.00, I² = 52%); use of clean delivery kits by 82% (average RR 1.82; 95% CI 1.10 to 3.02; four studies, n = 54,254; random-effects, Tau² = 0.23, I² = 90%); rates of institutional deliveries by 20% (average RR 1.20; 95% CI 1.04 to 1.39; 14 studies, n = 147,890; random-effects, Tau² = 0.05, I² = 80%); rates of early breastfeeding by 93% (average RR 1.93; 95% CI 1.55 to 2.39; 11 studies, n = 72,464; random-effects, Tau² = 0.14, I² = 98%), and healthcare seeking for neonatal morbidities by 42% (average RR 1.42; 95% CI 1.14 to 1.77, nine studies, n = 66,935, random-effects, Tau² = 0.09, I² = 92%). The review also showed a possible effect on increasing the uptake of iron/folic acid supplementation during pregnancy (average RR 1.47; 95% CI 0.99 to 2.17; six studies, n = 71,622; random-effects, Tau² = 0.26; I² = 99%). It has no impact on improving referrals for maternal morbidities, healthcare seeking for maternal morbidities, iron/folate supplementation, attendance of skilled birth attendance on delivery, and other neonatal care-related outcomes. We did not find studies that reported the impact of community-based intervention package on improving exclusive breastfeeding rates at six months of age. We assessed our primary outcomes for publication bias and observed slight asymmetry on the funnel plot for maternal mortality. Our review offers encouraging evidence that community-based intervention packages reduce morbidity for women, mortality and morbidity for babies, and improves care-related outcomes particularly in low- and middle-income countries. It has highlighted the value of integrating maternal and newborn care in community settings through a range of interventions, which can be packaged effectively for delivery through a range of community health workers and health promotion groups. While the importance of skilled delivery and facility-based services for maternal and newborn care cannot be denied, there is sufficient evidence to scale up community-based care through packages which can be delivered by a range of community-based workers.

The review authors found 26 randomised and quasi-randomised controlled studies evaluating the impact of community-based intervention packages for the prevention of maternal illness and death and in improving newborn health outcomes. These studies were mostly conducted in developing countries (India, Bangladesh, Pakistan, Nepal, China, Zambia, Malawi, Tanzania, South Africa, Ghana) with one additional study in Greece. Women in areas assigned to receive a community-based intervention package and with health workers receiving additional training had less illness and fewer complications during pregnancy and birth and there were fewer stillbirths, infant deaths around the time of birth and maternal ill-health. Community-based intervention packages were associated with improved uptake of tetanus immunisation, usage of clean delivery kits for home births and institutional deliveries. They also improved early initiation of breastfeeding and health-care seeking (by the mothers) for illnesses related to (their) babies. Whether these translate into improved newborn outcomes is unclear. This review highlights the value of integrating maternal and newborn care in community settings through a range of interventions which can be packaged effectively for delivery through a range of community health workers and health promotion groups. There is sufficient evidence to scale up community-based care through packages which can be delivered by a range of community-based workers. Most of the reviewed studies did not document the complete description and characteristics of the community health workers, especially the initial level of education and training, the level and amount of supervision provided, and the community ownership of these workers. This information would be of great relevance to policy and practice.

10.1002/14651858.CD007754.pub3

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cochrane-simplification-train-266

We found no new studies. This updated review therefore includes four studies with 278 participants. Most analyses were based on data from few participants and low-quality evidence, so our results should be interpreted with caution. Deliberate hypotension with propofol did not decrease TBL (millilitres) when compared with inhalation anaesthetics in either children (1 study; 70 participants; very low-quality evidence), or adults (1 study; 88 participants; moderate-quality evidence). Propofol improved the quality of the surgical field by less than one category on a scale from 0 (no bleeding) to 5 (severe bleeding) (mean difference -0.64, 95% CI -0.91 to -0.37; 4 studies; 277 participants; low-quality evidence), but no difference in operation time was reported (3 studies; 214 participants; low-quality evidence). Failure to lower blood pressure to target was less common in the propofol group (risk ratio of failure with propofol 0.24, 95% CI 0.09 to 0.66; 1 study; 88 participants; moderate-quality evidence). Using propofol to achieve deliberate hypotension probably improves the surgical field, but the effect is small. Deliberate hypotension with propofol did not decrease TBL and the operation time. However, due to the very low quality of the evidence, this conclusion is not definitive. Randomized controlled trials with good-quality methodology and large sample size are required to investigate the effectiveness of deliberate hypotension with propofol for FESS.

We included four studies in our review (278 participants). The studies were conducted between 2003 and 2010. Although all four included studies were randomized, some elements of their methodology suggest a low to unclear risk of bias in all trials. We found that propofol did not reduce measured overall blood loss in either children or adults (2 studies; 158 participants). Propofol might improve the quality of the surgical field a little (4 studies; 277 participants), but there was no difference in operation time (3 studies; 214 participants). Propofol was more reliable in achieving induced hypotension (1 study; 88 participants). No studies reported any adverse effects from induced hypotension with propofol. We found only four studies, which included a small total number of participants. The evidence from the studies were of moderate to very low quality, and therefore our results should be interpreted with caution. More studies are needed to confirm whether any important benefit is associated with the use of propofol.

10.1002/14651858.CD006623.pub3

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We included 10 trials, involving 847 participants. All studies examined CBT programmes provided to children or children and a non-offending parent. Control groups included wait list controls (n = 1) or treatment as usual (n = 9). Treatment as usual was, for the most part, supportive, unstructured psychotherapy. Generally the reporting of studies was poor. Only four studies were judged 'low risk of bias' with regards to sequence generation and only one study was judged 'low risk of bias' in relation to allocation concealment. All studies were judged 'high risk of bias' in relation to the blinding of outcome assessors or personnel; most studies did not report on these, or other issues of bias. Most studies reported results for study completers rather than for those recruited. Depression, post-traumatic stress disorder (PTSD), anxiety and child behaviour problems were the primary outcomes. Data suggest that CBT may have a positive impact on the sequelae of child sexual abuse, but most results were not statistically significant. Strongest evidence for positive effects of CBT appears to be in reducing PTSD and anxiety symptoms, but even in these areas effects tend to be 'moderate' at best. Meta-analysis of data from five studies suggested an average decrease of 1.9 points on the Child Depression Inventory immediately after intervention (95% confidence interval (CI) decrease of 4.0 to increase of 0.4; I2 = 53%; P value for heterogeneity = 0.08), representing a small to moderate effect size. Data from six studies yielded an average decrease of 0.44 standard deviations on a variety of child post-traumatic stress disorder scales (95% CI 0.16 to 0.73; I2 = 46%; P value for heterogeneity = 0.10). Combined data from five studies yielded an average decrease of 0.23 standard deviations on various child anxiety scales (95% CI 0.3 to 0.4; I2 = 0%; P value for heterogeneity = 0.84). No study reported adverse effects. The conclusions of this updated review remain the same as those when it was first published. The review confirms the potential of CBT to address the adverse consequences of child sexual abuse, but highlights the limitations of the evidence base and the need for more carefully conducted and better reported trials.

This review aimed to find out if cognitive-behavioural approaches (CBT) help reduce the negative impact of sexual abuse on children. Ten studies, in which a total of 847 children participated, met the inclusion criteria for the review. The reporting of studies was poor, and there appear to be significant weaknesses in study quality. The evidence suggests that CBT may have a positive impact on the effects of child sexual abuse, including depression, post-traumatic stress and anxiety, but the results were generally modest. Implications for practice and further research are noted.

10.1002/14651858.CD001930.pub3

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cochrane-simplification-train-268

Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias. We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo. Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference. When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference. The identified studies comprehensively address the objectives of the present review. Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants. The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review. Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes. Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.

We found evidence showing that antidepressants are better than placebo in terms of effectiveness and number of people leaving the study early. However, our findings also showed that antidepressants are less well tolerated than placebo, producing more dropouts due to adverse effects. Results are limited in the following ways: some studies were funded by pharmaceutical companies, and only short-term outcomes were assessed. We found almost no data on other clinically relevant outcomes, such as functioning and quality of life. The quality of the available evidence ranged from very low to high. Studies with outcomes assessed at longer-term follow-up visits should be carried out to establish whether the effect is transient or maintained. Trials should better report any harms experienced by participants during the trial. In addition, a further analysis with an approach called 'network meta-analysis' will include all psychopharmacological treatments available for panic disorder, and will likely shed further light on this compelling issue, also being able to provide more information with regard to comparative efficacy of different available interventions.

10.1002/14651858.CD010676.pub2

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We found 12 eligible studies (1149 participants). In four studies, renal denervation was compared to sham procedure; one study compared a proximal ablation to a complete renal artery denervation; in the remaining, renal denervation was tested against standard or intensified antihypertensive therapy. None of the included trials was designed to look at hard clinical end points as primary outcomes. When compared to control, there was low quality evidence that renal denervation did not reduce the risk of myocardial infarction (4 studies, 742 participants; RR 1.31, 95% CI 0.45 to 3.84), ischaemic stroke (4 studies, 823 participants; RR 1.15, 95% CI 0.36 to 3.72), or unstable angina (2 studies, 201 participants; RR 0.63, 95% CI 0.08 to 5.06), and moderate quality evidence that it had no effect on 24-hour ambulatory blood pressure monitoring (ABPM) systolic BP (5 studies, 797 participants; MD 0.28 mmHg, 95% CI -3.74 to 4.29), diastolic BP (4 studies, 756 participants; MD 0.93 mmHg, 95% CI -4.50 to 6.36), office measured systolic BP (6 studies, 886 participants; MD -4.08 mmHg, 95% CI -15.26 to 7.11), or diastolic BP (5 studies, 845 participants; MD -1.30 mmHg, 95% CI -7.30 to 4.69). Furthermore, low quality evidence suggested that this procedure produced no effect on either serum creatinine (3 studies, 736 participants, MD 0.01 mg/dL; 95% CI -0.12 to 0.14), estimated glomerular filtration rate (eGFR), or creatinine clearance (4 studies, 837 participants; MD -2.09 mL/min, 95% CI -8.12 to 3.95). Based on low-quality evidence, renal denervation significantly increased bradycardia episodes compared to control (3 studies, 220 participants; RR 6.63, 95% CI 1.19 to 36.84), while the risk of other adverse events was comparable or not assessable. Data were sparse or absent for all cause mortality, hospitalisation, fatal cardiovascular events, quality of life, atrial fibrillation episodes, left ventricular hypertrophy, sleep apnoea severity, need for renal replacement therapy, and metabolic profile. The quality of the evidence was low for cardiovascular outcomes and adverse events and moderate for lack of effect on blood pressure and renal function. In patients with resistant hypertension, there is low quality evidence that renal denervation does not change major cardiovascular events, and renal function. There was moderate quality evidence that it does not change blood pressure and and low quality evidence that it caused an increaseof bradycardia episodes. Future trials measuring patient-centred instead of surrogate outcomes, with longer follow-up periods, larger sample size and more standardized procedural methods are necessary to clarify the utility of this procedure in this population.

Twelve studies of variable quality were identified that included a total of 1149 participants. There was high heterogeneity among studies for design, methods, and blinding of investigators. Most of the studies assessed the impact of renal denervation on surrogate (e.g. blood pressure control), rather than patient-centred outcomes (e.g. mortality or quality of life). Overall, there was no evidence of benefits of renal denervation over standard treatment on cardiovascular morbidity and mortality. Similarly, renal denervation had no tangible effects on blood pressure control and renal function. However, it was associated with an increased risk of episodes of bradycardia (very slow heart rate). The quality of the evidence was low for cardiovascular morbidity and adverse events and moderate for lack of effect on blood pressure and renal function. The evidence is current to 17 February 2016. Current evidence is inconclusive to support the use of renal denervation to improve cardiovascular and renal risk and blood pressure control in patients with resistant hypertension. Future studies targeting patient-centred outcomes, with longer duration and larger number of participants are needed to identify whether individuals can benefit from this procedure.

