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cochrane-simplification-train-400

Eleven papers describing 10 unique trials met the inclusion criteria. The 10 trials reported results for nine antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate. Six of the eight drugs investigated in placebo-controlled trials were not better than placebo in reducing headache frequency per 28-day period during treatment (clonazepam, lamotrigine, oxcarbazepine, and vigabatrin) and/or in the proportion of responders (acetazolamide, carisbamate, lamotrigine, oxcarbazepine). One prospective, randomised, double-blind, single cross-over trial of 48 patients demonstrated a significant superiority of carbamazepine over placebo in the proportion of responders (OR 11.77; 95% confidence interval (CI) 3.92 to 35.32). The NNT was 2 (95% CI 2 to 3). In a small prospective, randomised, double-blind, parallel-group trial, levetiracetam 1000 mg was significantly superior to placebo in reducing headache frequency per 28-day period during treatment (MD -2.40; 95% CI -4.52 to -0.28; 26 patients), as well as in the proportion of responders (OR 26.07; 95% CI 1.30 to 521.91; 26 patients). The NNT was 2 (95% CI 1 to 4). The same trial examined levetiracetam 1000 mg versus topiramate 100 mg and found a small but significant difference favouring topiramate in headache frequency per 28-day period during treatment (MD 1.40; 95% CI 0.14 to 2.66; 28 patients). There was no significant difference between levetiracetam and topiramate in the proportion of responders (OR 0.71; 95% CI 0.16 to 3.23; 28 patients). Finally, one trial with 75 participants examined zonisamide versus topiramate (200 and 100 mg, respectively) and found no significant difference between them in reduction of headache frequency from baseline during the third month of treatment. Adverse events for active treatment versus placebo were available for all investigated drugs except levetiracetam, vigabatrin, and zonisamide. A high prevalence of adverse events was noted for carbamazepine, with a NNH of only 2 (95% CI 2 to 4). Available evidence does not allow robust conclusions regarding the efficacy of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate in the prophylaxis of episodic migraine among adults. Acetazolamide, carisbamate, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin were not more effective than placebo in reducing headache frequency. In one trial each, carbamazepine and levetiracetam were significantly superior to placebo in reducing headache frequency, and there was no significant difference in proportion of responders between zonisamide and active comparator. These three positive studies suffer from considerable methodological limitations.

These three drugs, along with one other (pregabalin), are the subject of separate Cochrane reviews. For the present review, researchers in The Cochrane Collaboration reviewed the evidence about the effect of other antiepileptics in adult patients (≥ 16 years of age) with 'episodic' migraine (headache on < 15 days per month). They examined research published up to 15 January 2013 and found 10 studies of nine different antiepileptics. The majority of these drugs were no better than placebo for migraine prophylaxis (acetazolamide, carisbamate, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin). In one study each, carbamazepine and levetiracetam were better than placebo, and there was no significant difference between zonisamide and topiramate (a drug proven to be effective for migraine prophylaxis). None of these studies was of high methodological quality. The quantity and quality of the evidence were such that no firm conclusions could be drawn about the effect or lack of effect of any of the antiepileptics studied.

cochrane-simplification-train-401

We included five RCTs with 414 participants. The comparisons in the included trials were as follows: CHM versus clomiphene, CHM plus clomiphene versus clomiphene (with or without ethinyloestradiol cyproterone acetate (CEA)), CHM plus follicle aspiration plus ovulation induction versus follicle aspiration plus ovulation induction alone, and CHM plus laparoscopic ovarian drilling (LOD) versus LOD alone. The overall quality of the evidence for most comparisons was very low. None of the included studies reported live birth rate, and only one study reported data on adverse events. When CHM was compared with clomiphene (with or without LOD in both arms), there was no evidence of a difference between the groups in pregnancy rates (odds ratio (OR) 1.98, 95% confidence interval (CI) 0.78 to 5.06; two studies, 90 participants, I² statistic = 0%, very low quality evidence). No study reported data on adverse events. When CHM plus clomiphene was compared with clomiphene (with or without CEA), there was low quality evidence of a higher pregnancy rate in the CHM plus clomiphene group (OR 2.62, 95% CI 1.65 to 4.14; three RCTs, 300 women, I² statistic = 0%,low quality evidence). No data were reported on adverse events. When CHM with follicle aspiration and ovulation induction was compared with follicle aspiration and ovulation induction alone, there was no evidence of a difference between the groups in pregnancy rates (OR 1.60, 95% CI 0.46 to 5.52; one study, 44 women, very low quality evidence), severe luteinized unruptured follicle syndrome (LUFS) (OR 0.60, 95% CI 0.06 to 6.14; one study, 44 women, very low quality evidence), ovarian hyperstimulation syndrome (OHSS) (OR 0.16, 95% CI 0.00 to 8.19; one study, 44 women, very low quality evidence) or multiple pregnancy (OR 0.60, 95% CI 0.06 to 6.14; one study, 44 women, very low quality evidence). When CHM with LOD was compared with LOD alone, there was no evidence of a difference between the groups in rates of pregnancy (OR 3.50, 95% CI 0.72 to 17.09; one study, 30 women, very low quality evidence), No data were reported on adverse events. There was no evidence of a difference between any of the comparison groups for any other outcomes. The quality of the evidence for all other comparisons and outcomes was very low. The main limitations in the evidence were failure to report live birth or adverse events, failure to describe study methods in adequate detail and imprecision due to very low event rates and wide CIs. There is insufficient evidence to support the use of CHM for women with PCOS and subfertility. No data are available on live birth, and there is no consistent evidence to indicate that CHM influences fertility outcomes. However there is very limited low quality evidence to suggest that the addition of CHM to clomiphene may improve pregnancy rates. There is insufficient evidence on adverse effects to indicate whether CHM is safe.

We searched evidence from commonly used databases and it is current to 9 June 2016. We included five RCTs with 414 participants. These included studies comparing CHM to western medicine, CHM plus western medicine versus western medicine, and CHM plus surgery versus surgery. All the included studies were in Chinese. All studies had fewer than six menstrual cycles treatment duration and less than one year follow-up duration. None of the included studies reported live birth, all reported pregnancy, two reported ovulation and only one reported adverse events. There was insufficient evidence to support the use of CHM for women with PCOS and subfertility. No data were available on live birth, and there was no consistent evidence to indicate that CHM improves fertility outcomes. When CHM was compared with clomiphene (with or without laparoscopic ovarian drilling (LOD) in both arms), the pregnancy rates were no different between the groups. When CHM with follicle aspiration and ovulation induction was compared with follicle aspiration and ovulation induction alone, pregnancy rates were no different between the groups. When CHM with LOD was compared with LOD alone, the pregnancy rates were no different between the groups. However there was limited low quality evidence to suggest that the addition of CHM to clomiphene may improve pregnancy rates. There was no evidence of a difference between any of the comparison groups for any other outcomes. There was insufficient evidence on adverse effects to indicate whether CHM is safe. The quality of the evidence was low or very low. The main limitations in the evidence were failure to report live birth or adverse events, failure to describe study methods in adequate detail, and imprecision, with very low event rates and wide confidence intervals.

cochrane-simplification-train-402

We identified five clinical trials that involved 3405 children for inclusion. For this 2016 update, we identified one new trial for inclusion. This trial was systematically reviewed but due to several sources of heterogeneity, was not included in the meta-analysis. The remaining four trials were of adequate methodological quality. In three RCTs that involved a total of 1826 healthy Finnish children attending daycare, there is moderate quality evidence that xylitol (in any form) can reduce the risk of AOM from 30% to around 22% compared with the control group (RR 0.75, 95% CI 0.65 to 0.88). Among the reasons for dropouts, there were no significant differences in abdominal discomfort and rash between the xylitol and the control groups. Xylitol was not effective in reducing AOM among healthy children during a respiratory infection (RR 1.13, 95% CI 0.83 to 1.53; moderate quality evidence) or among otitis-prone healthy children (RR 0.90, 95% CI 0.67 to 1.21; low-quality evidence). There is moderate quality evidence showing that the prophylactic administration of xylitol among healthy children attending daycare centres can reduce the occurrence of AOM. There is inconclusive evidence with regard to the efficacy of xylitol in preventing AOM among children with respiratory infection, or among otitis-prone children. The meta-analysis was limited because data came from a small number of studies, and most were from the same research group.

We identified five clinical trials that involved 3405 children, mostly from the same research group. Four trials were conducted in Finland and enrolled healthy children (three trials) or children with an acute respiratory infection (one trial). The fifth trial was conducted in the USA and enrolled otitis-prone children who were recruited from attendance at general medical practices. All five trials received governmental funding; and the Finnish study investigators have a US patent for the use of xylitol to treat respiratory infections. Xylitol, administered in chewing gum, lozenges or syrup, can reduce the occurrence of AOM among healthy children with no acute upper respiratory infection from 30% to 22%. There is no difference in side effects (namely, abdominal discomfort and rash). Based on these results we would expect that out of 1000 children up to 12 years of age, 299 would experience an AOM compared with between 194 and 263 children who would experience an AOM if they are provided with xylitol chewing gum. The preventive effect among healthy children with respiratory infection or among otitis-prone children is inconclusive. The quality of evidence was moderate for healthy children and children with respiratory infections but low for otitis-prone children.

cochrane-simplification-train-403

Our searches found no RCTs or Q-RCTs that met the eligibility criteria for this review. We are unable to reach any conclusion about the effectiveness of environmental or behavioural interventions for reducing physical activity limitation in community-dwelling visually impaired older people, as no eligible studies were found. However a number of studies reviewed included only the secondary outcome measures of this review. Although behavioural interventions delivered by occupational therapists have been shown to reduce the rate of falls, we are unable to conclude if this is due to reduced activity restriction (increased mobility) or reduced activity (lessening exposure to risk). There are inconclusive and conflicting results from trials evaluating the effectiveness of behavioural and environmental interventions aimed at improving quality of life. Further research is necessary (such as ongoing Dutch and UK trials considering the effectiveness of orientation and mobility training on activity restriction, physical activity, falls, fear of falling and quality of life in older adults with low vision, and the effect of an occupational therapist delivering home safety modification, coping strategies and exercise with older people with low vision) before any conclusions can be reached.