10.1002/14651858.CD011499.pub2

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cochrane-simplification-train-270

Of the 1233 patients enrolled in nine identified trials, 622 were treated with staples and 611 with manual suture. The following main results were obtained. a) Mortality, result based on 901 patients: RD -0.6%, 95% CI -2.8% to +1.6%. b) Overall dehiscence, result based on 1233 patients: RD 0.2%, 95% CI -5.0% to +5.3%. c) Clinical anastomotic dehiscence, result based on 1233 patients: RD -1.4%, 95% CI -5.2 to +2.3%. d) Radiological anastomotic dehiscence, result based on 825 patients: RD 1.2%, 95% CI -4.8% to +7.3%. e) Stricture, result based on 1042 patients: RD 4.6%, 95% CI 1.2% to 8.1%; NNT 17, 95% CI 12 to 31. f) Anastomotic haemorrhage, result based on 662 patients: RD 2.7%, 95% CI -0.1% to +5.5%. g) Reoperation, result based on 544 patients: RD 3.9%, 95% CI 0.3% to 7.4%. h) Wound infection, result based on 567 patients: RD 1.0%, 95% CI -2.2% to +4.3%. i) Anastomosis duration, result based on one study (159 patients): WMD -7.6 minutes, 95% CI -12.9 to -2.2 minutes. j) Hospital stay, result based on one study (159 patients): WMD 2.0 days, 95% CI -3.27 to +7.2 days. The evidence found was insufficient to demonstrate any superiority of stapled over handsewn techniques in colorectal anastomosis surgery, regardless of the level of anastomosis. There were no randomised clinical trials comparing these two types of anastomosis in elective conditions in the last decade. The relevance of this research question has possibly lost its strength where elective surgery is concerned. However, in risk situations, such as emergency surgery, trauma and inflammatory bowel disease, new clinical trials are needed.

The review with nine randomised controlled trials (1233 patients, 622 with stapling and 611 with the handsewing technique) compared the safety and effectiveness of stapled versus handsewn colorectal anastomosis surgery. Meta-analysis was performed using the risk difference and weighted mean difference, with corresponding 95% confidence intervals. Outcome measures were mortality, anastomotic dehiscence, narrowing (stricture), haemorrhage, need for reoperation, wound infection, anastomosis duration (time taken to perform the anastomosis) and hospital stay. No significant statistical differences were found except that stricture was more frequent with stapling (P < 0.05) and the time taken to perform the anastomosis was longer with handsewn techniques.

10.1002/14651858.CD003144.pub2

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We included five studies (446 participants) in this review. Meta analysis of three studies comparing hydrogel dressings with basic wound contract dressings found significantly greater healing with hydrogel: risk ratio (RR) 1.80, 95% confidence interval (CI) 1.27 to 2.56. The three pooled studies had different follow-up times (12 weeks, 16 weeks and 20 weeks) and also evaluated ulcers of different severities (grade 3 and 4; grade 2 and grade unspecified). One study compared a hydrogel dressing with larval therapy and found no statistically significant difference in the number of ulcers healed and another found no statistically significant difference in healing between hydrogel and platelet-derived growth factor. There was also no statistically significant difference in number of healed ulcers between two different brands of hydrogel dressing. All included studies were small and at unclear risk of bias and there was some clinical heterogeneity with studies including different ulcer grades. No included studies compared hydrogel with other advanced wound dressings. There is some evidence to suggest that hydrogel dressings are more effective in healing (lower grade) diabetic foot ulcers than basic wound contact dressings however this finding is uncertain due to risk of bias in the original studies. There is currently no research evidence to suggest that hydrogel is more effective than larval therapy or platelet-derived growth factors in healing diabetic foot ulcers, nor that one brand of hydrogel is more effective than another in ulcer healing. No RCTs comparing hydrogel dressings with other advanced dressing types were found.

This review (five studies involving a total of 446 people) suggests that hydrogel dressings may be more effective than basic wound contact dressings in healing foot ulcers in people with diabetes although the original research may be biased. There is insufficient research comparing hydrogel with advanced dressing types to allow conclusions to be drawn regarding relative effectiveness in terms of ulcer healing.

10.1002/14651858.CD009101.pub3

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We included 20 studies of people with suspected rotator cuff tears (1147 shoulders), of which six evaluated MRI and US (252 shoulders), or MRA and US (127 shoulders) in the same people. Many studies had design flaws, with the potential for bias, thus limiting the reliability of their findings. Overall, the methodological quality of the studies was judged to be low or unclear. For each test, we observed considerable heterogeneity in study results, especially between studies that evaluated US for the detection of full thickness tears and studies that evaluated MRA for the detection of partial thickness tears. The criteria for a positive diagnostic test (index tests and reference standard) varied between studies. Meta-analyses were not possible for studies that assessed MRA for detection of any rotator cuff tears or partial thickness tears. We found no statistically significant differences in sensitivity or specificity between MRI and US for detecting any rotator cuff tears (P = 0.13), or for detecting partial thickness tears (P = 1.0). Similarly, for the comparison between MRI, MRA and US for detecting full thickness tears, there was no statistically significant difference in diagnostic performance (P = 0.7). For any rotator cuff tears, the summary sensitivity and specificity were 98% (95% CI 92% to 99%) and 79% (95% CI 68% to 87%) respectively for MRI (6 studies, 347 shoulders), and 91% (95% CI 83% to 95%) and 85% (95% CI 74% to 92%) respectively for US (13 studies, 854 shoulders). For full thickness tears, the summary sensitivity and specificity were 94% (95% CI 85% to 98%) and 93% (95% CI 83% to 97%) respectively for MRI (7 studies, 368 shoulders); 94% (95% CI 80% to 98%) and 92% (95% CI 83% to 97%) respectively for MRA (3 studies, 183 shoulders); and 92% (95% CI 82% to 96%) and 93% (95% CI 81% to 97%) respectively for US (10 studies, 729 shoulders). Because few studies were direct head-to-head comparisons, we could not perform meta-analyses restricted to these studies. The test comparisons for each of the three classifications of the target condition were therefore based on indirect comparisons which may be prone to bias due to confounding. MRI, MRA and US have good diagnostic accuracy and any of these tests could equally be used for detection of full thickness tears in people with shoulder pain for whom surgery is being considered. The diagnostic performance of MRI and US may be similar for detection of any rotator cuff tears. However, both MRI and US may have poor sensitivity for detecting partial thickness tears, and the sensitivity of US may be much lower than that of MRI. The strength of evidence for all test comparisons is limited because most studies were small, heterogeneous and methodologically flawed, and there were few comparative studies. Well designed studies that directly compare MRI, MRA and US for detection of rotator cuff tears are needed.

We searched electronic databases up to February 2011, as well as trial registers, conference proceedings and reference lists of articles, for studies comparing diagnostic tests for people with suspected rotator cuff tears. Our review included 20 studies (1147 shoulders). Many studies had design flaws, which limited the reliability of their findings. We found that MRI, MRA and US may have similar accuracy for detecting the presence of full thickness tears. For identifying any tears (no distinction between partial or full thickness) or identifying partial thickness tears, MRI and US may also have similar accuracy. However, it appears that compared with US, MRI may be more sensitive in identifying partial thickness tears. With these results we can conclude that all three imaging tests (MRI, MRA and US) may help decisions regarding referral for surgery for people with suspected full thickness tears. Information on adverse effects of using these tests was not reported by the included studies.

10.1002/14651858.CD009020.pub2

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Ten included studies (11 publications) enrolled 480 participants with trigeminal neuralgia, diabetic neuropathy, and post stroke pain. Nine studies used a cross-over design, and one a parallel group design. Most of the studies were of short duration, lasting four weeks or less. No study provided first or second tier evidence for an efficacy outcome. Using third tier evidence, carbamazepine generally provided better pain relief than placebo in the three conditions studied, with some indication of pain improvement over mainly the short term, but with poorly defined outcomes, incomplete reporting, and in small numbers of participants. There were too few data in studies comparing carbamazepine with active comparators to draw any conclusions. In four studies 65% (113/173) of participants experienced at least one adverse event with carbamazepine, and 27% (47/173) with placebo; for every five participants treated, two experienced an adverse event who would not have done so with placebo. In eight studies 3% (8/268) of participants withdrew due to adverse events with carbamazepine, and none (0/255) with placebo. Serious adverse events were not reported consistently; rashes were associated with carbamazepine. Four deaths occurred in patients on carbamazepine, with no obvious drug association. Carbamazepine is probably effective in some people with chronic neuropathic pain, but with caveats. No trial was longer than four weeks, had good reporting quality, nor used outcomes equivalent to substantial clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Carbamazepine was developed to treat epilepsy, but it is now used to treat various forms of chronic pain. We performed searches (up to February 2014) to look for clinical trials where carbamazepine was used to treat neuropathic pain or fibromyalgia. We found 10 studies involving 418 people involved in testing carbamazepine. Studies were not generally of very good quality. Most were very small, as well as of short duration. Studies lasting only one or two weeks are unhelpful when pain can last for years. There was not enough good quality evidence to say how well carbamazepine worked in any neuropathic pain condition. Pooling four small studies showed that it was better than placebo, but the result cannot be relied upon. There was not enough information from these studies to make any reliable comment on adverse events or harm. Carbamazepine is probably helpful for some people with chronic neuropathic pain. It is not possible to know beforehand who will benefit and who will not.

10.1002/14651858.CD005451.pub3

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We included eight randomised controlled trials with 1699 participants across three comparisons. This abstract focuses on the primary outcomes of this review only. Scheduled phosphodiesterase type 5 inhibitors (PDE5I) versus placebo or no treatment Scheduled PDE5I may have little or no effect on short-term (up to 12 months) self-reported potency (risk ratio (RR) 1.13, 95% confidence interval (CI) 0.91 to1.41; very low quality evidence), which corresponds to 47 more men with self-reported potency per 1000 (95% CI 33 fewer to 149 more) and short-term erectile function as assessed by a validated instrument (RR 1.11, 95% CI 0.80 to 1.55; very low quality evidence), which corresponds to 28 more men per 1000 (95% CI 50 fewer to 138 more), but we are very uncertain of both of these findings. Scheduled PDE5I may result in fewer serious adverse events compared to placebo (RR 0.32, 95% CI 0.11 to 0.94; low quality evidence), though this does not appear biologically plausible and may represent a chance finding. We are also very uncertain of this finding. We found no long-term (longer than 12 months) data for any of the three primary outcomes. Scheduled PDE5I versus on-demand PDE5I Daily PDE5I appears to result in little to no difference in both short-term and long-term (greater than 12 months) self-reported potency (short term: RR 0.97, 95% CI 0.62 to 1.53; long term: RR 1.00, 95% CI 0.60 to 1.67; both very low quality evidence); this corresponds to nine fewer men with self-reported short-term potency per 1000 (95% CI 119 fewer to 166 more) and zero fewer men with self-reported long-term potency per 1000 (95% CI 153 fewer to 257 more). We are very uncertain of these findings. Daily PDE5I appears to result in little to no difference in short-term and long-term erectile function (short term: RR 1.00, 95% CI 0.65 to 1.55; long term; RR 0.74, 95% CI 0.48 to 1.14; both very-low quality evidence), which corresponds to zero men with short-term erectile dysfunction per 1000 (95% CI 80 fewer to 125 more) and 119 fewer men with long-term erectile dysfunction per 1000 (95% CI 239 fewer to 64 more). We are very uncertain of these findings. Scheduled PDE5I may result in little or no effects on short-term adverse events (RR 0.69 95% CI 0.12 to 4.04; very low quality evidence), which corresponds to seven fewer men with short-term serious adverse events (95% CI 18 fewer to 64 more), but we are very uncertain of these findings. We found no long-term data for serious adverse events. Scheduled PDE5I versus scheduled intraurethral prostaglandin E1 At short-term follow-up, daily PDE5I may result in little or no effect on self-reported potency (RR 1.10, 95% CI 0.79, to 1.52; very low quality evidence), which corresponds to 46 more men per 1000 (95% CI 97 fewer to 241 more). Daily PDE5I may result in a small improvement of erectile function (RR 1.64, 95% CI 0.84 to 3.20; very low quality evidence), which corresponds to 92 more men per 1000 (95% CI 23 fewer to 318 more) but we are very uncertain of both these findings. We found no long-term (longer than 12 months) data for any of the three primary outcomes. We found no evidence for any other comparisons and were unable to perform any of the preplanned subgroup analyses based on nerve-sparing approach, age or baseline erectile function. Based on mostly very-low and some low-quality evidence, penile rehabilitation strategies consisting of scheduled PDE5I use following radical prostatectomy may not promote self-reported potency and erectile function any more than on demand use.

We included eight randomised studies (clinical studies where people are randomly put into one of two or more treatment groups) with 1699 participants. Five trials compared the scheduled use of phosphodiesterase inhibitors (a type of medicine) to either no treatment or a placebo (a pretend drug with no effect). Two studies compared the use of phosphodiesterase inhibitors either as a daily prescription or as needed. One study compared the daily use of either a phosphodiesterase inhibitor or a medicine called prostaglandin E1 that is placed into the tip of the penis like a suppository. The main outcomes of this review that we felt were most important to men were how good they thought their erections were (self-reported potency), how good their erections were based on a specialised erection questionnaire (quality of erections) and any whether there were any major unwanted side effects. We found that the men who used these medicines on a scheduled basis may have had similar self-reported erections and quality of erections (based on questionnaires they filled out) as men who took no medication regularly or use it as needed. They also had similar rates of serious unwanted side effects and similar rates of stopping the drug before the end of the treatment duration. However, we are very uncertain of these findings. We were unable to research whether these results would be different in different groups of men based on whether the surgeon tried to preserve the nerves that help with erections or not, based on men's age and how good their erections were beforehand because we found no studies. The quality of evidence was very low for most main outcomes. That means we are very uncertain of the results of this review. Further research will likely change these findings.

10.1002/14651858.CD012414.pub2

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cochrane-simplification-train-275

We included four studies with 149 randomized participants. We identified two studies awaiting classification for which we were unable to assess eligibility and one ongoing study. Participants differed in severity of illness as assessed by APACHE II scores in three studies and further differences existed between comparisons and methods. One study compared propofol versus no agent, one study compared different doses of propofol and two studies compared propofol versus a benzodiazepine (flunitrazepam, one study; midazolam, one study). All studies reported randomization and allocation concealment inadequately. We judged all studies to have high risk of performance bias from personnel who were unblinded. We noted that some study authors had blinded study outcome assessors and participants for relevant outcomes. It was not appropriate to combine data owing to high levels of methodological heterogeneity. One study comparing propofol with no agent (13 participants) measured quantity and quality of sleep using polysomnography; study authors reported no evidence of a difference in duration of sleep or sleep efficiency, and reported disruption to usual REM (rapid eye movement sleep) with propofol. One study comparing different doses of propofol (30 participants) measured quantity and quality of sleep by personnel using the Ramsay Sedation Scale; study authors reported that more participants who were given a higher dose of propofol had a successful diurnal rhythm, and achieved a greater sedation rhythmicity. Two studies comparing propofol with a different agent (106 participants) measured quantity and quality of sleep using the Pittsburgh Sleep Diary and the Hospital Anxiety and Depression Scale; one study reported fewer awakenings of reduced duration with propofol, and similar total sleep time between groups, and one study reported no evidence of a difference in sleep quality. One study comparing propofol with another agent (66 participants) measured quantity and quality of sleep with the Bispectral Index and reported longer time in deep sleep, with fewer arousals. One study comparing propofol with another agent (40 participants) reported higher levels of anxiety and depression in both groups, and no evidence of a difference when participants were given propofol. No studies reported adverse events. We used the GRADE approach to downgrade the certainty of the evidence for each outcome to very low. We identified sparse data with few participants, and methodological differences in study designs and comparative agents introduced inconsistency, and we noted that measurement tools were imprecise or not valid for purpose. We found insufficient evidence to determine whether administration of propofol would improve the quality and quantity of sleep in adults in the ICU. We noted differences in study designs, methodology, comparative agents and illness severity amongst study participants. We did not pool data and we used the GRADE approach to downgrade the certainty of our evidence to very low.

The evidence is current to October 2017. We included four randomized controlled studies (clinical studies where people are randomly put into one of two or more treatment groups) with 149 participants in the review. Two studies are awaiting classification (because we could not assess their eligibility) and one study is ongoing. All participants were critically ill and were in the ICU. We did not combine the results from the studies because of differences in comparison (called control) treatments and study design. One study compared propofol with no agent. This study used polysomnography (which records brain waves, oxygen level in blood, heart rate, breathing, and eye and leg movements) to measure sleep quality and quantity. It reported no improvement in duration of sleep with propofol but participants woke up less often and for shorter lengths of time and described their sleep quality as being improved with propofol. One study compared a higher dose of propofol at night described as additional night sedation, with a constant day-time and night-time dose. This study used the Ramsay Sedation Scale (which is normally used by anaesthetists to assess how easily a person is roused) and reported that participants appeared to have an improved sleep rhythm. Two studies compared propofol with benzodiazepines (a tranquilizing medicine; flunitrazepam in one study and midazolam in one study). These studies used the Pittsburgh Sleep Diary and the Hospital Anxiety and Depression Scale to measure quantity and quality of sleep. The study with flunitrazepam reported fewer awakenings of reduced duration with propofol but similar total sleep time in each group and the study with midazolam reported no difference in sleep quality. The study with flunitrazepam also measured sleep with Bispectral Index (used by anaesthetists to assess depth of anaesthesia) and reported longer time in deep sleep, with fewer awakenings. The study with midazolam reported higher levels of anxiety and depression in both groups, and no difference when participants were given propofol. No study reported on side effects. We judged the evidence to be very low quality. We found only four small randomized controlled studies and the results of the studies were not consistent. We noted differences in illness severity of participants and the medicines that were compared with propofol in the included studies. Measuring quality of sleep using diaries, questionnaires and scoring systems is based on, or is influenced by, personal feelings or opinions, and we were concerned that staff and participants were aware which medicine they had been given; we believed that this could have influenced the results. Only one study used polysomnography, which is the most appropriate unbiased measurement tool for sleep. We were unable to collect sufficient evidence to determine whether propofol given at night to adults in the ICU improves quality and quantity of their sleep, as a way of helping recovery.

10.1002/14651858.CD012454.pub2

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Seven pralidoxime RCTs were found. Three RCTs including 366 patients studied pralidoxime vs placebo and four RCTs including 479 patients compared two or more different doses. These trials found quite disparate results with treatment effects ranging from benefit to harm. However, many studies did not take into account several issues important for outcomes. In particular, baseline characteristics were not balanced, oxime doses varied widely, there were substantial delays to treatment, and the type of organophosphate was not taken into account. Only one RCT compared the World Health Organization (WHO) recommended doses with placebo. This trial showed no clinical benefits and a trend towards harm in all sub-groups, despite clear evidence that these doses reactivated acetylcholinesterase in the blood. Current evidence is insufficient to indicate whether oximes are harmful or beneficial. The WHO recommended regimen (30 mg/kg pralidoxime chloride bolus followed by 8 mg/kg/hr infusion) is not supported. Further RCTs are required to examine other strategies and regimens. There are many theoretical and practical reasons why oximes may not be useful, particularly for late presentations of dimethyl OP and those with a large excess of OP that simply re-inhibits reactivated enzymes. Future studies should screen for patient sub-groups that may benefit and may need flexible dosing strategies as clinical effectiveness and doses may depend on the type of OP.

Many of the studies had substantial limitations. Generally, the studies done to date do not support the routine use of oximes, however, they cannot exclude that there would be some doses or situations where a benefit would occur. The reviewers found that not enough research has been done to see whether oximes are actually effective or to define the doses that are more likely to be helpful. More research is needed before any firm conclusions can be drawn.

10.1002/14651858.CD005085.pub2

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cochrane-simplification-train-277

Ten trials involving 617 patients satisfied the inclusion criteria. The interventions included low central venous pressure (CVP), autologous blood donation, haemodilution, haemodilution with controlled hypotension, and hypoventilation. Only one or two trials were included under most comparisons. All trials had a high risk of bias. There was no significant difference in the peri-operative mortality in any of the comparisons: low CVP versus no intervention (3 trials, 0/88 (0%) patients in the low CVP group versus 1/89 (1.1%) patients in the no intervention group); autologous blood donation versus no intervention (1 trial, 0/40 (0%) versus 0/39 (0%)); haemodilution versus no intervention (2 trials, 1/73 (1.4%) versus 3/77 (3.9%) in one of these trials); haemodilution with controlled hypotension versus no intervention (1 trial, 0/10 (0%) versus 0/10 (0%)); haemodilution with bovine haemoglobin (HBOC-201) versus haemodilution with hydroxy ethyl starch (HES) (1 trial, 1/6 (16.7%) versus 0/6 (0%)); hypoventilation versus no intervention (1 trial, 0/40 (0%) versus 0/39 (0%)). None of the trials reported long-term survival or quality of life. The risk ratio of requiring allogeneic blood transfusion was significantly lower in the haemodilution versus no intervention groups (3 trials, 16/115 (weighted proportion = 14.2%) versus 41/118 (34.7%), RR 0.41 (95% CI 0.25 to 0.66), P = 0.0003); and for haemodilution with controlled hypotension versus no intervention (1 trial, 0/10 (0%) versus 10/10 (100%), P < 0.0001). There were no significant differences in the allogeneic transfusion requirements in the other comparisons which reported this outcome, such as low CVP versus no intervention, autologous blood donation versus control, and hypoventilation versus no intervention. None of the interventions seemed to decrease peri-operative morbidity or offer any long-term survival benefit. Haemodilution shows promise in the reduction of blood transfusion requirements in liver resection surgery. However, there is a high risk of type I (erroneously concluding that an intervention is beneficial when it is actually not beneficial) and type II errors (erroneously concluding that an intervention is not beneficial when it is actually beneficial) because of the few trials included, the small sample size in each trial, and the high risk of bias in the trials. Further randomised clinical trials with low risk of bias and random errors that assess clinically important outcomes such as peri-operative mortality are necessary to assess any cardiopulmonary interventions aimed at decreasing blood loss and blood transfusion requirements in patients undergoing liver resections. Trials need to be designed to assess the effect of a combination of different interventions in liver resections.

This systematic review was aimed at determining whether any cardiopulmonary intervention (interventions that change the circulation or breathing during surgery) decreased blood loss or decreased allogeneic blood transfusion requirements in patients undergoing liver resections. This review included 10 trials with 617 patients. All trials had high risk of bias (with the possibility of overestimating the benefits and underestimating the harms of the treatment) and play of chance ('random error'). The interventions included low central venous pressure (CVP; lowering the pressure in the major veins), autologous blood donation (using the patient's own blood obtained prior to liver resection), haemodilution (replacing blood with other fluids), haemodilution with controlled hypotension (lowering the blood pressure in addition to diluting the blood), and hypoventilation (decreasing the rate of artificial breathing). They were compared with controls not receiving the interventions. There were no differences in the number of deaths or complications due to surgery in any of the comparisons. Long-term survival was not reported in any of the trials. Fewer patients required transfusion of blood donated by others when haemodilution or haemodilution with controlled hypotension were compared with a control group. The other comparisons did not decrease the transfusion requirements. However, there is a high risk of type I errors (erroneously concluding that an intervention is beneficial when it is actually not beneficial) and type II errors (erroneously concluding that an intervention is not beneficial when it is actually beneficial) because of the few trials included and the small sample size in each trial, as well as the inherent risk of bias (systematic errors which can result in overestimation of the benefits and underestimation of the harms of the intervention). Haemodilution showed promise in the reduction of blood transfusion requirements in patients undergoing liver resections. Further randomised clinical trials with low risk of bias (systematic errors) and low risk of play of chance (random errors) which assess clinically important outcomes (such as death and complications due to the operation) are necessary to assess cardiopulmonary interventions aimed at decreasing blood loss in liver resections. Trials need to be designed to assess the effect of a combination of different interventions during liver resections.

10.1002/14651858.CD007338.pub3

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cochrane-simplification-train-278

Twelve trials involving 1283 participants wereincluded; 1226 participants were used in the analysis (724 in the early refeeding group and 502 in the late refeeding group). Nine trials described their allocation sequence, but only two used concealed allocation. One trial reported single-blinding but did not clearly identify the person who was blinded. Early refeeding meant intake during or immediately after start of rehydration, while late refeeding meant intake only 20 hours to 48 hours after start of rehydration. Significant heterogeneity was noted in the data for the duration of diarrhoea. There was no significant difference between the two refeeding groups in the number of participants who needed unscheduled intravenous fluids (six trials with 813 participants), who experienced episodes of vomiting (five trials with 466 participants), and who developed persistent diarrhoea (four trials with 522 participants). The mean length of hospital stay was also similar (two trials with 246 participants). There was no evidence that early refeeding increases the risk of unscheduled intravenous fluid use, episodes of vomiting, and development of persistent diarrhoea. No conclusion could be made regarding the duration of diarrhoea.

The authors identified 12 trials that met their inclusion criteria, with a total of 1283 children under 5 years; of these, 1226 were used in the analysis (724 given early refeeding; 502 given late refeeding). There was no significant difference between the two refeeding groups in the number of participants who needed unscheduled intravenous fluids (813 participants, 6 trials), who experienced episodes of vomiting (466 participants, 5 trials), and who developed persistent diarrhoea i.e. greater than 14 days in duration (522 participants, 4 trials). The mean length of hospital stay was also similar (246 participants, 2 trials).There is therefore no evidence to suggest that early refeeding increases the risk of complications after acute diarrhoea such as the need for IV fluids, or increases the risk of developing persistent diarrhoea. Further studies are needed to fully examine other parameters such as duration of diarrhoea, and effect on weight gain.