We searched for evidence from high quality trials on environmental or behavioural interventions in older adults, living in the community or in residential settings, with irreversible vision impairment which aimed to reduce activity restriction or increase general physical activity. We found no trials that met the inclusion criteria for the review. Further research into this highly important issue needs to be done before any conclusions can be made.

cochrane-simplification-train-404

We included three studies, two of which evaluated the progression from MCI to ADD, and one evaluated the progression from MCI to any form of dementia. Progression from MCI to ADD was evaluated in 448 participants. The studies reported data on 401 participants with 1.6 years of follow-up and in 47 participants with three years of follow-up. Sixty-one (15.2%) participants converted at 1.6 years follow-up; nine (19.1%) participants converted at three years of follow-up. Progression from MCI to any form of dementia was evaluated in five participants with 1.5 years of follow-up, with three (60%) participants converting to any form of dementia. There were concerns regarding applicability in the reference standard in all three studies. Regarding the domain of flow and timing, two studies were considered at high risk of bias. MCI to ADD; Progression from MCI to ADD in those with a follow-up between two to less than four years had a sensitivity of 67% (95% CI 30 to 93) and a specificity of 71% (95% CI 54 to 85) by visual assessment (n = 47, 1 study). Progression from MCI to ADD in those with a follow-up between one to less than two years had a sensitivity of 89% (95% CI 78 to 95) and a specificity of 58% (95% CI 53 to 64) by visual assessment, and a sensitivity of 87% (95% CI 76 to 94) and a specificity of 51% (95% CI 45 to 56) by quantitative assessment by the standardised uptake value ratio (SUVR)(n = 401, 1 study). MCI to any form of dementia; Progression from MCI to any form of dementia in those with a follow-up between one to less than two years had a sensitivity of 67% (95% CI 9 to 99) and a specificity of 50% (95% CI 1 to 99) by visual assessment (n = 5, 1 study). MCI to any other forms of dementia (non-ADD); There was no information regarding the progression from MCI to any other form of dementia (non-ADD). Although sensitivity was good in one included study, considering the poor specificity and the limited data available in the literature, we cannot recommend routine use of 18F-florbetapir PET in clinical practice to predict the progression from MCI to ADD. Because of the poor sensitivity and specificity, limited number of included participants, and the limited data available in the literature, we cannot recommend its routine use in clinical practice to predict the progression from MCI to any form of dementia. Because of the high financial costs of 18F-florbetapir, clearly demonstrating the DTA and standardising the process of this modality are important prior to its wider use.

The evidence is current to May 2017. We found three studies including 453 participants with MCI. Two studies evaluated the progression from MCI to ADD and one study evaluated the progression from MCI to any form of dementia. Regarding the two studies that evaluated the progression from MCI to ADD, one study had 401 participants with a follow-up of 1.6 years and the mean age was 72 years. The other study had 47 participants with a follow-up of three years, and the mean age was 72 years. The other study that looked at any form of dementia included 5 participants over 90 years old. Two of the studies were funded by the test manufacturer. The main limitation of this review was that our findings were based on only three studies, with insufficient detail on how the people were selected, whether the information from the scan was assessed separately from the final diagnosis. The studies were considered to be at high risk of bias due to potential conflicts of interest detected. In this review, we found the following results based on the three studies. At a follow-up of 1.6 years, using visual assessment, the scan correctly classified 89% of the participants who progressed to ADD but only 58% of the participants who did not progress to ADD. This means that in a group of 100 people with MCI, 15% of whom will develop ADD, we would expect 13 of 15 people to have a positive result and the other 2 participants to be falsely negative. Also 49 people who will not develop ADD would have a negative result, but 36 people who will not develop ADD would have a positive result (false positives). In the study that followed up people for three years and used visual assessment, the scan correctly classified 67% of people who progressed to ADD and 71% who did not progress to ADD. This means that in a group of 100 people with MCI, 19 of whom will develop ADD, we would expect 13 people to have a positive result of the scan and 6 people to have a falsely negative result. In addition, 58 of 81 participants who will not progress to ADD would have a negative result, but 23 people who will not develop ADD would have a positive result (false positives). The small number of participants evaluated at three years lowered our confidence on these estimates of accuracy. Regarding progression to any form of dementia, the extremely small number of participants meant that we were unable to provide meaningful estimates of accuracy. We conclude that 18F-florbetapir PET scans cannot be recommended for routine use in clinical practice to predict the progression from MCI to ADD or any form of dementia based on the currently available data. More studies are needed to demonstrate its usefulness.

cochrane-simplification-train-405

Of the 16 identified trials, four (112 participants) were eligible for inclusion. Two trials evaluated 59 people with haemophilia A and B undergoing 63 dental extractions. Trials compared the use of a different type (tranexamic acid or epsilon-aminocaproic acid) and regimen of antifibrinolytic agents as haemostatic support to the initial replacement treatment. Neither trial specifically addressed mortality (one of this review's primary outcomes); however, in the frame of safety assessments, no fatal adverse events were reported. The second primary outcome of blood loss was assessed after surgery and these trials showed the reduction of blood loss and requirement of post-operative replacement treatment in people receiving antifibrinolytic agents compared with placebo. The remaining primary outcome of need for re-intervention was not reported by either trial. Two trials reported on 53 people with haemophilia A and B with inhibitors treated with different regimens of recombinant activated factor VII (rFVIIa) for haemostatic coverage of 33 major and 20 minor surgical interventions. Neither of the included trials specifically addressed any of the review's primary outcomes (mortality, blood loss and need for re-intervention). In one trial a high-dose rFVIIa regimen (90 μg/kg) was compared with a low-dose regimen (35 μg/kg); the higher dose showed increased haemostatic efficacy, in particular in major surgery, with shorter duration of treatment, similar total dose of rFVIIa administered and similar safety levels. In the second trial, bolus infusion and continuous infusion of rFVIIa were compared, showing similar haemostatic efficacy, duration of treatment and safety. There is insufficient evidence from randomised controlled trials to assess the most effective and safe haemostatic treatment to prevent bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgical procedures. Ideally large, adequately powered, and well-designed randomised controlled trials would be needed, in particular to address the cost-effectiveness of such demanding treatments in the light of the increasing present economic constraints, and to explore the new challenge of ageing patients with haemophilia or other congenital bleeding disorders. However, performing such trials is always a complex task in this setting and presently does not appear to be a clinical and research priority. Indeed, major and minor surgeries are effectively and safely performed in these individuals in clinical practice, with the numerous national and international recommendations and guidelines providing regimens for treatment in this setting mainly based on data from observational, uncontrolled studies.

We searched for randomised controlled trials comparing the efficacy (mortality, blood loss, need for re-intervention, subjective assessment of efficacy, duration and dose of therapy) and the safety of any type of treatment given to people with congenital bleeding disorders during any type of surgery. We found four trials to be included in this review. Two trials evaluated 59 people with haemophilia A or B receiving antifibrinolytic drugs (agents that reduce the breakdown of clots) or placebo in addition to the initial standard treatment before dental extractions. The remaining two trials evaluated 53 people with haemophilia A or B and inhibitors (antibodies that act against the factor concentrate therapy) receiving an different clotting concentrate, recombinant activated factor VII, both during and after surgery. These two trials evaluated different treatment options: high-dose compared with low-dose and a single large (bolus) infusion compared with continuous infusion. The trials included in this review provide some information in two specific situations in people with congenital bleeding disorders undergoing surgery. However, on the whole, there is not enough evidence from trials to define the best treatments for the various types of disease and types of surgery. Further trials would be useful to improve our knowledge but are difficult to carry out and currently do not appear to be a clinical priority. Indeed, both major and minor surgery are safely performed in clinical practice in these individuals based on local experience and data from uncontrolled studies.

cochrane-simplification-train-406

We included eight studies (358 participants), five assessing TAP blocks, three assessing rectus sheath blocks; with moderate risk of bias overall. All studies had a background of general anaesthesia in both arms in most cases. Compared with no TAP block or saline placebo, TAP block resulted in significantly less postoperative requirement for morphine at 24 hours (mean difference (MD) -21.95 mg, 95% confidence interval (CI) -37.91 to 5.96; five studies, 236 participants) and 48 hours (MD -28.50, 95% CI -38.92 to -18.08; one study of 50 participants) but not at two hours (all random-effects analyses). Pain at rest was significantly reduced in two studies, but not a third. Only one of three included studies of rectus sheath blocks found a reduction in postoperative analgesic requirements in participants receiving blocks. One study, assessing number of participants who were pain-free after their surgery, found more participants who received a rectus sheath block to be pain-free for up to 10 hours postoperatively. As with TAP blocks, rectus sheath blocks made no apparent impact on nausea and vomiting or sedation scores. No studies have compared TAP block with other analgesics such as epidural analgesia or local anaesthetic infiltration into the abdominal wound. There is only limited evidence to suggest use of perioperative TAP block reduces opioid consumption and pain scores after abdominal surgery when compared with no intervention or placebo. There is no apparent reduction in postoperative nausea and vomiting or sedation from the small numbers of studies to date. Many relevant studies are currently underway or awaiting publication.

However, there have not been any systematic reviews evaluating the effectiveness of the TAP block in reducing pain after surgery. We have searched for research investigating the effectiveness of rectus sheath (a similar block to TAP) and TAP blocks in providing pain relief after abdominal surgery. We have included eight studies, with a total of 358 participants in this review, that show some limited evidence that TAP blocks improve pain relief after abdominal surgery. More research is indicated, comparing TAP blocks with other standard methods of pain relief such as, morphine medication, epidural analgesia and local anaesthetic injection into and around the surgical wound. There are many studies currently underway or awaiting publication which assess the effectiveness of the TAP block and compare it with other techniques. We intend to include these studies in an updated version of this review in the near future.

cochrane-simplification-train-407

For this update we identified one new study (43 participants), but it did not contribute any data for analysis. The review included 13 studies using sumatriptan 85 mg or 50 mg plus naproxen 500 mg to treat attacks of mild, moderate, or severe pain intensity. Twelve studies contributed data for analyses: 3663 participants received combination treatment, 3682 placebo, 964 sumatriptan, and 982 naproxen. We judged only one small study to be at high risk of bias for any of the criteria evaluated; it did not contribute to any analyses. Overall, the combination was better than placebo for the primary outcomes of pain-free and headache relief at two hours. The NNT for pain-free at two hours was 3.1 (95% confidence interval 2.9 to 3.5) when the baseline pain was mild (50% response with sumatriptan plus naproxen compared with 18% with placebo), and 4.9 (4.3 to 5.7) when baseline pain was moderate or severe (28% with sumatriptan plus naproxen compared with 8% with placebo) (high quality evidence). Using 50 mg of sumatriptan, rather than 85 mg, in the combination did not significantly change the result. Treating early, when pain was still mild, was significantly better than treating once pain was moderate or severe for pain-free responses at two hours and during the 24 hours post dose. Adverse events were mostly mild or moderate in severity and rarely led to withdrawal; they were more common with the combination than with placebo (moderate quality evidence). Where the data allowed direct comparison, combination treatment was superior to either monotherapy, but adverse events were less frequent with naproxen than with sumatriptan (moderate quality evidence). The conclusions of this review were not changed. Combination treatment was effective in the acute treatment of migraine headaches. The effect was greater than for the same dose of either sumatriptan or naproxen alone, but additional benefits over sumatriptan alone were not large. More participants achieved good relief when medication was taken early in the attack, when pain was still mild. Adverse events were more common with the combination and sumatriptan alone than with placebo or naproxen alone.