10.1002/14651858.CD007296.pub2

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We included three small RCTs enrolling 79 participants. Two trials did not use a placebo in the control arms and the third trial used air placebo. Two included studies reported no mortality. We judged all three of the included studies to be at low risk or unclear risk across all risk of bias categories; we did not judge any of the studies to be at high risk of bias in any category. Our pooled analysis of the three trials revealed that duration of mechanical ventilation was not significantly different between the groups (mean difference (MD) -63.04, 95% confidence interval (CI) -130.43 to 4.35 hours) but duration of intensive care unit (ICU) stay was less in the surfactant group compared to the control group: MD -3.31, 95% CI -6.38 to -0.25 days. After excluding one trial which produced significant heterogeneity, the duration of mechanical ventilation and duration of ICU stay were significantly lower in the surfactant group compared to the control group: MD -28.99, 95% CI -40.10 to -17.87 hours; and MD -1.81, 95% CI -2.42 to -1.19 days, respectively. Use of surfactant had favourable effects on oxygenation and CO2 elimination. No adverse effects and no complications were observed in any of the three included studies. The level of evidence for duration of mechanical ventilation, duration of intensive care unit stay, oxygenation parameters, and carbon dioxide parameters was of moderate quality. Use of surfactant had favourable effects on duration of mechanical ventilation, duration of ICU stay, oxygenation, and CO2 elimination. However, the studies are few and small (n = 79) so available evidence is insufficient to establish the effectiveness of surfactant therapy for bronchiolitis in critically ill infants who require mechanical ventilation. There is a need for larger trials with adequate power and a cost-effectiveness analysis to evaluate the effectiveness of exogenous surfactant therapy for infants with bronchiolitis who require intensive care management.

The evidence is current to June 2015. Three small randomised controlled trials (RCTs) enrolling 79 participants were included in the review. All studies included children younger than 2.5 years with a diagnosis of bronchiolitis who required mechanical ventilation. Two studies did not include a placebo (a substance having no active effect) for comparison. None of the included studies provided a source of funding. Two included studies reported no mortality. Use of surfactant for mechanically ventilated infants and children with bronchiolitis did not decrease the duration of mechanical ventilation. However, the intervention decreased duration of stay in the intensive care unit and had favourable effects on oxygenation and carbon dioxide removal. No complications were observed in any of the three included studies. The level of evidence for duration of mechanical ventilation, duration of intensive care unit stay, oxygenation parameters, and carbon dioxide parameters was of moderate quality. The limited number of studies with small numbers of participants was the reason for moderate quality, and are limitations of this review. There is a need for larger trials to establish any benefits of surfactant for bronchiolitis in critically ill infants and children.

10.1002/14651858.CD009194.pub3

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A total of 16 studies were included. All studies reported on TAUS and EUS as separate tests and not as a combination of tests. All studies were at high or unclear risk of bias, ten studies had high applicability concerns in participant selection (because of inappropriate participant exclusions) or reference standards (because of lack of follow-up for non-operated polyps), and three studies had unclear applicability concerns in participant selection (because of high prevalence of gallbladder polyps) or index tests (because of lack of details on ultrasound equipment and performance). A meta-analysis directly comparing results of TAUS and EUS in the same population could not be performed because only limited studies executed both tests in the same participants. Therefore, the results below were obtained only from indirect test comparisons. There was significant heterogeneity amongst all comparisons (target conditions) on TAUS and amongst studies on EUS for differentiating true and pseudo polyps. Detection of gallbladder polyps: Six studies (16,260 participants) used TAUS. We found no studies on EUS. The summary sensitivity and specificity of TAUS for the detection of gallbladder polyps was 0.84 (95% CI 0.59 to 0.95) and 0.96 (95% CI 0.92 to 0.98), respectively. In a cohort of 1000 people, with a 6.4% prevalence of gallbladder polyps, this would result in 37 overdiagnosed and seven missed gallbladder polyps. Differentiation between true polyp and pseudo gallbladder polyp: Six studies (1078 participants) used TAUS; the summary sensitivity was 0.68 (95% CI 0.44 to 0.85) and the summary specificity was 0.79 (95% CI 0.57 to 0.91). Three studies (209 participants) used EUS; the summary sensitivity was 0.85 (95% CI 0.46 to 0.97) and the summary specificity was 0.90 (95% CI 0.78 to 0.96). In a cohort of 1000 participants with gallbladder polyps, with 10% having true polyps, this would result in 189 overdiagnosed and 32 missed true polyps by TAUS, and 90 overdiagnosed and 15 missed true polyps by EUS. There was no evidence of a difference between the diagnostic accuracy of TAUS and EUS (relative sensitivity 1.06, P = 0.70, relative specificity 1.15, P = 0.12). Differentiation between dysplastic polyps/carcinomas and adenomas/pseudo polyps of the gallbladder: Four studies (1,009 participants) used TAUS; the summary sensitivity was 0.79 (95% CI 0.62 to 0.90) and the summary specificity was 0.89 (95% CI 0.68 to 0.97). Three studies (351 participants) used EUS; the summary sensitivity was 0.86 (95% CI 0.76 to 0.92) and the summary specificity was 0.92 (95% CI 0.85 to 0.95). In a cohort of 1000 participants with gallbladder polyps, with 5% having a dysplastic polyp/carcinoma, this would result in 105 overdiagnosed and 11 missed dysplastic polyps/carcinomas by TAUS and 76 overdiagnosed and seven missed dysplastic polyps/carcinomas by EUS. There was no evidence of a difference between the diagnostic accuracy of TAUS and EUS (log likelihood test P = 0.74). Although TAUS seems quite good at discriminating between gallbladder polyps and no polyps, it is less accurate in detecting whether the polyp is a true or pseudo polyp and dysplastic polyp/carcinoma or adenoma/pseudo polyp. In practice, this would lead to both unnecessary surgeries for pseudo polyps and missed cases of true polyps, dysplastic polyps, and carcinomas. There was insufficient evidence that EUS is better compared to TAUS in differentiating between true and pseudo polyps and between dysplastic polyps/carcinomas and adenomas/pseudo polyps. The conclusions are based on heterogeneous studies with unclear criteria for diagnosis of the target conditions and studies at high or unclear risk of bias. Therefore, results should be interpreted with caution. Further studies of high methodological quality, with clearly stated criteria for diagnosis of gallbladder polyps, true polyps, and dysplastic polyps/carcinomas are needed to accurately determine diagnostic accuracy of EUS and TAUS.

A total of 16 studies were included. All studies reported on TAUS and EUS as separate tests and did not use a combination of TAUS and EUS. Six studies (16,260 participants) used TAUS for diagnosis of gallbladder polyps. No studies on the diagnosis of gallbladder polyps by EUS were found. Six studies (1,078 participants) used TAUS and three studies (209 participants) used EUS for differentiating between true and pseudo polyps. Four studies (1,009 participants) used TAUS and three studies (351 participants) used EUS for differentiating between (pre)cancerous and benign polyps. In a general population of 1000 people (in which 6.4% have a gallbladder polyp), TAUS will overdiagnose 37 people without a polyp as having a polyp, and in 7 people with a polyp, the polyp will be missed. In a population of 1000 people with a gallbladder polyp, of which 10% have a true polyp, 189 people with a pseudo polyp will be indicated as having a true polyp by TAUS, and 90 people by EUS. These people may be treated, which is not necessary. In 32 people, the true polyp will be misclassified as a pseudo polyp by TAUS and in 15 people by EUS. These people would not be treated, while they may need treatment. In a population of 1000 people with a gallbladder polyp, of which 5% have a (pre)cancerous polyp, 105 people with a benign polyp will be indicated as having a (pre)cancerous polyp by TAUS, and 75 people by EUS. These people may be overtreated for a (precursor of) cancer, which is not there. In 11 people, the (pre)cancerous polyp will be misclassified as a benign polyp by TAUS, and in 7 people by EUS. These participants may not receive proper treatment for their (precursor of) cancer. TAUS will correctly diagnose 956 out of 1000 people regarding the presence or absence of gallbladder polyps. For differentiating between polyp types, fewer people will be correctly diagnosed by TAUS, leading to unnecessary treatment for pseudo polyps and neglect of (pre)cancerous polyps. There was insufficient evidence that EUS is better than TAUS in differentiating between true and pseudo polyps and between (pre)cancerous and benign polyps. All studies were either at high or unclear risk of bias and 13 studies had either high or unclear applicability concerns. This may undermine the validity of the studies. Further studies of high methodological quality and with clearly reported criteria for diagnosis of gallbladder polyps, true polyps, and (pre)cancerous polyps are necessary.

10.1002/14651858.CD012233.pub2

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cochrane-simplification-train-281

Fifty-three studies with a total of more than 25,000 participants met the inclusion criteria. A large proportion of studies recruited people in healthcare settings or with specific health needs. Most studies provided NRT. Behavioural support was typically provided by specialists in cessation counselling, who offered between four and eight contact sessions. The planned maximum duration of contact was typically more than 30 minutes but less than 300 minutes. Overall, studies were at low or unclear risk of bias, and findings were not sensitive to the exclusion of any of the six studies rated at high risk of bias in one domain. One large study (the Lung Health Study) contributed heterogeneity due to a substantially larger treatment effect than seen in other studies (RR 3.88, 95% CI 3.35 to 4.50). Since this study used a particularly intensive intervention which included extended availability of nicotine gum, multiple group sessions and long term maintenance and recycling contacts, the results may not be comparable with the interventions used in other studies, and hence it was not pooled in other analyses. Based on the remaining 52 studies (19,488 participants) there was high quality evidence (using GRADE) for a benefit of combined pharmacotherapy and behavioural treatment compared to usual care, brief advice or less intensive behavioural support (RR 1.83, 95% CI 1.68 to 1.98) with moderate statistical heterogeneity (I² = 36%). The pooled estimate for 43 trials that recruited participants in healthcare settings (RR 1.97, 95% CI 1.79 to 2.18) was higher than for eight trials with community-based recruitment (RR 1.53, 95% CI 1.33 to 1.76). Compared to the first version of the review, previous weak evidence of differences in other subgroup analyses has disappeared. We did not detect differences between subgroups defined by motivation to quit, treatment provider, number or duration of support sessions, or take-up of treatment. Interventions that combine pharmacotherapy and behavioural support increase smoking cessation success compared to a minimal intervention or usual care. Updating this review with an additional 12 studies (5,000 participants) did not materially change the effect estimate. Although trials differed in the details of their populations and interventions, we did not detect any factors that modified treatment effects apart from the recruitment setting. We did not find evidence from indirect comparisons that offering more intensive behavioural support was associated with larger treatment effects.

In July 2015 we searched for studies which tested combinations of behavioural support and medication to help smokers to stop compared to usual care or brief behavioural support. People who smoked were recruited mainly in health care settings. Some trials only enrolled people who said they wanted to try to quit at that time, but some included people who weren't planning to quit. Studies had to report how many people had stopped smoking after at least six months. We found 53 studies with a total of over 25,000 participants. One very large study found a large benefit. It gave intensive support including nicotine gum, multiple group sessions, and long term contact to help people stay quit or encourage additional quit attempts. Because it was not typical of most treatment programmes, it was not included when we estimated the likely benefit, although it shows that such intensive support can be very effective. Based on the remaining 52 studies, we found high quality evidence that using a combination of behavioural support and medication increases the chances of successfully quitting after at least six months. Combining the results suggests that the chance of success is increased by 70 to 100 percent compared to just brief advice or support. There was some evidence that the effect tended to be larger when participants were recruited in healthcare settings. There was no clear evidence that providing more contact increased the number of people who quit smoking at six months or longer. .

10.1002/14651858.CD008286.pub3

cochrane-simplification-train-282

cochrane-simplification-train-282

We included six RCTs (708 women analysed) on ICI and IUI in donor sperm treatment. Two studies compared IUI and ICI in natural cycles, two studies compared IUI and ICI in gonadotrophin-stimulated cycles, and two studies compared timing of IUI and ICI. There was very low-quality evidence; the main limitations were risk of bias due to poor reporting of study methods, and serious imprecision. IUI versus ICI in natural cycles There was insufficient evidence to determine whether there was any clear difference in live birth rate between IUI and ICI in natural cycles (odds ratio (OR) 3.24, 95% confidence interval (CI) 0.12 to 87.13; 1 RCT, 26 women; very low-quality evidence). There was only one live birth in this study (in the IUI group). IUI resulted in higher clinical pregnancy rates (OR 6.18, 95% CI 1.91 to 20.03; 2 RCTs, 76 women; I² = 48%; very low-quality evidence). No multiple pregnancies or miscarriages occurred in this study. IUI versus ICI in gonadotrophin-stimulated cycles There was insufficient evidence to determine whether there was any clear difference in live birth rate between IUI and ICI in gonadotrophin-stimulated cycles (OR 2.55, 95% CI 0.72 to 8.96; 1 RCT, 43 women; very low-quality evidence). This suggested that if the chance of a live birth following ICI in gonadotrophin-stimulated cycles was assumed to be 30%, the chance following IUI in gonadotrophin-stimulated cycles would be between 24% and 80%. IUI may result in higher clinical pregnancy rates than ICI (OR 2.83, 95% CI 1.38 to 5.78; 2 RCTs, 131 women; I² = 0%; very low-quality evidence). IUI may be associated with higher multiple pregnancy rates than ICI (OR 2.77, 95% CI 1.00 to 7.69; 2 RCTs, 131 women; I² = 0%; very low-quality evidence). This suggested that if the risk of multiple pregnancy following ICI in gonadotrophin-stimulated cycles was assumed to be 10%, the risk following IUI would be between 10% and 46%. We found insufficient evidence to determine whether there was any clear difference between the groups in miscarriage rates in gonadotrophin-stimulated cycles (OR 1.97, 95% CI 0.43 to 9.04; 2 RCTs, overall 67 pregnancies; I² = 50%; very low-quality evidence). Timing of IUI and ICI We found no studies that reported on live birth rates. We found a higher clinical pregnancy rate when IUI was timed one day after a rise in blood levels of luteinising hormone (LH) compared to IUI two days after a rise in blood levels of LH (OR 2.00, 95% CI 1.14 to 3.53; 1 RCT, 351 women; low-quality evidence). We found insufficient evidence to determine whether there was any clear difference in clinical pregnancy rates between ICI timed after a rise in urinary levels of LH versus a rise in basal temperature plus cervical mucus scores (OR 1.31, 95% CI 0.42 to 4.11; 1 RCT, 56 women; very low-quality evidence). Neither of these studies reported multiple pregnancy or miscarriage rates as outcomes. There was insufficient evidence to determine whether there was a clear difference in live birth rates between IUI and ICI in natural or gonadotrophin-stimulated cycles in women who started with donor sperm treatment. There was insufficient evidence available for the effect of timing of IUI or ICI on live birth rates. Very low-quality data suggested that in gonadotrophin-stimulated cycles, IUI may be associated with a higher clinical pregnancy rate than ICI, but also with a higher risk of multiple pregnancy rate. We concluded that the current evidence was too limited to choose between IUI or ICI, in natural cycles or with ovarian stimulation, in donor sperm treatment.

We found six randomised controlled trials, including 708 women. Two studies compared IUI and ICI in natural cycles. Two studies compared IUI and ICI in gonadotrophin-stimulated cycles. Two studies compared the timing of IUI and ICI. The evidence is current to December 2017. There was insufficient evidence to determine whether there was any clear difference between IUI and ICI in live birth rates, in either natural cycles or in gonadotrophin-stimulated cycles. As there was only one live birth in the small study using natural cycles, we could not make any meaningful comparison between the groups. The evidence on gonadotrophin-stimulated cycles suggested that if the live birth rate following ICI was assumed to be 30%, the chance of live birth rate following IUI in gonadotrophin-stimulated cycles would be between 24% and 80%. For IUI and ICI in natural cycles, no multiple pregnancies were reported. In gonadotrophin-stimulated cycles, IUI was associated with higher multiple pregnancy rates than ICI. The evidence suggested that if the risk of multiple pregnancy following ICI in gonadotrophin-stimulated cycles was assumed to be 10%, the risk of multiple pregnancy following IUI would be between 10% and 46%. We concluded that the evidence was too limited to encourage or discourage either IUI or ICI, in natural cycles or with ovarian stimulation in donor sperm treatment. Following GRADE assessment, we found that the evidence for all outcomes was of very low quality. The main limitations were risk of bias, due to poor reporting of study methods, and serious imprecision, due to the limited number of studies and small study sizes.

10.1002/14651858.CD000317.pub4

cochrane-simplification-train-283

cochrane-simplification-train-283

We included one RCT of 42 women with high-risk GTN who were randomised to MAC (methotrexate, actinomycin D and chlorambucil) or the modified CHAMOCA regimen (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, doxorubicin, melphalan and vincristine). There were no statistically significant differences in efficacy of the two regimens; however women in the MAC group experienced statistically significantly less toxicity overall and less haematological toxicity than women in the CHAMOCA group. During the study period, six women in the CHAMOCA group died compared with one in the MAC group. This study was stopped early due to unacceptable levels of toxicity in the CHAMOCA group. We identified no RCTs comparing EMA/CO with MAC or other chemotherapy regimens. CHAMOCA is not recommended for GTN treatment as it is more toxic and not more effective than MAC. EMA/CO is currently the most widely used first-line combination chemotherapy for high-risk GTN, although this regimen has not been rigorously compared to other combinations such as MAC or FAV in RCTs. Other regimens may be associated with less acute toxicity than EMA/CO; however, proper evaluation of these combinations in high-quality RCTs that include long-term surveillance for secondary cancers is required. We acknowledge that, given the low incidence of GTN, RCTs in this field are difficult to conduct, hence multicentre collaboration is necessary.

We undertook this review to try to determine which combination/s of drugs are the most effective for the first-line drug treatment of high-risk GTN, and with the least side effects. We found only one small, older study that compared a drug combination abbreviated as CHAMOCA with one called MAC. The CHAMOCA regimen, which is no longer recommended for GTN treatment, was found to be extremely toxic to the blood and bone marrow, with no greater effect against the cancer than the MAC regimen. Based on the available evidence, it is currently not possible to determine whether EMA/CO is the most effective and least toxic drug combination as no high-quality studies have been conducted comparing this combination with other combinations. GTN is a rare cancer and so studies in this field are difficult to conduct, therefore researchers need to collaborate in order to produce the necessary high-quality evidence.

10.1002/14651858.CD005196.pub4

cochrane-simplification-train-284

cochrane-simplification-train-284

We identified 14,488 unique records, and assessed 1030 in full text for eligibility. We found 58 studies meeting our inclusion criteria, including 22 RCTs, 3 NRCTs, 14 CBA studies, and 19 ITS studies, with a total of 1,180,096 participants. The median length of follow-up was 10 months. The studies included children, teenagers and adults, and were implemented in a variety of settings, including schools, retailing and food service establishments. We judged most studies to be at high or unclear risk of bias in at least one domain, and most studies used non-randomised designs. The studies examine a broad range of interventions, and we present results for these separately. Labelling interventions (8 studies): We found moderate-certainty evidence that traffic-light labelling is associated with decreasing sales of SSBs, and low-certainty evidence that nutritional rating score labelling is associated with decreasing sales of SSBs. For menu-board calorie labelling reported effects on SSB sales varied. Nutrition standards in public institutions (16 studies): We found low-certainty evidence that reduced availability of SSBs in schools is associated with decreased SSB consumption. We found very low-certainty evidence that improved availability of drinking water in schools and school fruit programmes are associated with decreased SSB consumption. Reported associations between improved availability of drinking water in schools and student body weight varied. Economic tools (7 studies): We found moderate-certainty evidence that price increases on SSBs are associated with decreasing SSB sales. For price discounts on low-calorie beverages reported effects on SSB sales varied. Whole food supply interventions (3 studies): Reported associations between voluntary industry initiatives to improve the whole food supply and SSB sales varied. Retail and food service interventions (7 studies): We found low-certainty evidence that healthier default beverages in children’s menus in chain restaurants are associated with decreasing SSB sales, and moderate-certainty evidence that in-store promotion of healthier beverages in supermarkets is associated with decreasing SSB sales. We found very low-certainty evidence that urban planning restrictions on new fast-food restaurants and restrictions on the number of stores selling SSBs in remote communities are associated with decreasing SSB sales. Reported associations between promotion of healthier beverages in vending machines and SSB intake or sales varied. Intersectoral approaches (8 studies): We found moderate-certainty evidence that government food benefit programmes with restrictions on purchasing SSBs are associated with decreased SSB intake. For unrestricted food benefit programmes reported effects varied. We found moderate-certainty evidence that multicomponent community campaigns focused on SSBs are associated with decreasing SSB sales. Reported associations between trade and investment liberalisation and SSB sales varied. Home-based interventions (7 studies): We found moderate-certainty evidence that improved availability of low-calorie beverages in the home environment is associated with decreased SSB intake, and high-certainty evidence that it is associated with decreased body weight among adolescents with overweight or obesity and a high baseline consumption of SSBs. Adverse outcomes reported by studies, which may occur in some circumstances, included negative effects on revenue, compensatory SSB consumption outside school when the availability of SSBs in schools is reduced, reduced milk intake, stakeholder discontent, and increased total energy content of grocery purchases with price discounts on low-calorie beverages, among others. The certainty of evidence on adverse outcomes was low to very low for most outcomes. We analysed interventions targeting sugar-sweetened milk separately, and found low- to moderate-certainty evidence that emoticon labelling and small prizes for the selection of healthier beverages in elementary school cafeterias are associated with decreased consumption of sugar-sweetened milk. We found low-certainty evidence that improved placement of plain milk in school cafeterias is not associated with decreasing sugar-sweetened milk consumption. The evidence included in this review indicates that effective, scalable interventions addressing SSB consumption at a population level exist. Implementation should be accompanied by high-quality evaluations using appropriate study designs, with a particular focus on the long-term effects of approaches suitable for large-scale implementation.

We found 58 studies, which included more than one million adults, teenagers and children. Most studies lasted about one year, and were done in schools, stores or restaurants. Some studies used methods that are not very reliable. For example, in some studies participants were simply asked how much SSB they drank, which is not very reliable, as people sometimes forget how much SSB they drank. Some of the findings of our review may therefore change when more and better studies become available. We have found some evidence that some of the measures implemented to help people drink fewer SSBs have been successful, including the following: ▪ Labels which are easy to understand, such as traffic-light labels, and labels which rate the healthfulness of beverages with stars or numbers. ▪ Limits to the availability of SSB in schools (e.g. replacing SSBs with water in school cafeterias). ▪ Price increases on SSBs in restaurants, stores and leisure centres. ▪ Children’s menus in chain restaurants which include healthier beverages as their standard beverage. ▪ Promotion of healthier beverages in supermarkets. ▪ Government food benefits (e.g. food stamps) which cannot be used to buy SSBs. ▪ Community campaigns focused on SSBs. ▪ Measures that improve the availability of low-calorie beverages at home, e.g. through home deliveries of bottled water and diet beverages. We have also found some evidence that improved availability of drinking water and diet beverages at home can help people lose weight. There are also other measures which may influence how much SSB people drink, but for these the available evidence is less certain. Some, but not all studies found that such measures can have effects which were not intended and which may be negative. Some studies reported that profits of stores and restaurants decreased when the measures were implemented, but other studies showed that profits increased or stayed the same. Children who get free drinking water in schools may drink less milk. Some studies reported that people were unhappy with the measures. We also looked at studies on sugar-sweetened milk. We found that small prizes for children who chose plain milk in their school cafeteria, as well as emoticon labels, may help children drink less sugar-sweetened milk. However, this may also drive up the share of milk which is wasted because children choose but do not drink it. Our review shows that measures which change the environment in which people make beverage choices can help people drink less SSB. Based on our findings we suggest that such measures may be used more widely. Government officials, business people and health professionals implementing such measures should work together with researchers to find out more about their effects in the short and long term.

10.1002/14651858.CD012292.pub2

cochrane-simplification-train-285

cochrane-simplification-train-285

Four trials involving 649 participants were included in this review. Two of these trials (459 participants) were designed as randomised, double-blind, placebo-controlled trials with an adequate methodological description; the other two trials (190 participants) described an inadequate methodological design. All four trials with 649 participants were included in the meta-analysis. Significant differences were noted in rates of restenosis, recurrence angina pectoris, and serious cardiovascular adverse events between Xiongshao capsule plus conventional western medicine and the same conventional western medicine alone; RR values (95% CIs) were 0.41 (0.22 to 0.75), 0.47 (0.31 to 0.72), and 0.47 (0.25 to 0.90), respectively. Xiongshao capsule plus conventional western medicine showed more significant reductions in restenosis (RR 0.52, 95% CI 0.33 to 0.80), recurrence angina pectoris (RR 0.26, 95% CI 0.18 to 0.38), and serious cardiovascular adverse events (RR 0.45, 95% CI 0.28 to 0.70) than the same conventional western medicine plus placebo. Safety outcomes and adverse events of the Xiongshao capsule were reported in two trials, which reported no adverse events. The summary estimates indicate a protective effect of Xiongshao on restenosis and suggest that Xiongshao capsule may be used to prevent restenosis after a PCI procedure in CHD patients. However, this evidence is derived from small randomised trials, all conducted in China, and two of the included trials showed important methodological limitations that undermine the validity of the findings. Additional high-quality research trials with sufficient sample size are required.