On 28 October 2015, we looked for clinical trials using sumatriptan plus naproxen to treat migraine headache in adults. People were given either a combination of sumatriptan and naproxen, sumatriptan only, naproxen only, or a placebo (dummy) treatment. They did not know which treatment they were taking, and nor did the health professionals looking after them. We found 13 studies, of which 12 (with about 9300 people) provided information on how well the combination treatment worked. The combination of sumatriptan plus naproxen was better than placebo for relieving acute migraine attacks in adults. When the starting headache intensity was mild, 5 in 10 (50%) of people treated with the combination were pain-free at two hours compared with about 2 in 10 (18%) with placebo. Almost 6 in 10 (58%) people with moderate or severe pain who were treated with the combination had pain reduced to mild or none at two hours, compared with 3 in 10 (27%) with placebo. The combination was also better than the same dose of either drug given alone in these people. Results were 5 in 10 (52%) people with sumatriptan alone or about 4 in 10 (44%) with naproxen alone. The combination was better than placebo or either drug alone for relief of other migraine symptoms (nausea, sensitivity to light or sound) and loss of ability to function normally. Adverse events of dizziness, tingling or burning of the skin, sleepiness (somnolence), nausea, indigestion (dyspepsia), dry mouth, and chest discomfort were more common with sumatriptan (alone or in combination) than with placebo or naproxen. They were generally of mild to moderate severity and rarely led to withdrawal from the studies. The studies were carried out to high standards and were generally large enough to give reliable results, so that most of the results for efficacy were of high quality. Results for adverse events were downgraded to moderate quality because there were fewer events.

cochrane-simplification-train-408

A total of three studies involving 144 eligible participants were included in the review. Two of the studies (56 participants) compared an early version of acceptance and commitment therapy (ACT) with CBT, and one study (88 eligible participants) compared extended behavioural activation with CBT. No other studies of third wave CBT were identified. The two ACT studies were assessed as being at high risk of performance bias and researcher allegiance. Post-treatment results, which were based on dropout rates, showed no evidence of any difference between third wave CBT and other psychological therapies for the primary outcomes of efficacy (risk ratio (RR) of clinical response 1.14, 95% confidence interval (CI) 0.79 to 1.64; very low quality) and acceptability. Results at two-month follow-up showed no evidence of any difference between third wave CBT and other psychological therapies for clinical response (2 studies, 56 participants, RR 0.22, 95% CI 0.04 to 1.15). Moderate statistical heterogeneity was indicated in the acceptability analyses (I2 = 41%). Very low quality evidence suggests that third wave CBT and CBT approaches are equally effective and acceptable in the treatment of acute depression. Evidence is limited in quantity, quality and breadth of available studies, precluding us from drawing any conclusions as to their short- or longer-term equivalence. The increasing popularity of third wave CBT approaches in clinical practice underscores the importance of completing further studies to compare various third wave CBT approaches with other psychological therapy approaches to inform clinicians and policymakers on the most effective forms of psychological therapy in treating depression.

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) to help people become aware of their thoughts and accept them in a non-judgemental way. The aim of the review was to find out whether third wave CBT was more effective and acceptable than other psychological therapy approaches for people with acute depression. The review included three studies, involving a total of 144 people. The studies examined two different forms of third wave CBT, consisting of acceptance and commitment therapy (ACT) (two studies) and extended behavioural activation (BA) (one study). All three studies compared these third wave CBT approaches with CBT. The results suggested that third wave CBT and CBT approaches were equally effective in treating depression. However, the quality of evidence was very low because of the small number of studies of poor quality that we included in the review; therefore it is not possible to conclude whether third wave CBT approaches might be more effective and acceptable than other psychological therapies in the short term or over a longer period of time. Given the increasing popularity of third wave CBT approaches in clinical practice, further studies should be prioritised to establish whether third wave CBT approaches are more helpful than other psychological therapies in treating people with acute depression.

cochrane-simplification-train-409

Seven trials were included (362 participants randomized, data from 264 participants available for analysis); six of parallel design and one a partial cross-over design. One multicenter trial was conducted in Canada; the remaining six were single centre undertaken in the UK, USA, Iran and in the Netherlands. All trials had a high risk of bias for participant blinding and use of patient-reported outcomes. Evidence was retrieved on four interventions: psycho-education (DVD plus information booklet versus information booklet alone; computerised learning versus no intervention); cognitive therapy (auto-hypnosis (self-hypnosis) versus control); and behavioural therapy (relaxation (progressive or self control) versus no treatment). We also aimed to assess psychodynamic therapy and systemic therapy, but no trials were identified. Heterogeneity of the outcome measures and measurements precluded meta-analyses. No trial reported the cost of the psychological intervention and family adjustment. DVD plus information booklet compared to information booklet alone One trial (108 participants) showed coping strategies may lower pre-contemplation scores and negative thoughts, mean difference (MD) -0.24 (95%CI -0.48 - 0.00, low-certainty evidence), however, other measures of coping strategies in the same trial suggest little or no difference between groups, e.g. contemplation, MD (-0.09, 95%CI -0.32 – 0.14, low-certainty evidence). The same trial measured QoL and showed little or no difference between treatment groups for the physical domain, MD 0.59 (95% CI -3.66 to 4.84, low-certainty evidence), but may improve scores in the mental health domain for those receiving the booklet plus DVD compared to booklet alone, MD (4.70, 95% CI 0.33 to 9.07, low-certainty evidence). Mood or personal well-being were not reported. Computerised learning compared to no intervention Two trials (57 participants) reported on interventions aimed at children and adolescents and their impact on promoting a sense of self-efficacy (primary outcome 'Mood and personal well-being'), but only one showed an increase, MD 7.46 (95%CI 3.21 to 11.71, 17 participants, very low-certainty evidence); the second did not report control group data. One trial (30 participants) showed the intervention did not improve self-efficacy in adults, but appropriate data could not be extracted. Two trials (47 participants) reported coping strategies; one only reported within-group differences from baseline, the second showed an increase from baseline in coping strategies in the Internet program group compared to the no intervention group (disease-specific knowledge, MD 2.45 (95% CI 0.89 to 4.01); self-management ability and transition readiness, MD 19.90 (95% CI 3.61 to 36.19; low-certainty evidence). One trial reported QoL but with insufficient information to calculate changes from baseline; no difference in post-treatment scores was seen between groups, MD -8.65, 95% CI -18.30 to 1.00, very low-certainty evidence). Auto-hypnosis (self-hypnosis) compared to control There were two older trials that reported on this intervention (50 participants) focusing mainly on the secondary outcome 'physical health'; only one trial reported the primary outcome ‘mood and personal well-being’ (only within-group differences in the treatment group). Coping strategies and QoL were not assessed in the trials. Relaxation (progressive or self control) compared to no treatment Only one trial (seven participants) from 1985, was included which focused on 'physical health' and did not report on any of our primary outcomes. Not all of the seven included trials analysed the effects of the interventions on our primary outcomes (mood and personal well-being, coping strategies and QoL). Three trials were conducted in the 1970s and 1980s using techniques of auto-hypnosis or relaxation and, in accordance with the needs and therapeutic possibilities of the time, they focused on secondary outcomes, e.g. frequency of bleeding (physical health) and adherence to the intervention. The four newer trials assessed psycho-educational interventions all mediated by the use of technologies (DVD or computer) and often created according to age needs of the target group. In these cases, attention was shifted to our pre-defined primary outcomes. This review has identified low- and very low-certainty evidence, prompting caution in its interpretation. The major problem we encountered was the heterogeneity of trial designs, of interventions and of outcome measures used across the trials. We strongly suggest that researchers consider developing a core outcome set to streamline future research; randomization was proven to be safe and acceptable, and blinding should be considered for those assessing patient-reported outcomes.

We included trials comparing people with hemophilia receiving any psychological intervention compared with other individuals receiving a different intervention or no intervention at all. We found seven trials with 362 people with hemophilia aged between 6 and 65 years of age. Trials compared either a DVD plus information booklet or computerised learning or auto-hypnosis (self-hypnosis) or relaxation techniques to no treatment and people were selected for one treatment or the other randomly. The trials lasted from one to six months. All treatments were safe, no major side effects were reported. Psycho-educational interventions in children and adolescents seemed to promote a sense of self-efficacy and better self-management skills, but the quality of the evidence suggests that more rigorous experimental design is required. One trial in adults did not show any effect. Self-hypnosis and relaxation techniques were not tested for the primary outcome but were useful in decreasing the number and severity of joint bleeds when drug treatment was not available. The effects of these interventions on quality of life vary. The major problem we encountered in this review is the difference in trial designs, interventions and outcome measures used across the trials. We strongly suggest that researchers in the field consider developing a core outcome set to streamline future research. Randomization was proven to be safe and acceptable in this research field, and blinding of outcome assessors should be considered in the presence of patient-reported outcomes. The overall quality of the evidence was low to very low.

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Of 785 identified citations, 20 trials from 1990 to 2011 enrolling 1652 participants fulfilled the inclusion criteria. We judged most of the trials to be at low or unclear risk of bias across the six domains, and we judged four studies to have elements of high risk of bias; we did not classify any studies at overall low risk of bias. The quality of evidence was low for five of the seven outcomes (very low N = 1, moderate N = 1) and there was heterogeneity among the studies. There was a variety of adult participants and the procedures were performed by a wide range of differently experienced operators in different situations. There was no evidence of a difference in the rate of the primary outcomes: mortality directly related to the procedure (Peto odds ratio (POR) 0.52, 95% confidence interval (CI) 0.10 to 2.60, I² = 44%, P = 0.42, 4 studies, 257 participants, low quality evidence); and serious, life-threatening adverse events - intraoperatively: risk ratio (RR) 0.93, 95% CI 0.57 to 1.53, I² = 27%, P = 0.78, 12 studies, 1211 participants, low quality evidence,and direct postoperatively: RR 0.72, 95% CI 0.41 to 1.25, I² = 24%, P = 0.24, 10 studies, 984 participants, low quality evidence. PTs significantly reduce the rate of the secondary outcome, wound infection/stomatitis by 76% (RR 0.24, 95% CI 0.15 to 0.37, I² = 0%, P < 0.00001, 12 studies, 936 participants, moderate quality evidence) and the rate of unfavourable scarring by 75% (RR 0.25, 95% CI 0.07 to 0.91, I² = 86%, P = 0.04, 6 studies, 789 participants, low quality evidence). There was no evidence of a difference in the rate of the secondary outcomes, major bleeding (RR 0.70, 95% CI 0.45 to 1.09, I² = 47%, P = 0.12, 10 studies, 984 participants, very low quality evidence) and tracheostomy tube occlusion/obstruction, accidental decannulation, difficult tube change (RR 1.36, 95% CI 0.65 to 2.82, I² = 22%, P = 0.42, 6 studies, 538 participants, low quality evidence). When compared to STs, PTs significantly reduce the rate of wound infection/stomatitis (moderate quality evidence) and the rate of unfavourable scarring (low quality evidence due to imprecision and heterogeneity). In terms of mortality and the rate of serious adverse events, there was low quality evidence that non-significant positive effects exist for PTs. In terms of the rate of major bleeding, there was very low quality evidence that non-significant positive effects exist for PTs. However, because several groups of participants were excluded from the included studies, the number of participants in the included studies was limited, long-term outcomes were not evaluated, and data on participant-relevant outcomes were either sparse or not available for each study, the results of this meta-analysis are limited and cannot be applied to all critically ill adults.

The evidence is current to May 2015. We included 20 studies from 1990 to 2011, enrolling 1652 adult participants hospitalized in the ICU, who were scheduled for planned tracheotomy. None of the studies were funded. The application of percutaneous techniques, does not reduce the rate of death, of serious, life-threatening complications (e.g. injuries to the windpipe or the oesophagus), major bleeding or problems with the tracheostomy tube (blockage, accidental loss, difficult tube change). There was some evidence that using percutaneous techniques results in fewer cases of wound infections (- 76%) and unfavourable scarring (- 75%). The quality of the evidence varied by outcome from moderate (wound infection) to low (death, serious complications, unfavourable scarring, problems with the tracheostomy tube) and to very low (major bleeding). Reasons for the limitations are: great differences among the studies, results not similar across the studies, and not enough data. Based on the available data, we conclude that percutaneous tracheostomies offer benefits for some of the outcomes when compared with surgical tracheostomies. However, because several groups of participants were excluded from the included studies (i.e. people with unfavourable neck structure, bleeding disorders or emergency situations), the number of participants in the included studies was limited, long-term outcomes were not evaluated, and data on participant-relevant outcomes were either sparse or not available for each study, the results of this meta-analysis are limited and cannot be applied to all critically ill adults.

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We included 18 RCTs (739 participants) that tested the effectiveness of a broad range of physiotherapy-based interventions. Overall, there was a paucity of high quality evidence concerning physiotherapy treatment for pain and disability in people with CRPS I. Most included trials were at 'high' risk of bias (15 trials) and the remainder were at 'unclear' risk of bias (three trials). The quality of the evidence was very low or low for all comparisons, according to the GRADE approach. We found very low quality evidence that graded motor imagery (GMI; two trials, 49 participants) may be useful for improving pain (0 to 100 VAS) (mean difference (MD) −21.00, 95% CI −31.17 to −10.83) and functional disability (11-point numerical rating scale) (MD 2.30, 95% CI 1.12 to 3.48), at long-term (six months) follow-up, in people with CRPS I compared to usual care plus physiotherapy; very low quality evidence that multimodal physiotherapy (one trial, 135 participants) may be useful for improving 'impairment' at long-term (12 month) follow-up compared to a minimal 'social work' intervention; and very low quality evidence that mirror therapy (two trials, 72 participants) provides clinically meaningful improvements in pain (0 to 10 VAS) (MD 3.4, 95% CI −4.71 to −2.09) and function (0 to 5 functional ability subscale of the Wolf Motor Function Test) (MD −2.3, 95% CI −2.88 to −1.72) at long-term (six month) follow-up in people with CRPS I post stroke compared to placebo (covered mirror). There was low to very low quality evidence that tactile discrimination training, stellate ganglion block via ultrasound and pulsed electromagnetic field therapy compared to placebo, and manual lymphatic drainage combined with and compared to either anti-inflammatories and physical therapy or exercise are not effective for treating pain in the short-term in people with CRPS I. Laser therapy may provide small clinically insignificant, short-term, improvements in pain compared to interferential current therapy in people with CRPS I. Adverse events were only rarely reported in the included trials. No trials including participants with CRPS II met the inclusion criteria of this review. The best available data show that GMI and mirror therapy may provide clinically meaningful improvements in pain and function in people with CRPS I although the quality of the supporting evidence is very low. Evidence of the effectiveness of multimodal physiotherapy, electrotherapy and manual lymphatic drainage for treating people with CRPS types I and II is generally absent or unclear. Large scale, high quality RCTs are required to test the effectiveness of physiotherapy-based interventions for treating pain and disability of people with CRPS I and II. Implications for clinical practice and future research are considered.

We searched for clinical trials of physiotherapy up to 12 February 2015. We included 18 trials that had 739 participants with CRPS I. In most of these trials the participants had CRPS I of the arm and hand. We did not find any clinical trials that included participants with CRPS II. Overall we did not find any good quality clinical trials of physiotherapy aimed at reducing the pain and disability of CRPS I in adults. Most included trials were not well designed and contained only small numbers of patients. We did find some low quality trials suggesting that two broadly similar types of rehabilitation training, known as 'graded motor imagery' (GMI) and 'mirror therapy', might be useful for reducing the pain and disability associated with CRPS I after traumatic events or surgery or a stroke. From the limited evidence available it appears that some types of electrotherapy, such as ultrasound and pulsed electromagnetic field therapy, as well as a type of massage therapy known as manual lymphatic drainage, are not effective. Most studies did not report on adverse events and so we do not know if these treatments have any harmful side-effects. On the whole, because of the limited number and low quality of available trials for the various physiotherapy treatments, we cannot be sure if any of the physiotherapy treatments we evaluated are effective for treating the pain and disability of CRPS I in adults. It is possible that some treatments, such as GMI or mirror therapy, might be effective. Further high quality clinical trials of physiotherapy are needed in order to find out if any of the different types of physiotherapy treatment are effective at improving pain and disability in people with CRPS.

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We included 13 RCTs, although we could only extract data to meta-analyse 12 trials, which involved 3720 participants including children, adults (aged around 40 years) and older people. We found that probiotics were better than placebo when measuring the number of participants experiencing episodes of acute URTI (at least one episode: odds ratio (OR) 0.53; 95% confidence interval (CI) 0.37 to 0.76, P value < 0.001, low quality evidence; at least three episodes: OR 0.53; 95% CI 0.36 to 0.80, P value = 0.002, low quality evidence); the mean duration of an episode of acute URTI (mean difference (MD) -1.89; 95% CI -2.03 to -1.75, P value < 0.001, low quality evidence); reduced antibiotic prescription rates for acute URTIs (OR 0.65; 95% CI 0.45 to 0.94, moderate quality evidence) and cold-related school absence (OR 0.10; 95% CI 0.02 to 0.47, very low quality evidence). Probiotics and placebo were similar when measuring the rate ratio of episodes of acute URTI (rate ratio 0.83; 95% CI 0.66 to 1.05, P value = 0.12, very low quality evidence) and adverse events (OR 0.88; 95% CI 0.65 to 1.19, P value = 0.40, low quality evidence). Side effects of probiotics were minor and gastrointestinal symptoms were the most common. We found that some subgroups had a high level of heterogeneity when we conducted pooled analyses and the evidence level was low or very low quality. Probiotics were better than placebo in reducing the number of participants experiencing episodes of acute URTI, the mean duration of an episode of acute URTI, antibiotic use and cold-related school absence. This indicates that probiotics may be more beneficial than placebo for preventing acute URTIs. However, the quality of the evidence was low or very low.

After searching for all relevant trials in scientific databases, we identified 13 randomised controlled trials (RCTs) published up to July 2014. We could extract and pool data from 12 RCTs, which involved 3720 participants (both genders), including children, adults (aged around 40 years) and older people from Finland, Spain, Sweden, the United States, Croatia, Chile, Thailand and Japan. Probiotics were found to be better than placebo in reducing the number of participants experiencing episodes of acute URTI by about 47% and the duration of an episode of acute URTI by about 1.89 days. Probiotics may slightly reduce antibiotic use and cold-related school absence. Side effects of probiotics were minor and gastrointestinal symptoms were the most common. The quality of the evidence is low or very low mainly due to poorly conducted trials, for example with unclear randomisation method and blinding. Some trials were supported by manufacturers of the tested probiotics and some trials had a very small sample size. Overall, we found probiotics to be better than placebo in preventing acute URTIs. However, more trials are needed to confirm this conclusion.