We identified four trials that tested treatments based on Xiongshao capsule. Two trials compared Xiongshao capsule plus conventional western medicine with the same conventional western medicine plus placebo; the other two trials compared Xiongshao capsule plus conventional western medicine with the same conventional western medicine alone for preventing restenosis after a PCI procedure in CHD patients. These trials reported that use of Xiongshao capsule caused a significant reduction in the incidence rates of restenosis, recurrence angina pectoris, and serious cardiovascular adverse events with no substantive adverse effects following a PCI procedure. Therefore Xiongshao capsule may represent a choice for the prevention of in-stent restenosis following a PCI procedure. However, although summary estimates indicate a protective effect of Xiongshao on restenosis, evidence is derived in part from small randomised trials, all conducted in China, with some methodological limitations that undermine the validity of the findings. Additional high-quality research trials with sufficient sample size are required.

10.1002/14651858.CD009581.pub2

cochrane-simplification-train-286

cochrane-simplification-train-286

We included three new RCTs in this update, which now comprises 10 studies with a total of 614 participants. We judged most trials as having uncertain risk of bias regarding randomization. Other than this, the overall risk of bias was low. Most included trials had small sample sizes. All of the trials assessed the primary outcome of conversion to general anaesthesia. Ten trials comparing anaesthesia performed with hyperbaric and isobaric bupivacaine failed to show any difference in need for conversion to general anaesthesia (RR 0.33, 95% CI 0.09 to 1.17, 614 participants, very low quality of evidence). Nine trials also failed to show a difference in the need for supplemental analgesics (RR 0.61, 95% CI 0.26 to 1.41, 554 participants, very low quality of evidence). Four trials comparing requirement for ephedrine did not show any difference (RR 0.89, 95% CI 0.57 to 1.38, 256 participants, very low quality of evidence). Seven trials did not provide convincing evidence of difference in nausea and vomiting (RR 0.99, 95% CI 0.57 to 1.72, 433 participants, low quality of evidence). Three trials failed to show a difference in headache (OR 1.82, 95% CI 0.47 to 6.99, 234 participants, low quality of evidence). Two trials showed that the time until sensory block to the thoracic 4th (T4) spinal level was shorter with hyperbaric bupivacaine (MD -1.06 minutes, 95% CI -1.80 to -0.31, 128 participants, moderate quality of evidence). Six trials showed no difference in the amount of ephedrine used (RR 0.23, 95% CI -1.65 to 2.12, 386 participants, moderate quality of evidence). Three trials failed to show any difference in high block (RR 0.88, 95% CI 0.16 to 4.90, 205 participants). Data are limited for some of the outcomes. Reporting of the included trials is less than optimal. For these reasons the overall quality of evidence is low or very low for most of the outcomes, based on the GRADE method of assessment. This review found that intrathecal hyperbaric bupivacaine had a more rapid onset of sensory blockade at the 4th thoracic vertebra (T4) level than isobaric bupivacaine. Hower, despite incorporating more data in the analysis, we found little evidence that the need for conversion to general anaesthesia and supplemental analgesia differed between the hyperbaric or isobaric bupivacaine groups. This is mainly due to the rarity of these outcomes, variability in the dose, use of adjuvant drugs and differences in the technique used for regional anaesthesia. There were no differences in the adverse effects studied. Any possible advantage of hyperbaric bupivacaine needs to be confirmed in larger randomized trials. In future research, criteria for conversion to general anaesthesia need to be defined objectively and applied uniformly.

The evidence is current to March 2016. We found 10 clinical trials evaluating these two types of bupivacaine, involving 614 women. The studies assessed the following effects of the two types of medicine: women needing to switch to general anaesthesia, additional drugs for pain relief or low blood pressure, experiencing nausea and vomiting, headache and excessive numbness. We found that all the studies had been done properly. None of them reported their source of funding. We await responses from the authors of two more studies, and will cover these when we next update the review. We found that there is insufficient evidence to establish whether denser or normal bupivacaine is the more effective in reducing the need for: a) switching to general anaesthesia; b) additional pain relief medication. Denser bupivacaine had a more rapid onset of pain relief. Due to the differences among the included studies in doses given, variety of additional drugs used for pain relief, variation in regional anaesthesia techniques and the small numbers of participants, we rated the overall quality of evidence for different outcomes from very low to moderate, as very few women experienced untoward events in all trials. We conclude that the denser form provides faster pain relief than the normal one. More research is required to be certain about the effectiveness of the denser form for other outcomes.

10.1002/14651858.CD005143.pub3

cochrane-simplification-train-287

cochrane-simplification-train-287

We identified one randomised controlled trial including 541 participants that compared partial nephrectomy to radical nephrectomy. The median follow-up was 9.3 years. Based on low quality evidence, we found that time-to-death of any cause was decreased using partial nephrectomy (HR 1.50, 95% CI 1.03 to 2.18). This corresponds to 79 more deaths (5 more to 173 more) per 1000. Also based on low quality evidence, we found no difference in serious adverse events (RR 2.04, 95% CI 0.19 to 22.34). Findings are consistent with 4 more surgery-related deaths (3 fewer to 78 more) per 1000. Based on low quality evidence, we found no difference in time-to-recurrence (HR 1.37, 95% CI 0.58 to 3.24). This corresponds to 12 more recurrences (14 fewer to 70 more) per 1000. Due to the nature of reporting, we were unable to analyse overall rates for immediate and long-term adverse events. We found no evidence on haemodialysis or quality of life. Reasons for downgrading related to study limitations (lack of blinding, cross-over), imprecision and indirectness (a substantial proportion of patients were ultimately found not to have a malignant tumour). Based on the finding of a single trial, we were unable to conduct any subgroup or sensitivity analyses. Partial nephrectomy may be associated with a decreased time-to-death of any cause. With regards to surgery-related mortality, cancer-specific survival and time-to-recurrence, partial nephrectomy appears to result in little to no difference.

We searched the medical literature until 24 February 2017. We included one study with 541 study participants that randomly assigned participants with localised tumours of the kidney that were thought to be cancerous. On average, participants were followed for 9.3 years. Participants who had only the tumour taken out appear to be more likely to die from any cause than participants that had the tumour and the whole kidney taken out. There appeared to be little to no difference in the time until the tumour comes back or in the risk of serious complications resulting in death. We did not find any evidence as to how the groups compared when it comes to the need for haemodialysis or how their quality of life compared. The quality of evidence was low. This means that we have limited confidence in the results and that the true effect of partial nephrectomy may be substantially different.

10.1002/14651858.CD012045.pub2

cochrane-simplification-train-288

cochrane-simplification-train-288

We included 19 RCTs in 6461 participants who were followed for one to eight years. Seven trials assessed the effects of supplemental GLA and 12 of LA, none DGLA or AA; the omega-6 fats usually displaced dietary saturated or monounsaturated fats. We assessed three RCTs as being at low summary risk of bias. Primary outcomes: we found low-quality evidence that increased intake of omega-6 fats may make little or no difference to all-cause mortality (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.12, 740 deaths, 4506 randomised, 10 trials) or CVD events (RR 0.97, 95% CI 0.81 to 1.15, 1404 people experienced events of 4962 randomised, 7 trials). We are uncertain whether increasing omega-6 fats affects CVD mortality (RR 1.09, 95% CI 0.76 to 1.55, 472 deaths, 4019 randomised, 7 trials), coronary heart disease events (RR 0.88, 95% CI 0.66 to 1.17, 1059 people with events of 3997 randomised, 7 trials), major adverse cardiac and cerebrovascular events (RR 0.84, 95% CI 0.59 to 1.20, 817 events, 2879 participants, 2 trials) or stroke (RR 1.36, 95% CI 0.45 to 4.11, 54 events, 3730 participants, 4 trials), as we assessed the evidence as being of very low quality. We found no evidence of dose-response or duration effects for any primary outcome, but there was a suggestion of greater protection in participants with lower baseline omega-6 intake across outcomes. Additional key outcomes: we found increased intake of omega-6 fats may reduce myocardial infarction (MI) risk (RR 0.88, 95% CI 0.76 to 1.02, 609 events, 4606 participants, 7 trials, low-quality evidence). High-quality evidence suggests increasing omega-6 fats reduces total serum cholesterol a little in the long term (mean difference (MD) −0.33 mmol/L, 95% CI −0.50 to −0.16, I2 = 81%; heterogeneity partially explained by dose, 4280 participants, 10 trials). Increasing omega-6 fats probably has little or no effect on adiposity (body mass index (BMI) MD −0.20 kg/m2, 95% CI −0.56 to 0.16, 371 participants, 1 trial, moderate-quality evidence). It may make little or no difference to serum triglycerides (MD −0.01 mmol/L, 95% CI −0.23 to 0.21, 834 participants, 5 trials), HDL (MD −0.01 mmol/L, 95% CI −0.03 to 0.02, 1995 participants, 4 trials) or low-density lipoprotein (MD −0.04 mmol/L, 95% CI −0.21 to 0.14, 244 participants, 2 trials, low-quality evidence). This is the most extensive systematic assessment of effects of omega-6 fats on cardiovascular health, mortality, lipids and adiposity to date, using previously unpublished data. We found no evidence that increasing omega-6 fats reduces cardiovascular outcomes other than MI, where 53 people may need to increase omega-6 fat intake to prevent 1 person from experiencing MI. Although benefits of omega-6 fats remain to be proven, increasing omega-6 fats may be of benefit in people at high risk of MI. Increased omega-6 fats reduce serum total cholesterol but not other blood fat fractions or adiposity.

Evidence in this review is current to May 2017. We found 19 studies recruiting 6461 adults. These studies assessed the effects of higher compared to lower omega-6 fat intake on heart and circulatory diseases as well as deaths. We found that three trials were highly trustworthy (with good designs that produce reliable evidence). Studies took place in North America, Asia, Europe and Australia, and eight were funded only by national or charitable agencies. Participants increased their omega-6 fats or maintained their usual fats for at least one year and up to eight years. We found that increasing omega-6 fats may make little or no difference to deaths or cardiovascular events but may reduce risk of heart attacks (low-quality evidence). Evidence was weakened by study design problems, small numbers of events, low numbers of participants from developing countries, and few women. Evidence suggests that increasing omega-6 fats reduces blood cholesterol (high-quality evidence), probably has little or no effect on body weight adjusted for height (all moderate-quality evidence), and may make little or no difference to triglycerides, high-density lipoprotein (HDL, the 'good' cholesterol) or low-density lipoprotein (LDL, the 'bad' cholesterol, low-quality evidence).

10.1002/14651858.CD011094.pub4

cochrane-simplification-train-289

cochrane-simplification-train-289

Sixteen trials (3689 participants) compared day hospitals with comprehensive care (five trials), domiciliary care (seven trials) or no comprehensive care (four trials). Overall there was low quality evidence from these trials for the following results. For the outcome of death, there was no strong evidence for or against day hospitals compared to other treatments overall (odds ratio (OR) 1.05; 95% CI 0.85 to 1.28; P = 0.66), or to comprehensive care (OR 1.26; 95% CI 0.87 to 1.82; P = 0.22), domiciliary care (OR 0.97; 95% CI 0.61 to 1.55; P = 0.89), or no comprehensive care (OR 0.88; 95% CI 0.63 to 1.22; P = 0.43). For the outcome of death or deterioration in activities of daily living (ADL), there was no strong evidence for day hospital attendance compared to other treatments (OR 1.07; 95% CI 0.76 to 1.49; P = 0.70), or to comprehensive care (OR 1.18; 95% CI 0.63 to 2.18; P = 0.61), domiciliary care (OR 1.41; 95% CI 0.82 to 2.42; P = 0.21) or no comprehensive care (OR 0.76; 95% CI 0.56 to 1.05; P = 0.09). For the outcome of death or poor outcome (institutional care, dependency, deterioration in physical function), there was no strong evidence for day hospitals compared to other treatments (OR 0.92; 95% CI 0.74 to 1.15; P = 0.49), or compared to comprehensive care (OR 1.05; 95% CI 0.79 to 1.40; P = 0.74) or domiciliary care (OR 1.08; 95% CI 0.67 to 1.74; P = 0.75). However, compared with no comprehensive care there was a difference in favour of day hospitals (OR 0.72; 95% CI 0.53 to 0.99; P = 0.04). For the outcome of death or institutional care, there was no strong evidence for day hospitals compared to other treatments overall (OR 0.85; 95% CI 0.63 to 1.14; P = 0.28), or to comprehensive care (OR 1.00; 95% CI 0.69 to 1.44; P = 0.99), domiciliary care (OR 1.05; 95% CI 0.57 to1.92; P = 0. 88) or no comprehensive care (OR 0.63; 95% CI 0.40 to 1.00; P = 0.05). For the outcome of deterioration in ADL, there was no strong evidence that day hospital attendance had a different effect than other treatments overall (OR 1.11; 95% CI 0.68 to 1.80; P = 0.67) or compared with comprehensive care (OR 1.21; 0.58 to 2.52; P = 0.61), or domiciliary care (OR 1.59; 95% CI 0.87 to 2.90; P = 0.13). However, day hospital patients showed a reduced odds of deterioration compared with those receiving no comprehensive care (OR 0.61; 95% CI 0.38 to 0.97; P = 0.04) and significant subgroup differences (P = 0.04). For the outcome of requiring institutional care, there was no strong evidence for day hospitals compared to other treatments (OR 0.84; 95% CI 0.58 to 1.21; P = 0.35), or to comprehensive care (OR 0.91; 95% CI 0.70 to 1.19; P = 0.49), domiciliary care (OR 1.49; 95% CI 0.53 to 4.25; P = 0.45), or no comprehensive care (OR 0.58; 95% CI 0.28 to 1.20; P = 0.14). There is low quality evidence that medical day hospitals appear effective compared to no comprehensive care for the combined outcome of death or poor outcome, and for deterioration in ADL. There is no clear evidence for other outcomes, or an advantage over other medical care provision.