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Four trials fulfilled the selection criteria: one of azathioprine (27 participants), two of IFN beta-1a (77 participants in total) and one of methotrexate (60 participants). The risk of bias was considered low in the trials of IFN beta-1a and methotrexate but high in the trial of azathioprine. None of the trials showed significant benefit in any of the outcomes selected by their authors. The results of the outcomes which approximated most closely to the primary outcome for this review were as follows. In the azathioprine trial there was a median improvement in the Neuropathy Impairment Scale (scale range 0 to 280) after nine months of 29 points (range 49 points worse to 84 points better) in the azathioprine and prednisone treated participants compared with 30 points worse (range 20 points worse to 104 points better) in the prednisone alone group. There were no reports of adverse events. In a cross-over trial of IFN beta-1a with 20 participants, the treatment periods were 12 weeks. The median improvement in the Guy's Neurological Disability Scale (range 1 to 10) was 0.5 grades (interquartile range (IQR) 1.8 grades better to zero grade change) in the IFN beta-1a treatment period and 0.5 grades (IQR 1.8 grades better to 1.0 grade worse) in the placebo treatment period. There were no serious adverse events in either treatment period. In a parallel group trial of IFN beta-1a with 67 participants, none of the outcomes for this review was available. The trial design involved withdrawal from ongoing IVIg treatment. The primary outcome used by the trial authors was total IVIg dose administered from week 16 to week 32 in the placebo group compared with the IFN beta-1a groups. This was slightly but not significantly lower in the combined IFN beta-1a groups (1.20 g/kg) compared with the placebo group (1.34 g/kg, P = 0.75). There were four participants in the IFN beta-1a group and none in the placebo group with one or more serious adverse events, risk ratio (RR) 4.50 (95% confidence interval (CI) 0.25 to 80.05). The methotrexate trial had a similar design involving withdrawal from ongoing corticosteroid or IVIg treatment. At the end of the trial (approximately 40 weeks) there was no significant difference in the change in the Overall Neuropathy Limitations Scale, a disability scale (scale range 0 to 12), the median change being 0 (IQR −1 to 0) in the methotrexate group and 0 (IQR −0.75 to 0) in the placebo group. These changes in disability might have been confounded by the reduction in corticosteroid or IVIg dose required by the protocol. There were three participants in the methotrexate group and one in the placebo with one or more serious adverse events, RR 3.56 (95% CI 0.39 to 32.23). Low-quality evidence from randomised trials does not show significant benefit from azathioprine or interferon beta-1a and moderate-quality evidence from one randomised trial does not show significant benefit from a relatively low dose of methotrexate for the treatment of CIDP. None of the trials was large enough to rule out small or moderate benefit. The evidence from observational studies is insufficient to avoid the need for randomised controlled trials to discover whether these drugs are beneficial. Future trials should have improved designs, more sensitive outcome measures relevant to people with CIDP, and longer treatment durations.

We found four trials. A trial with 27 participants compared the effects of azathioprine together with steroids to steroids alone for nine months. Azathioprine is a drug that is often used to treat autoimmune diseases because it suppresses the harmful immune cells. This trial had a parallel-group design, which means that the participants were divided into groups that each received only one of the treatments. A cross-over design trial with 10 participants compared the immune-regulating drug interferon (IFN) beta-1a with placebo (dummy treatment) for 12 weeks. The cross-over design means that all participants received both treatments in random order. A parallel-group trial with 67 participants also compared interferon beta-1a with placebo, but for 32 weeks. Another parallel-group trial with 60 participants compared the cytotoxic drug methotrexate with placebo for 40 weeks. The IFN beta-1a trials, but not the azathioprine or methotrexate trials, received pharmaceutical company support or sponsorship. None of these trials showed significant benefit or harm from the drugs. We selected disability scores as our primary measure of the effect of treatment. All the trials were too small to detect or rule out anything but major benefit or harm. We rated the quality of the evidence as moderate or low for IFN beta-1a and methotrexate because of problems with trial design, and because the small number of participants made the result imprecise. We rated the quality of the evidence for azathioprine as low because of lack of blinding and imprecision. Observational studies of these and other drugs, including the cytotoxic drugs cyclophosphamide, ciclosporin, mycophenolate, rituximab, alemtuzumab and natalizumab, peripheral blood stem cell transplantation, and the immune regulating drug interferon (IFN) alfa, exist but are of insufficient quality to determine whether any of these treatments are beneficial. The evidence is up to date to May 2016.

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Only two studies, with a total of 65 participants, were eligible for inclusion in the review. Overall the quality of the two studies was low, with small study populations and significant sources of bias, so we were not able to use all the data in our comparisons. . The studies were old from 1968 and 1972, and would be unlikely to pass modern peer review standard. We were only able to find short-term data and only trials randomising zuclopenthixol dihydrochloride. We also hoped to identify data for zuclopenthixol acetate versus placebo and zuclopenthixol decanoate versus placebo comparisons. We were unable to identify any studies that included data on these two fairly widely used drugs. For our primary outcome of interest, clinically significant improvement, we found one study that provided useable data. Global state measured by clinical global impression scale (CGI) improvement showed different ratings when assessed by a psychiatrist or a nurse.The psychiatrist scores failed to achieve statistical significance, however when assessed by nursing staff, the difference favouring zuclopenthixol did reach statistical significance (1 RCT n = 29, RR 2.57 95% CI 1.06 to 6.20, very low quality data). There was also evidence of increased sedation with those treated with zuclopenthixol when compared with placebo (1 RCT n = 29, RR 4.67 95% CI 1.23 to 17.68, very low quality data). 'Leaving the study early' data were equivocal. No useable data were available for outcomes such as relapse, mental state, death, quality of life, service use or economic costs. For people with schizophrenia this review shows that zuclopenthixol dihydrochloride may help with the symptoms of schizophrenia. The review provides some trial evidence that, if taking zuclopenthixol dihydrochloride, people may experience some adverse effects and sedation compared with placebo. However this evidence is of very low quality and with some significant sources of bias. There are no data for zuclopenthixol decanoate or zuclopenthixol acetate. For clinicians, the available trial data on the absolute effectiveness of zuclopenthixol dihydrochloride do support its use but the limited nature of the data and significant sources of bias make conclusions hard to draw. Zuclopenthixol in all three forms is a commonly used antipsychotic and it is disappointing that there are so few data regarding its use.

We searched for randomised controlled trials comparing zuclopenthixol with placebo in 2013. We found only two studies with 65 participants which could be included in this review. Overall the quality of these studies was low, with small numbers of people and significant bias. The studies were old, from 1968 and 1972, and would be unlikely to pass modern peer review standards. Only short-term information and data could be found, and only about zuclopenthixol dihydrochloride. The information is very limited but suggests that zuclopenthixol can lead to improvement in global state in comparison with placebo. However, there is also increased risk of side effects such as sedation,and tiredness. Given the low quality of information and age of the two studies, further research is needed, particularly further research on zuclopenthixol compared to newer and more recent antipsychotic drugs.

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We included 16 studies (involving 13,123 participants) in this systematic review, two of which were of high quality. These two studies showed that nicotine sublingual tablet and varenicline increased the quit rate over placebo (risk ratio (RR) 2.60 (95% confidence interval (CI) 1.29 to 5.24) and RR 3.34 (95% CI 1.88 to 5.92)). Pooled results of two studies also showed a positive effect of bupropion compared with placebo (RR 2.03 (95% CI 1.26 to 3.28)). When pooling these four studies, we found high-quality evidence for the effectiveness of pharmacotherapy plus high-intensity behavioural treatment compared with placebo plus high-intensity behavioural treatment (RR 2.53 (95% CI 1.83 to 3.50)). Furthermore, we found some evidence that high-intensity behavioural treatment increased abstinence rates when compared with usual care (RR 25.38 (95% CI 8.03 to 80.22)) or low-intensity behavioural treatment (RR 2.18 (95% CI 1.05 to 4.49)). Finally, the results showed effectiveness of various combinations of psychosocial and pharmacological interventions. We found high-quality evidence in a meta-analysis including four (1,540 participants) of the 16 included studies that a combination of behavioural treatment and pharmacotherapy is effective in helping smokers with COPD to quit smoking. Furthermore, we conclude that there is no convincing evidence for preferring any particular form of behavioural or pharmacological treatment.

We looked for studies that included adult men and women who were current smokers and had a diagnosis of COPD. We included studies that assessed the effectiveness of any behavioural support or medication, or both as an aid to quit smoking. We included studies that compared different types of treatment or compared treatment to stop smoking with no treatment or 'usual care'. We only included studies that reported how many people had stopped smoking after at least six months of follow-up. We carried out the most recent search for studies in March 2016. We found high-quality evidence from a collection of four (1,540 participants) of the total 16 included studies (13,123 participants) in this review. Overall, we found evidence that smokers with COPD who receive a combination of high-intensity behavioural support and medication are more than twice as likely to quit as people who receive behavioural support alone. We found no clear evidence that one particular form of behavioural support or medication is better than another. It is still unclear whether smokers with COPD are different from smokers without COPD with regard to which treatments work best to help them stop smoking. We are quite confident in the finding that a combination of behavioural support and medication works better than behavioural support alone. However, we were not able to combine the results of many of the studies because the treatments or the outcomes of the studies were too different from each other.

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We included five studies, involving 756 participants. Three studies assessed the effect of brief psychological therapies, one assessed the impact of a self-help booklet, and one the effect of collaborative care. The disparate nature of the trials covering different patient populations, interventions and outcomes meant that it was not possible to pool data meaningfully across studies. There was no evidence of a protective effect of brief psychological therapy or educational booklets on preventing disability. There was evidence from one trial of a reduction in both post-traumatic stress disorder (PTSD) and depressive symptoms one month after injury in those who received a collaborative care intervention combined with a brief psycho-educational intervention, however this was not retained at follow up. Overall mental health status was the only disability outcome affected by any intervention. In three trials the psychosocial intervention had a detrimental effect on the mental health status of patients. This review provides no convincing evidence of the effectiveness of psychosocial interventions for the prevention of disability following traumatic physical injury. Taken together, our findings cannot be considered as supporting the provision of psychosocial interventions to prevent aspects of disability arising from physical injury. However, these conclusions are based on a small number of disparate trials with small to moderate sample sizes and are therefore necessarily cautious. More research, using larger sample sizes, and similar interventions and patient populations to enable pooling of results, is needed before these findings can be confirmed.

This review identified five randomised controlled trials, involving 756 participants, which evaluated psychosocial interventions for the prevention of disability following traumatic injury. No convincing evidence was found supporting the efficacy of these interventions. In particular, self-help booklets and interpersonal therapies had no effect on preventing disability. There was some evidence that a more complex intervention involving collaborative care reduced symptoms of depression and PTSD in the short but not the medium term. There was evidence from three trials that psychosocial interventions had a detrimental effect on mental health. Taken together, our findings cannot be taken as supporting the provision of psychosocial interventions to prevent aspects of disability arising from physical injury. These results suggest that future interventions should focus on screening patients at risk of poor outcomes and only treating those who develop subsequent problems. However, the strength of these conclusions is limited by the small size and varied nature of many of the trials, which means that their results cannot be pooled.

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There were a total of 2276 subjects across the 34 included studies; 1264 subjects were assigned to exercise interventions. The 34 studies comprised 47 interventions that included exercise. Effects of several disparate interventions on global well-being, selected FM signs and symptoms, and physical function in individuals with FM were summarized using standardized mean differences (SMD). There is moderate quality evidence that aerobic-only exercise training at recommended intensity levels has positive effects global well-being (SMD 0.49, 95% CI: 0.23 to 0.75) and physical function (SMD 0.66, 95% CI: 0.41 to 0.92) and possibly on pain (SMD 0.65, 95% CI: -0.09 to 1.39) and tender points (SMD 0.23, 95% CI: -0.18 to 0.65). Strength and flexibility remain under-evaluated. There is 'gold' level evidence (www.cochranemsk.org) that supervised aerobic exercise training has beneficial effects on physical capacity and FM symptoms. Strength training may also have benefits on some FM symptoms. Further studies on muscle strengthening and flexibility are needed. Research on the long-term benefit of exercise for FM is needed.

In the studies, aerobic exercises were done for at least 20 minutes once a day (or twice for at least 10 minutes), 2 to 3 days a week. Strength training was done 2 to 3 times a week and with at least 8 to 12 repetitions per exercise. The exercise programs lasted between 2 ½ to 24 weeks. When compared to no exercising, aerobic exercise training may: - improve overall well-being by 7 points on a scale of 0 to 100. - improve ability to perform aerobic exercise; by using 2.8 ml/kg/minute more oxygen when walking on a treadmill. - increase the amount of pressure that can be applied to a tender point by 0.23 kgs/cm2 before the onset of pain. - reduce pain by 1.3 on a scale of 0 to 10. - have unknown effects on fatigue, depression or stiffness. These results are based on moderate quality evidence. Best estimate of what happens to people with fibromyalgia who take part in strength training: When compared to no exercise, strength training may: - reduce pain by 49 fewer points on scale of 0 to 100. - improve overall well-being by 41 points on a scale of 0 to 100. - lead to 2 fewer active tender points on a scale of 0-18. These results are based on low quality evidence. The numbers given are our best estimate. When possible, we have also presented a range because there is a 95 percent chance that the true effect of the treatment lies somewhere within that range.

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Five studies are included (2187 women). It was not possible for the intervention to be blinded, and it is not clear what impact lack of blinding would have on the outcomes reported. For other 'Risk of bias' domains studies were either at low or unclear risk of bias. One study reported on ECV that was undertaken and completed before 37 weeks' gestation compared with no ECV. No difference was found in the rate of non-cephalic presentation at birth (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.64 to 1.69; participants = 102). One study reported on a policy of ECV that was initiated before term (33 weeks) and up until 40 weeks' gestation and which could be repeated up until delivery compared with no ECV. This study showed a decrease in the rate of non-cephalic presentation at birth (RR 0.59, 95% CI 0.45 to 0.77; participants = 179). Three studies reported on ECV started at between 34 to 35 weeks' gestation compared with beginning at 37 to 38 weeks' gestation. Pooled results suggested that early ECV reduced the risk of non-cephalic presentation at birth (RR 0.81, 95% CI 0.74 to 0.90; participants = 1906; studies = three; I² = 0%, evidence graded high quality), failure to achieve vaginal cephalic birth (RR 0.90, 95% CI 0.83 to 0.97; participants = 1888; studies = three; I² = 0%, evidence graded high quality), and vaginal breech delivery (RR 0.44, 95% CI 0.25 to 0.78; participants = 1888; studies = three; I² = 0%, evidence graded high quality). The difference between groups for risk of caesarean was not statistically significant (RR 0.92, 95% CI 0.85 to 1.00; participants = 1888; studies = three; I² = 0%, evidence graded high quality). There was evidence that risk of preterm labour was increased with early ECV compared with ECV after 37 weeks (6.6% in the ECV group and 4.3% for controls) (RR 1.51, 95% CI 1.03 to 2.21; participants = 1888; studies = three; I² = 0%, evidence graded high quality). There was no clear difference between groups for low infant Apgar score at five minutes or perinatal death (stillbirth plus neonatal mortality up to seven days) (evidence graded as low quality for both outcomes). Compared with no ECV attempt, ECV commenced before term reduces non-cephalic presentation at birth. Compared with ECV at term, beginning ECV at between 34 to 35 weeks may have some benefit in terms of decreasing the rate of non-cephalic presentation, and risk of vaginal breech birth. However, early ECV may increase risk of late preterm birth, and it is important that any future research reports infant morbidity outcomes. Results of the review suggest that there is a need for careful discussion with women about the timing of the ECV procedure so that they can make informed decisions.

This review included five randomised controlled studies with an overall total of 2187 women, the studies were at low or unclear risk of bias although it was not possible to "blind" women and staff to this intervention. Results showed that if ECV is done near the middle of the third trimester (32 to 34 weeks), it increases the chances that the baby will be lying head down at full term. Three trials including 1888 women found that beginning ECV at between 34 and 36 weeks compared with beginning ECV after 37 weeks (at term) had a 19% decrease in the rate of non-cephalic presentation at birth, a 10% reduction in the risk of failing to achieve a cephalic vaginal birth, and a considerably reduced chance of a breech vaginal delivery, however, early ECV may significantly increase the chances of late preterm birth. The quality of the evidence for these outcomes was graded as high. The evidence on the possible advantages and disadvantages of early (before 37 weeks) external cephalic version (ECV) will require careful discussion with women about the timing of the ECV procedure so that they can make informed decisions.

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Thirty-two studies were included in this review. However, only 22 studies, involving 2658 women, provided data for analysis. All the women in the included studies had a caesarean section under general anaesthesia. The studies covered a number of comparisons, but were mostly small and of unclear or poor quality. When compared with no treatment or placebo, there was a significant reduction in the risk of intragastric pH < 2.5 with antacids (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.09 to 0.32, two studies, 108 women), H2 antagonists (RR 0.09, 95% CI 0.05 to 0.18, two studies, 170 women) and proton pump antagonists (RR 0.26, 95% CI 0.14 to 0.46, one study 80 women). H2 antagonists were associated with a reduced the risk of intragastric pH < 2.5 at intubation when compared with proton pump antagonists (RR 0.39, 95% CI 0.16 to 0.97, one study, 120 women), but compared with antacids the findings were unclear. The combined use of 'antacids plus H2 antagonists' was associated with a significant reduction in the risk of intragastric pH < 2.5 at intubation when compared with placebo (RR 0.02, 95% CI 0.00 to 0.15, one study, 89 women) or compared with antacids alone (RR 0.12, 95% CI 0.02 to 0.92, one study, 119 women). The quality of the evidence was poor, but the findings suggest that the combination of antacids plus H2 antagonists was more effective than no intervention, and superior to antacids alone in preventing low gastric pH. However, none of the studies assessed potential adverse effects or substantive clinical outcomes. These findings are relevant for all women undergoing caesarean section under general anaesthesia.

Thirty-two studies were included in this review. However, only 22 studies, involving 2658 women, provided data for analysis, looking at interventions given prior to caesarean section for reducing the risk of aspiration. There were several different drugs and drug combinations being considered and the studies were generally of poor or questionable quality. Antacids (like sodium citrate), H2 receptor antagonists (like ranitidine), proton pump antagonists (like omeprazole), all reduced the acidity of the stomach contents. An antacid plus an H2 receptor antagonist also reduced acidity. In theory, a combination like this, where the antacid acts quickly and the H2 receptor antagonists takes a little longer, should protect at periods of greatest risk, i.e. the beginning and end of the procedure (i.e. intubation and extubation). More research is needed to identify the best combination of drugs and to check for possible adverse effects.

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Twenty-two studies (reported in 25 publications) involving 228,615 pregnancies (including 1067 with Down's syndrome) were included. Studies were generally high quality, although differential verification was common with invasive testing of only high risk pregnancies. Ten studies made direct comparisons between tests. Thirty-two different test combinations were evaluated formed from combinations of eight different tests and maternal age; first trimester nuchal translucency (NT) and the serum markers AFP, uE3, total hCG, free βhCG, Inhibin A, PAPP-A and ADAM 12. We looked at tests combining first and second trimester markers with or without ultrasound as complete tests, and we also examined stepwise and contingent strategies. Meta-analysis of the six most frequently evaluated test combinations showed that a test strategy involving maternal age and a combination of first trimester NT and PAPP-A, and second trimester total hCG, uE3, AFP and Inhibin A significantly outperformed other test combinations that involved only one serum marker or NT in the first trimester, detecting about nine out of every 10 Down's syndrome pregnancies at a 5% false positive rate. However, the evidence was limited in terms of the number of studies evaluating this strategy, and we therefore cannot recommend one single screening strategy. Tests involving first trimester ultrasound with first and second trimester serum markers in combination with maternal age are significantly better than those without ultrasound, or those evaluating first trimester ultrasound in combination with second trimester serum markers, without first trimester serum markers. We cannot make recommendations about a specific strategy on the basis of the small number of studies available.

For Down's syndrome screening, where tests were carried out in the first and second trimester and combined to give an overall risk, we found that a test comprised of first trimester nuchal translucency and PAPP-A, and second trimester total hCG, uE3, AFP and Inhibin A was the most sensitive test, detecting nine out of 10 pregnancies affected by Down's syndrome. Five per cent of pregnant women receiving a high risk test result based on this combination would not be affected by Down's syndrome. There were relatively few studies assessing these tests and therefore we cannot make a strong recommendation about the best test.Other important information to considerThe ultrasound tests themselves have no adverse effects for the woman, and blood tests can cause discomfort, bruising and, rarely, infection. However, some women who have a high risk screening test result, and are given amniocentesis or CVS have a risk of miscarrying a baby unaffected by Down’s. Parents will need to weigh up this risk when deciding whether or not to have an amniocentesis or CVS following a high risk screening test result.