They are out-patient facilities which older patients attend for a full or near full day and receive multidisciplinary health care ‘under one roof.’ Sixteen trials involving 3689 participants were included in this review and compared day hospitals with other comprehensive services (including inpatient and outpatient services), home based care and no comprehensive services. Attendance at a day hospital offers benefits compared to providing no treatment which include reducing the risk of needing more help with daily activities such as washing or dressing. Furthermore, patients are less likely to suffer one of the following: dying, being institutionalised or becoming more dependent on others. There is no apparent benefit when day hospitals are compared with other comprehensive services or home care. The economic value of day hospitals when compared with other health care services remains unclear.

10.1002/14651858.CD001730.pub3

cochrane-simplification-train-290

cochrane-simplification-train-290

Nine studies (3345 women) were included. Oral oestrogens did not reduce UTI compared to placebo (4 studies, 2798 women: RR 1.08, 95% CI 0.88 to 1.33). Vaginal oestrogens versus placebo reduced the number of women with UTIs in two small studies using different application methods. The RR for one was 0.25 (95% CI 0.13 to 0.50) and 0.64 (95% CI 0.47 to 0.86) in the second. Two studies compared oral antibiotics versus vaginal oestrogens (cream (1), pessaries (1)). There was very significant heterogeneity and the results could not be pooled. Vaginal cream reduced the proportion of UTIs compared to antibiotics in one study and in the second study antibiotics were superior to vaginal pessaries. Adverse events for vaginal oestrogens were breast tenderness, vaginal bleeding or spotting, nonphysiologic discharge, vaginal irritation, burning and itching. Based on only two studies comparing vaginal oestrogens to placebo, vaginal oestrogens reduced the number of UTIs in postmenopausal women with RUTI, however this varied according to the type of oestrogen used and the treatment duration.

This review identified nine studies (3345 women) treated with oestrogens versus placebo, no treatment or antibiotics. Vaginal oestrogens reduced the number of UTIs when compared to placebo. All studies reported adverse events for the oestrogen treatment groups. These included breast tenderness, vaginal bleeding or spotting, vaginal discharge, vaginal irritation, burning and itching.

10.1002/14651858.CD005131.pub2

cochrane-simplification-train-291

cochrane-simplification-train-291

We included 72 trials (52,678 women). Oral or sublingual misoprostol compared with placebo is effective in reducing severe PPH (oral: seven trials, 6225 women, not totalled due to significant heterogeneity; sublingual: risk ratio (RR) 0.66; 95% confidence interval (CI) 0.45 to 0.98; one trial, 661 women) and blood transfusion (oral: RR 0.31; 95% CI 0.10 to 0.94; four trials, 3519 women). Compared with conventional injectable uterotonics, oral misoprostol was associated with higher risk of severe PPH (RR 1.33; 95% CI 1.16 to 1.52; 17 trials, 29,797 women) and use of additional uterotonics, but with a trend to fewer blood transfusions (RR 0.84; 95% CI 0.66 to 1.06; 15 trials; 28,213 women). Additional uterotonic data were not totalled due to heterogeneity. Misoprostol use is associated with significant increases in shivering and a temperature of 38º Celsius compared with both placebo and other uterotonics. Oral or sublingual misoprostol shows promising results when compared with placebo in reducing blood loss after delivery. The margin of benefit may be affected by whether other components of the management of the third stage of labour are used or not. As side-effects are dose-related, research should be directed towards establishing the lowest effective dose for routine use, and the optimal route of administration. Neither intramuscular prostaglandins nor misoprostol are preferable to conventional injectable uterotonics as part of the management of the third stage of labour especially for low-risk women; however, evidence has been building for the use of oral misoprostol to be effective and safe in areas with low access to facilities and skilled healthcare providers and future research on misoprostol use in the community should focus on implementation issues.

After her baby is born, the woman's womb (uterus) contracts and bleeding decreases. If the womb does not contract, postpartum haemorrhage (heavy bleeding) can occur, which can be life threatening. A prostaglandin, oxytocin and ergometrine are all drugs that cause contractions of the womb (uterotonics). This review of 72 randomised controlled trials, involving 52,678 women, found that oral or sublingual prostaglandin (misoprostol) is effective in reducing severe haemorrhage after giving birth and the need for blood transfusions. Misoprostol is not as effective as oxytocin and has more side-effects. The main side-effects are shivering, high temperature and diarrhoea, occurring in a significant proportion of women. Twenty-six of the trials included centres in low- and middle-income countries only. Misoprostol may be useful in places where injectable uterotonics are not available, perhaps because of poor access to skilled healthcare providers. Injectable prostaglandin may be effective in reducing blood loss but has adverse effects of vomiting, abdominal pain and diarrhoea and costs more.

10.1002/14651858.CD000494.pub4

cochrane-simplification-train-292

cochrane-simplification-train-292

Four small studies (224 participants) were included in the review. Little information was provided about the process of allocating participants to groups. None of the studies used independent outcome assessors, and evidence suggested researcher allegiance towards the active treatments. The four studies examined a diversity of third wave CBT approaches (extended behavioural activation, acceptance and commitment therapy and competitive memory training) and control conditions. None of the studies conducted follow-up assessments. The results showed a significant difference in clinical response rates in favour of third wave CBT when compared with treatment as usual (TAU) conditions (three studies, 170 participants, risk ratio (RR) 0.51, 95% confidence interval (CI) 0.27 to 0.95; very low quality). No significant difference in treatment acceptability based on dropout rates was found between third wave CBT approaches and TAU (four studies, 224 participants, RR 1.01, 95% CI 0.08 to 12.30; very low quality). Both analyses showed substantial statistical heterogeneity. Very low quality evidence suggests that third wave CBT approaches appear to be more effective than treatment as usual in the treatment of acute depression. The very small number of available studies and the diverse types of interventions and control comparators, together with methodological limitations, limit the ability to draw any conclusions on their effect in the short term or over a longer term. The increasing popularity of third wave CBT approaches in clinical practice underscores the importance of completing further studies of third wave CBT approaches in the treatment of acute depression, on a short- and long-term basis, to provide evidence of their effectiveness to policy-makers, clinicians and users of services.

In this review, we focused on third wave CBT approaches, a group of psychological therapies that target the process of thoughts (rather than their content, as in CBT), helping people to become aware of their thoughts and to accept them in a non-judgemental way. The aim of the review was to find out whether third wave CBT was effective and acceptable to people in the acute phase of depression. The review included four studies, involving a total of 224 people. The studies examined three different forms of third wave CBT, consisting of extended behavioural activation (two studies), acceptance and commitment therapy (ACT) (one study) and another form of third wave CBT called competitive mind training (one study). Three of the studies compared third wave CBT approaches with treatment as usual control conditions. The fourth study compared ACT with a psychological placebo condition. The results suggested that third wave CBT approaches were effective on a short-term basis in treating depression. However, the quality of evidence was very low because of the small number of studies/participants included in the review, together with the diverse client groups, interventions and control conditions used and possible allegiance of researchers towards the active treatments, making it difficult to draw conclusions with any confidence. It is notable, too, that none of the studies looked at the long-term effect of third wave CBT approaches. Given the increasing popularity of third wave CBT approaches in clinical practice, further well-designed studies should be prioritised to establish whether third wave CBT approaches are helpful in treating people with acute depression.

10.1002/14651858.CD008705.pub2

cochrane-simplification-train-293

cochrane-simplification-train-293

We identified seven studies including 1774 participants. We judged three studies to be at high risk of bias and four to be at unclear risk. Each study provided face-to-face behavioural support delivered by pharmacy staff, and required pharmacy personnel training. Typically such programmes comprised support starting before quit day and continuing with weekly appointments for several weeks afterwards. Comparators were either minimal or less intensive behavioural support for smoking cessation, typically comprising a few minutes of one-off advice on how to quit. Participants in both intervention and control arms received equivalent smoking cessation pharmacotherapy in all but one study. All studies took place in high-income countries, and recruited participants visiting pharmacies. We pooled six studies of 1614 participants and detected a benefit of more intensive behavioural smoking cessation interventions delivered by community pharmacy personnel compared with less intensive cessation interventions at longest follow-up (RR 2.30, 95% CI 1.33 to 3.97; I2 = 54%; low-certainty evidence). Community pharmacists can provide effective behavioural support to people trying to stop smoking. However, this conclusion is based on low-certainty evidence, limited by risk of bias and imprecision. Further research could change this conclusion.

We searched for relevant studies in January 2019, and found seven studies including 1774 people. Three studies took place in the UK, and one each in Australia, United States, Qatar, and Italy. Each study provided face-to-face behavioural support delivered by pharmacy staff, who received specific training. Studies compared the structured programme to less intensive support to stop smoking. We found evidence that more intensive structured care given by community pharmacy staff probably helps more people to quit smoking than less intensive support to quit. We found low-quality evidence that community pharmacy support helps people to quit smoking. Limitations of the evidence came from potential problems with the ways some of the studies were carried out and the low numbers of people who quit smoking across the included studies, which means we are not sure how effective these programmes really are.

10.1002/14651858.CD003698.pub3

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cochrane-simplification-train-294

Three randomised controlled trials (633 participants) were included in this updated review. No significant differences in hospital mortality were noted between the study group (with omentoplasty) and the control group (without omentoplasty) (RR 1.28, 95% CI 0.49 to 3.39). None of the included studies reported differences in long-term survival between the two groups. The incidence of postoperative anastomotic leakage was significantly less among study participants treated with omentoplasty than among those treated without (RR 0.25, 95% CI 0.11 to 0.55), but the additional benefit was seen in the subgroup analysis only for participants undergoing a transhiatal oesophagogastrectomy (THE) procedure (RR 0.23, 95% CI 0.07 to 0.79); transthoracic oesophagogastrectomy (TTE) (RR 0.19, 95% CI 0.03 to 1.03); or three-field oesophagectomy (RR 0.33, 95% CI 0.09 to 1.19 ). Omentoplasty did not significantly improve other surgery-related complications, such as anastomotic stricture (RR 0.91, 95% CI 0.33 to 2.57). However, participants treated with omentoplasty could reduce the duration of hospitalisation compared with that seen in the control group (MD -2.13, 95% CI -3.57 to -0.69). Omentoplasty may provide additional benefit in decreasing the incidence of anastomotic leakage after oesophagectomy and oesophagogastrostomy for patients with oesophageal cancer without increasing or decreasing other complications, especially among those treated with THE. It also has the potential to reduce the duration of hospital stay after operation. Further randomised controlled trials are needed to investigate the influences of omentoplasty on the incidence of anastomotic leakage and anastomotic stricture, long-term survival, duration of hospital stay and quality of life after oesophagectomy and oesophagogastrostomy when different surgical approaches are used.

This updated systematic review, including 633 participants in three randomised controlled trials, suggests that omentoplasty could reduce the incidence of anastomotic leakage and the duration of hospital stay after operation. Although the difference in anastomotic leakage was significant only among patients undergoing THE, the risk ratios of omentoplasty for THE and TTE were similar. In addition, omentoplasty does not appear to increase or decrease hospital mortality nor the incidence of postoperative complications, such as anastomotic stricture, pulmonary and cardiac complications, infection, vocal cord palsy and perijejunostomy leakage. Additional clinical trials are needed to investigate the influences of omentoplasty on the incidence of anastomotic leakage and anastomotic stricture, long-term survival, duration of hospital stay and quality of life after oesophagectomy and oesophagogastrostomy when different surgical approaches are used.