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Two trials including a total of 81 participants fulfilled the inclusion criteria for this review. All participants in both studies had a history of postnatal depression and were not taking antidepressant medication at baseline. Both trials were conducted by the same research group. Risk of bias was low or unclear in most domains for both studies. We were unable to perform a meta-analysis due to the small number of studies. One study compared nortriptyline with placebo and did not find any evidence that nortriptyline was effective in preventing postnatal depression. In this study, 23% (6/26) of women who took nortriptyline and 24% (6/25) of women who took placebo experienced postnatal depression (RR 0.96, 95% CI 0.36 to 2.59, very low quality evidence) in the first 17 weeks postpartum. One woman taking nortriptyline developed mania; and one side effect, constipation, was more common among women taking nortriptyline than those taking placebo. The second study compared sertraline with placebo. In this study, 7% (1/14) of women who took sertraline developed postnatal depression in the first 17 weeks postpartum compared with 50% (4/8) of women who took placebo. It is uncertain whether sertraline reduces the risk of postnatal depression (RR 0.14, 95% CI 0.02 to 1.07, very low quality evidence). One woman taking sertraline had a hypomanic episode. Two side effects (dizziness and drowsiness) were more common among women taking sertraline than women taking placebo. Conclusions are limited by the small number of studies, small sample sizes and incomplete outcome data due to study drop-out which may have led to bias in the results. We have assessed the certainty of the evidence as very low, based on the GRADE system. No data were available on secondary outcomes of interest including child development, the mother‒infant relationship, breastfeeding, maternal daily functioning, family relationships or maternal satisfaction. Due to the limitations of the current evidence base, such as the low statistical power of the included studies, it is not possible to draw any clear conclusions about the effectiveness of antidepressants for the prevention of postnatal depression. It is striking that no new eligible trials have been completed in the period of over a decade since the last published version of this review. Larger trials are needed which include comparisons of antidepressant drugs with other prophylactic treatments (e.g. psychological interventions), and examine adverse effects for the fetus or infant. Future reviews in this area may benefit from broadening their focus to examine the effectiveness of antidepressants for the prevention of perinatal (i.e. antenatal or postnatal) depression, which could include studies comparing antidepressant discontinuation with continuation for the prevention of relapse of depression during pregnancy and the postnatal period.

We identified two small, relevant trials. All the women in these trials had a history of postnatal depression, but were not depressed or using antidepressants at the beginning of the studies. Both studies compared antidepressant medicine with placebo. Women started taking the medicine or placebo on the first day after giving birth. In the larger study (56 women), the antidepressant given to women was nortriptyline, which is a tricyclic antidepressant. In the other study (25 women), the antidepressant used was sertraline which is a selective serotonin reuptake inhibitor (SSRI); these types of antidepressants work in different ways. The women and the researchers assessing the outcomes in both studies did not know which women were taking antidepressants and which placebo (i.e. both studies were 'double-blind'). Both studies were funded by the National Institute of Mental Health (NIMH), a US government organisation. There was no evidence that nortriptyline prevented postnatal depression. During the 17-week treatment period, 6 of the 26 women taking nortriptyline experienced postnatal depression compared with 6 of the 25 women taking placebo. One woman taking nortriptyline developed mania (a state of abnormally high arousal and energy level), and constipation was more common among women taking nortriptyline, but other unwanted, or harmful, effects did not differ between groups. In the sertraline study, 1 of the 14 women taking sertraline developed postnatal depression compared with 4 of the 8 women taking placebo (during the 17-week treatment period). This study was very small, so we can't be sure whether the difference between sertraline and placebo is due to chance, or whether sertraline does prevent postnatal depression among women with a history of postnatal depression. One woman taking sertraline experienced a hypomanic episode (a state like mania but less severe); and dizziness and drowsiness were more common among women taking sertraline than women taking placebo. This evidence is current to February 2018. We could only identify two relevant studies, which had small numbers of participants and inconsistent findings, and were conducted by the same research group. Therefore we consider the quality of evidence in this review to be very low. Further studies with larger samples are needed before we can know whether antidepressants can prevent postnatal depression. It is worth noting that no new relevant trials have been completed in the 10 years since we last examined this evidence. It may be useful for future medical studies to investigate whether antidepressants can prevent depression during pregnancy as well as during the postnatal period; and whether women who continue to take antidepressants during pregnancy (compared with stopping medication) are less likely to have a relapse of depression at this time. We also need studies which have longer follow-ups periods; examine outcomes and side effects for both the mother and fetus or breastfeeding infant; and compare antidepressants with other preventative interventions (such as psychological therapies).

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Four studies (634 participants) met the inclusion criteria. Two of the included studies included only patients with AHFS following acute myocardial infarction (AMI); one study excluded patients with overt AMI; and one study included participants with AHFS with and without acute coronary syndromes. Based on a single study, there was no significant difference in the rapidity of symptom relief between intravenous nitroglycerin/N-acetylcysteine and intravenous frusemide/morphine after 30 minutes (fixed-effect MD -0.30, 95% CI -0.65 to 0.05), 60 minutes (fixed-effect MD -0.20, 95% CI -0.65 to 0.25), three hours (fixed-effect MD 0.20, 95% CI -0.27 to 0.67) and 24 hours (fixed-effect MD 0.00, 95% CI -0.31 to 0.31). There is no evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following outcome measures: requirement for mechanical ventilation, systolic blood pressure (SBP) change after three hours and 24 hours, diastolic blood pressure (DBP) change after 30, 60 and 90 minutes, heart rate change at 30 minutes, 60 minutes, three hours and 24 hours, pulmonary artery occlusion pressure (PAOP) change after three hours and 18 hours, cardiac output (CO) change at 90 minutes and three hours and progression to myocardial infarction. There is a significantly higher incidence of adverse events after three hours with nitroglycerin compared with placebo (odds ratio 2.29, 95% CI 1.26 to 4.16) based on a single study. There was no consistent evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following secondary outcome measures: SBP change after 30 and 60 minutes, heart rate change after 90 minutes, and PAOP change after 90 minutes. None of the included studies reported healthcare costs as an outcome measure. There were no data reported by any of the studies relating to the acceptability of the treatment to the patients (patient satisfaction scores). Overall there was a paucity of relevant quality data in the included studies. Assessment of overall risk of bias in these studies was limited as three of the studies did not give sufficient detail to allow assessment of potential risk of bias. There appears to be no significant difference between nitrate vasodilator therapy and alternative interventions in the treatment of AHFS, with regard to symptom relief and haemodynamic variables. Nitrates may be associated with a lower incidence of adverse effects after three hours compared with placebo. However, there is a lack of data to draw any firm conclusions concerning the use of nitrates in AHFS because current evidence is based on few low-quality studies.

The four studies in this review included 634 patients with AHFS and employed two types of nitrates (isosorbide dinitrate and nitroglycerin). The studies compared nitrates with frusemide and morphine, frusemide alone, hydralazine, prenalterol, intravenous nesiritide and placebo. The study population in the trials was predominantly male (469/634 or 74% of all the patients included in the studies were male). The findings of this review indicate that there is no significant difference between nitrates and alternative treatment interventions for patients with AHFS in terms of healthcare outcomes. Nitrates appeared to be well tolerated in all four studies. Headaches is the most common side effect reported by patients. Headaches occurred more frequently when compared with nesiritide. There appeared to be no significant difference in the occurrence of symptomatic hypotension, pain, nausea and angina between patients administered nitroglycerin and nesiritide. The included studies did not report healthcare costs as an outcome measure. The limitations of the review include the following: there were few studies eligible for inclusion (only four); the quality of the studies were relatively poor; the study participants were predominantly male; and all the eligible studies were conducted in developed Western countries. Consequently, the findings may not be generalisable to other healthcare settings and to females. The review also found no consistent evidence to support a difference in AHFS patients receiving nitrates or alternative interventions with regard to many of the healthcare outcome measures studied. Due to these limitations, the results of the review preclude definitive conclusions regarding the effectiveness and safety of nitrates compared with alternative interventions in the treatment of patients with AHFS.

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We included 44 completed RCTs (4781 participants) and 50 ongoing studies. The number of participants in each trial varied (10 to 521) as did the length of follow-up (6 to 24 months). Participants ages ranged from 12 to 17.5 years in all trials that reported mean age at baseline. Most of the trials used a multidisciplinary intervention with a combination of diet, physical activity and behavioural components. The content and duration of the intervention, its delivery and the comparators varied across trials. The studies contributing most information to outcomes of weight and body mass index (BMI) were from studies at a low risk of bias, but studies with a high risk of bias provided data on adverse events and quality of life. The mean difference (MD) of the change in BMI at the longest follow-up period in favour of BCI was -1.18 kg/m2 (95% confidence interval (CI) -1.67 to -0.69); 2774 participants; 28 trials; low quality evidence. BCI lowered the change in BMI z score by -0.13 units (95% CI -0.21 to -0.05); 2399 participants; 20 trials; low quality evidence. BCI lowered body weight by -3.67 kg (95% CI -5.21 to -2.13); 1993 participants; 20 trials; moderate quality evidence. The effect on weight measures persisted in trials with 18 to 24 months' follow-up for both BMI (MD -1.49 kg/m2 (95% CI -2.56 to -0.41); 760 participants; 6 trials and BMI z score MD -0.34 (95% CI -0.66 to -0.02); 602 participants; 5 trials). There were subgroup differences showing larger effects for both BMI and BMI z score in studies comparing interventions with no intervention/wait list control or usual care, compared with those testing concomitant interventions delivered to both the intervention and control group. There were no subgroup differences between interventions with and without parental involvement or by intervention type or setting (health care, community, school) or mode of delivery (individual versus group). The rate of adverse events in intervention and control groups was unclear with only five trials reporting harms, and of these, details were provided in only one (low quality evidence). None of the included studies reported on all-cause mortality, morbidity or socioeconomic effects. BCIs at the longest follow-up moderately improved adolescent's health-related quality of life (standardised mean difference 0.44 ((95% CI 0.09 to 0.79); P = 0.01; 972 participants; 7 trials; 8 comparisons; low quality of evidence) but not self-esteem. Trials were inconsistent in how they measured dietary intake, dietary behaviours, physical activity and behaviour. We found low quality evidence that multidisciplinary interventions involving a combination of diet, physical activity and behavioural components reduce measures of BMI and moderate quality evidence that they reduce weight in overweight or obese adolescents, mainly when compared with no treatment or waiting list controls. Inconsistent results, risk of bias or indirectness of outcome measures used mean that the evidence should be interpreted with caution. We have identified a large number of ongoing trials (50) which we will include in future updates of this review.