10.1002/14651858.CD008446.pub3

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cochrane-simplification-train-295

Seven randomized controlled trials (1249 participants) which met our inclusion criteria compared acyclovir to placebo or no treatment (five trials) and valacyclovir to placebo (two trials). The effect of antepartum antiviral prophylaxis on neonatal herpes could not be estimated. There were no cases of symptomatic neonatal herpes in the included studies in either the treatment or placebo groups. Women who received antiviral prophylaxis were significantly less likely to have a recurrence of genital herpes at delivery (relative risk (RR) 0.28, 95% confidence interval (CI) 0.18 to 0.43, I2 = 0%). Women who received antiviral prophylaxis were also significantly less likely to have a cesarean delivery for genital herpes (RR 0.30, 95% CI 0.20 to 0.45, I2 = 27.3%). Women who received antiviral prophylaxis were significantly less likely to have HSV detected at delivery (RR 0.14, 95% CI 0.05 to 0.39, I2 = 0%). Women with recurrent genital herpes simplex virus should be informed that the risk of neonatal herpes is low. There is insufficient evidence to determine if antiviral prophylaxis reduces the incidence of neonatal herpes. Antenatal antiviral prophylaxis reduces viral shedding and recurrences at delivery and reduces the need for cesarean delivery for genital herpes. Limited information exists regarding the neonatal safety of prophylaxis. The risks, benefits, and alternatives to antenatal prophylaxis should be discussed with women who have a history and prophylaxis initiated for women who desire intervention.

The review assessed whether antiviral drugs given to pregnant women with herpes before a recurrence might be effective in reducing transmission to the baby. Seven studies were identified involving 1249 women. Giving antiviral drugs reduces viral shedding and recurrences at labor and birth. They also reduced the use of cesarean, but there is no evidence of reduction in neonatal herpes. Women should also be informed that the risk of the baby getting herpes during birth is low.

10.1002/14651858.CD004946.pub2

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cochrane-simplification-train-296

We included 12 studies (in 13 publications) in this review, but interpretability and generalizability of these studies is difficult and the study designs used were at high risk of bias. The additional yield (calculated by dividing the additional 'unique' yield identified by checking reference lists by the total number of studies found to be eligible within the study) of relevant studies identified through checking reference lists ranged from 2.5% to 42.7%. Only two studies reported yield information by publication type (dissertations and systematic reviews). No cost data were reported although one study commented that it was impossible to isolate the time spent on reference tracking since this was done in parallel with the critical appraisal of each paper, and for that particular study costs were not specifically estimated. There is some evidence to support the use of checking reference lists for locating studies in systematic reviews. However, this evidence is derived from weak study designs. In situations where the identification of all relevant studies through handsearching and database searching is difficult, it would seem prudent that authors of reviews check reference lists to supplement their searching. The challenge, therefore, is for review authors to recognize those situations.

We found 12 studies that explored whether or not checking reference lists was useful for systematic reviews. These studies reported a range of results, from identifying only a few additional studies (2.5%: 2 of 79 included studies) to identifying many additional studies (42.7%: 111 of 260 included studies) through checking reference lists. Unfortunately, none of the studies looked at how much time or money were spent on the process of checking reference lists, and it was suggested this would be almost impossible to estimate. Unfortunately our findings are based on weak information. The data do suggest that in situations where researchers may have difficulty locating information, checking through the reference lists may be an important way to reduce the risk of missing relevant information.

10.1002/14651858.MR000026.pub2

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cochrane-simplification-train-297

We found nine trials with 855 participants that randomised participants to fewer-than-four-ports laparoscopic cholecystectomy (n = 427) versus four-port laparoscopic cholecystectomy (n = 428). Most trials included low anaesthetic risk participants undergoing elective laparoscopic cholecystectomy. Seven of the nine trials used a single port laparoscopic cholecystectomy and the remaining two trials used three-port laparoscopic cholecystectomy as the experimental intervention. Only one trial including 70 participants had low risk of bias. Fewer-than-four-ports laparoscopic cholecystectomy could be completed successfully in more than 90% of participants in most trials. The remaining participants were mostly converted to four-port laparoscopic cholecystectomy but some participants had to undergo open cholecystectomy. There was no mortality in either group in the seven trials that reported mortality (318 participants in fewer-than-four-ports laparoscopic cholecystectomy group and 316 participants in four-port laparoscopic cholecystectomy group). The proportion of participants with serious adverse events was low in both treatment groups and the estimated RR was compatible with a reduction and substantial increased risk with the fewer-than-four-ports group (6/318 (1.9%)) and four-port laparoscopic cholecystectomy group (0/316 (0%)) (RR 3.93; 95% CI 0.86 to 18.04; 7 trials; 634 participants; very low quality evidence). The estimated difference in the quality of life (measured between 10 and 30 days) was imprecise (standardised mean difference (SMD) 0.18; 95% CI -0.05 to 0.42; 4 trials; 510 participants; very low quality evidence), as was the proportion of participants in whom the laparoscopic cholecystectomy had to be converted to open cholecystectomy between the groups (fewer-than-four ports 3/289 (adjusted proportion 1.2%) versus four port: 5/292 (1.7%); RR 0.68; 95% CI 0.19 to 2.35; 5 trials; 581 participants; very low quality evidence). The fewer-than-four-ports laparoscopic cholecystectomy took 14 minutes longer to complete (MD 14.44 minutes; 95% CI 5.95 to 22.93; 9 trials; 855 participants; very low quality evidence). There was no clear difference in hospital stay between the groups (MD -0.01 days; 95% CI -0.28 to 0.26; 6 trials; 731 participants) or in the proportion of participants discharged as day surgery (RR 0.92; 95% CI 0.70 to 1.22; 1 trial; 50 participants; very low quality evidence) between the two groups. The times taken to return to normal activity and work were shorter by two days in the fewer-than-four-ports group compared with four-port laparoscopic cholecystectomy (return to normal activity: MD -1.20 days; 95% CI -1.58 to -0.81; 2 trials; 325 participants; very low quality evidence; return to work: MD -2.00 days; 95% CI -3.31 to -0.69; 1 trial; 150 participants; very low quality evidence). There was no significant difference in cosmesis scores at 6 to 12 months between the two groups (SMD 0.37; 95% CI -0.10 to 0.84; 2 trials; 317 participants; very low quality evidence). There is very low quality evidence that is insufficient to determine whether there is any significant clinical benefit in using fewer-than-four-ports laparoscopic cholecystectomy compared with four-port laparoscopic cholecystectomy. The safety profile of using fewer-than-four ports is yet to be established and fewer-than-four-ports laparoscopic cholecystectomy should be reserved for well-designed randomised clinical trials.

We identified nine trials that compared fewer-than-four-ports laparoscopic cholecystectomy with four-port laparoscopic cholecystectomy. In these nine studies, 855 participants were included. Four hundred and twenty seven participants underwent fewer-than-four-ports laparoscopic cholecystectomy while the remaining 428 participants underwent four-port laparoscopic cholecystectomy. The choice of the treatment that the participants received was determined by a method similar to toss of a coin so that the two treatments were given to participants with similar characteristics. Most of these studies included low anaesthetic risk patients undergoing planned laparoscopic cholecystectomy. Fewer-than-four-ports laparoscopic cholecystectomy could be completed successfully in more than 90% of participants in most of the trials. The remaining participants were mostly converted to four-port laparoscopic cholecystectomy but some participants had to undergo open cholecystectomy (through a large incision in the abdomen). There was no mortality in either group in the seven trials that reported mortality (634 participants in the two groups). There was no significant difference in the proportion of participants who developed serious complications, quality of life between 10 and 30 days after operation, proportion of participants in whom the laparoscopic operation had to be converted to open cholecystectomy, or in the length of hospital stay between the groups. Fewer-than-four-ports laparoscopic cholecystectomy took about 15 minutes longer to complete than four-port laparoscopic cholecystectomy. The time taken to return to normal activity was one day shorter and time taken to return to work two days shorter in the fewer-than-four-ports group compared with four-port laparoscopic cholecystectomy. There was no significant difference in the cosmetic appearance between the two groups at 6 to 12 months after surgery. There appears to be no advantage of fewer-than-four-ports laparoscopic cholecystectomy in terms of decreasing surgical complications, hospital stay, or in improving quality of life and cosmetic appearance. In contrast, the safety of fewer-than-four port laparoscopic cholecystectomy is yet to be established. Fewer-than-four-ports laparoscopic cholecystectomy cannot be recommended routinely outside well-designed clinical trials. Most of the trials were of high risk of bias, that is, there is possibility of arriving at wrong conclusions because of the way that the trial was conducted. The overall quality of evidence was very low. Further well-designed randomised clinical trials (which have low probability to arrive at wrong conclusions because of chance and because of participant or researcher prejudice) are necessary to determine whether fewer-than-four-ports laparoscopic cholecystectomy is safe and whether there is any advantage of fewer-than-four-ports laparoscopic cholecystectomy over four-port laparoscopic cholecystectomy.

10.1002/14651858.CD007109.pub2

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cochrane-simplification-train-298

No RCTs of interventions were identified. Eleven observational studies were included - two medical records reviews, one matched pair study, one clinician interview study, two studies documenting clinicians' decisions and five postal surveys. Three measures of recruitment were used, invitation to participate, entry into RCT and reported entry to RCT. Five studies explored the effect of patient characteristics. The effect of age and prognosis varied between trials. Six studies considered the association between clinicians' views and recruitment. Clinicians who agreed to participate because they were acquainted with the researchers were less likely to participate than those otherwise motivated (1 study, 2-sided p = 0.04 Fisher's exact test) and (Odds Ratio [OR] 0.4, 95% Confidence Interval [CI] 0.2 to 0.9, 1 study). Clinicians who had recruited were more likely to report some difficulties including "trials involve extra work" (OR 92.94, 95% CI 4.54 - 1902.11; p ≤ 0.01, 1 study) and "inviting patients to participate is embarrassing" (chi-square 15.55, df = 1, p < 0.0001, 1 study). The effect of the need to discuss clinical uncertainty was unclear but concern that the doctor-patient relationship would be adversely affected by participation was a deterrent (chi-square = 7.25, df = 1, p = 0.007, 1 study). The impact of factors varied across studies. Researchers need to be aware that aspects of the design and conduct of trials can affect clinicians' willingness to invite patients to participate. Further research is needed.

Randomised controlled trials (RCTs) are needed to provide robust evidence of the relative efficacy and safety of treatments. In many RCTs, clinicians (i.e. healthcare professionals inviting patients to take part in an RCT in which they provide at least one of the interventions) only invite a small proportion of the people who are eligible for trials to take part. Observational studies have been conducted to explore reasons for this but the results do not identify any factors that appear to have a consistent impact on recruitment.

10.1002/14651858.MR000021.pub3

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cochrane-simplification-train-299

Ten trials involving 11,795 women met the inclusion criteria. We found no trials of freestanding birth centres or Snoezelen rooms. Allocation to an alternative setting increased the likelihood of: no intrapartum analgesia/anesthesia (six trials, n = 8953; RR 1.18, 95% CI 1.05 to 1.33); spontaneous vaginal birth (eight trials; n = 11,202; RR 1.03, 95% CI 1.01 to 1.05); breastfeeding at six to eight weeks (one trial, n = 1147; RR 1.04, 95% CI 1.02 to 1.06); and very positive views of care (two trials, n = 1207; RR 1.96, 95% CI 1.78 to 2.15). Allocation to an alternative setting decreased the likelihood of epidural analgesia (eight trials, n = 10.931; RR 0.80, 95% CI 0.74 to 0.87); oxytocin augmentation of labour (eight trials, n = 11,131; RR 0.77, 95% CI 0.67 to 0.88); instrumental vaginal birth (eight trials, n = 11,202; RR 0.89, 95% CI 0.79 to 0.99), and episiotomy (eight trials, n = 11,055; RR 0.83, 95% CI 0.77 to 0.90). There was no apparent effect on other adverse maternal or neonatal outcomes. Care by the same or separate staff had no apparent effects. No conclusions could be drawn regarding the effects of continuity of caregiver or architectural characteristics. In several of the trials included in this review, the design features of the alternative setting were confounded by important differences in the organizational models for care (separate staff for the alternative setting, offering more continuity of caregiver), and thus it is difficult to draw inferences about the independent effects of the physical birth environment. Hospital birth centres are associated with lower rates of medical interventions during labour and birth and higher levels of satisfaction, without increasing risk to mothers or babies.

The primary aim of this review is to evaluate the effects, on labour and birth outcomes, of care in an alternative institutional birth setting compared with care in a conventional hospital labour ward. We included ten trials involving 11,795 women. We found no trials of freestanding birth centres. When compared to conventional institutional settings, alternative settings were associated with reduced likelihood of medical interventions, increased likelihood of spontaneous vaginal birth, increased maternal satisfaction, and greater likelihood of continued breastfeeding at one to two months postpartum, with no apparent risks to mother or baby. Unfortunately, in several trials, the design features of the alternative setting were confounded by differences in the organizational models of care (including separate staff and more continuity of caregiver in the alternative setting), and thus it is not possible to draw conclusions about the independent effects of the design of the birth environment. We conclude that women and policy makers should be informed about the benefits of institutional settings which focus on supporting normal labour and birth.

10.1002/14651858.CD000012.pub4