We found 44 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) comparing diet, physical activity and behavioural (where habits are changed or improved) treatments (interventions) to a variety of control groups delivered to 4781 overweight or obese adolescents aged 12 to 17 years. Our systematic review reports on the effects of multidisciplinary interventions, dietary interventions and physical activity interventions compared with a control group (no intervention, 'usual care,' enhanced usual care or some other therapy if it was also delivered to the intervention group). The adolescents in the included studies were monitored (called follow-up) for between six months and two years. The average age of adolescents ranged from 12 to 17.5 years. Most studies reported the body mass index (BMI). BMI is a measure of body fat and is calculated by dividing weight (in kilograms) by the square of the body height measured in metres (kg/m2). We summarised the results of 28 studies in 2774 adolescents reporting BMI, which on average was 1.18 kg/m2 lower in the intervention groups compared with the control groups. We summarised the results of 20 studies in 1993 adolescents reporting weight, which on average was 3.67 kg lower in the intervention groups compared with the control groups. BMI reduction was maintained at 18 to 24 months of follow-up (monitoring participants until the end of the study), which on average was 1.49 kg/m2 lower in the intervention groups compared with the control groups. The interventions moderately improved health-related quality of life (a measure of a person's satisfaction with their life and health) but we did not find firm evidence of an advantage or disadvantage of these interventions for improving self-esteem, physical activity and food intake. No study reported on death from any cause, morbidity (illnesses) or socioeconomic effects (such as days away from school). Three studies reported no side effects, one reported no serious side effects, one did not provide details of side effects and the rest of the studies did not report whether side effects occurred or not. We identified 50 ongoing studies which we will include in future updates of our review. This evidence is up to date as of July 2016. The overall quality of the evidence was rated as low for most of the outcomes (results) measured, mainly because of limited confidence in how studies were performed, inconsistent results between the studies and the way that some outcomes used do not capture obesity outcomes directly. Also, there were just a few studies for some outcomes, with small numbers of included adolescents.

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We identified one study (290 randomised participants) that investigated the effectiveness of decision aids compared to standard information in the informed consent process for clinical trials. This study reported two separate decision aid randomised controlled trials (RCTs). The decision aid trials were nested within two different parent trials focusing on breast cancer in postmenopausal women. One trial focused on informed consent for treatment in women who had previously had surgery for ductal carcinoma in situ (DCIS), the other on informed consent for prevention in women at high risk for breast cancer. Two different decision aids were used in these RCTs, and were compared with standard information. The pooled findings highlight the uncertainty surrounding most reported outcomes, including knowledge, decisional conflict, anxiety, trial participation and attrition. There was very low quality evidence that decision aids lower levels of decisional regret to a small degree (MD -5.53, 95% CI -10.29 to -0.76). No data were identified on several prespecified primary outcomes, including accurate risk perception, values-based decision, or whether potential participants recognised that a decision needed to be made, were able to identify features of options that matter most to individuals, or were involved in the decision. There was insufficient evidence to determine whether decision aids to support the informed consent process for clinical trials are more effective than standard information. Additional well designed, adequately powered clinical trials in more diverse clinical and social populations are needed to strengthen the results of this review. More generally, future research on which outcomes are most relevant for assessment in this context would be helpful.

We reviewed the evidence about the effect of specific tools, called decision aids, which aim to improve decision making in the informed consent process for people who are considering participating in a clinical trial. These tools were compared to the standard process used for informed consent in clinical trials. There is currently not enough evidence to draw conclusions about the effectiveness of decision aids in the informed consent process for clinical trials. In clinical trials, one healthcare treatment is compared to another treatment or to no treatment. Before potential participants sign a consent form where they agree to take part in a clinical trial they must be given information about what will be expected of them and what they can expect. Research has shown that this information is often not as good as it could be. For example, people often misunderstand the information they have been given. Decision aids, which are tools that assist people to think about what matters most to them, support decision making for treatment and screening. Presenting information about trial participation through decision aids might improve the informed consent process by improving participants' knowledge, certainty with the decision and enabling them to consider what matters most to them personally. We searched the literature for studies where potential trial participants were randomly allocated to receive decision aids, compared to no decision aids or to other types of information for informed consent. We found one study, which reported data from two separate decision aid trials, where people who were given a decision aid alongside standard information were compared to people who were given standard information alone. When data from these two trials were combined, the results were inconclusive and not able to show whether people given the decision aid had any more or less knowledge or uncertainty about their decision, or were more or less likely to participate in a trial, than the people who were only given standard information. However, people who used the decision aid may have felt less regret about their decision. Overall there was very low quality evidence to support these findings, which means that there may be uncertainty around the results, and therefore, further research is required.

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A total of 15 trials were identified, two of which (with data for a total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that recombinant factor VIIa and activated prothrombin complex concentrate appeared to have a similar haemostatic effect in both trials, without increasing thromboembolic risk. Based on the separate analysis of the two available randomised trials, recombinant factor VIIa and activated prothrombin complex concentrate were found to be similar in efficacy and safety. However, there is a need for further, well-designed, adequately-powered, randomised controlled trials to assess the relative benefits and risks of using recombinant factor VIIa compared to human plasma-derived concentrates in people with haemophilia with inhibitors. It is advisable that researchers in the field define commonly agreed objective outcome measures in order to enable the pooling of their results, thus increasing the power of comparisons. To date, data could not be combined in a formal meta-analysis. For the same reason reporting concordant and discordant pairs in cross-over trials is recommended.

The review included two trials with 69 people (aged one to 55 years) with severe haemophilia with inhibitors. Both trials compared recombinant factor VIIa with activated prothrombin complex concentrate and people were selected for one treatment or the other randomly. We found two clinical trials comparing Novoseven®and FEIBA®. The trials did not show a difference in how well the two products worked and both were tolerated equally well with no clotting complications. We conclude that both recombinant factor VIIa and plasma-derived concentrates can be used to treat bleeds in people with haemophilia and inhibitors. There were some major problems with regards to the way both trials were designed, in relation to knowing which treatment group each person was in (both before the trial was started and during) and also how missing results were handled.

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Three trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infection) in neutropenic cancer patients (849 patients, 58 deaths). The second trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). The third trial compared fluconazole to voriconazole for prophylaxis of fungal infections in patients receiving allogeneic stem cell transplantation (600 patients, number of deaths not stated). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the trial authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from the analysis by the trial authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication to counter side effects and replacement of electrolytes or use of salt water. This choice of comparator resulted in a marked difference in the duration of treatment on the trial drugs (77 days with voriconazole versus 10 days with amphotericin B) and precluded meaningful comparisons of the benefits and harms of the two drugs. The third trial failed to find a difference in fungal free survival or invasive fungal infections at 180 days when voriconazole was compared to fluconazole. Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of fungal infections in neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions. For prophylactic fungal treatment in patients receiving allogeneic stem cell transplantation, there was no difference between voriconazole and fluconazole regarding fungal free survival or invasive fungal infections.

We identified three studies. Our most recent search for studies was done in January 2014. One trial compared voriconazole to liposomal amphotericin B in 849 men and women (58 deaths) with cancer and a poor immune system. Treatment was most often given for seven days. The treatment was provided in patients where a fungal infection was suspected because they had a fever that could not otherwise be explained. The second trial compared voriconazole to amphotericin B deoxycholate in 391 men and women (98 deaths) with cancer and a poor immune system. Voriconazole was given for 77 days on average whereas liposomal amphotericin B deoxycholate was given for 10 days on average. The treatment was given when patients were known or suspected to have a specific fungal infection (Aspergillus). The third trial compared voriconazole to fluconazole in 600 men and women (the number of deaths was not stated) with cancer who had undergone a transplantation of their bone marrow after high-dose chemotherapy that suppresses their immune system. The treatment was given to prevent fungal infections. All studies were sponsored by the manufacturer of the study drug, voriconazole. This review found that voriconazole was inferior to liposomal amphotericin B for treatment of suspected fungal infections. More patients treated with voriconazole died and a claimed benefit in terms of fewer new fungal infections disappeared when we included patients that had been excluded without good reason from the analyses presented in the published article. We also found that voriconazole has not been compared with amphotericin B when given under optimal conditions for the treatment of invasive aspergillosis, and that voriconazole was no better than fluconazole in patients undergoing a bone marrow transplantation for preventing invasive fungal infections or for extending the time patients survive without a fungal infection. The first and second trial were seriously misleading. The first trial analysed the results of the study in a different way from that originally planned, which favoured the study drug voriconazole. The second study compared voriconazole to a drug (liposomal amphotericin B) that was given at substandard dose, which means the results of the study are not meaningful. The third study should have presented how many patients died but did not.

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We included 56 trials with 4826 participants randomized to an exercise (n = 2286) or comparison (n = 1985) group. Cancer diagnoses in trial participants included breast, prostate, gynecologic, hematologic, and other. Thirty-six trials were conducted among participants who were currently undergoing active treatment for their cancer, 10 trials were conducted among participants both during and post active cancer treatment, and the remaining 10 trials were conducted among participants scheduled for active cancer treatment. Mode of exercise intervention differed across trials and included walking by itself or in combination with cycling, resistance training, or strength training; resistance training; strength training; cycling; yoga; or Qigong. HRQoL and its domains were assessed using a wide range of measures. The results suggest that exercise interventions compared with control interventions have a positive impact on overall HRQoL and certain HRQoL domains. Exercise interventions resulted in improvements in: HRQoL from baseline to 12 weeks' follow-up (SMD 0.33; 95% CI 0.12 to 0.55) or when comparing difference in follow-up scores at 12 weeks (SMD 0.47; 95% CI 0.16 to 0.79); physical functioning from baseline to 12 weeks' follow-up (SMD 0.69; 95% CI 0.16 to 1.22) or 6 months (SMD 0.28; 95% CI 0.00 to 0.55); or when comparing differences in follow-up scores at 12 weeks (SMD 0.28; 95% CI 0.11 to 0.45) or 6 months (SMD 0.29; 95% CI 0.07 to 0.50); role function from baseline to 12 weeks' follow-up (SMD 0.48; 95% CI 0.07 to 0.90) or when comparing differences in follow-up scores at 12 weeks (SMD 0.17; 95% CI 0.00 to 0.34) or 6 months (SMD 0.32; 95% CI 0.03 to 0.61); and, in social functioning at 12 weeks' follow-up (SMD 0.54; 95% CI 0.03 to 1.05) or when comparing differences in follow-up scores at both 12 weeks (SMD 0.16; 95% CI 0.04 to 0.27) and 6 months (SMD 0.24; 95% CI 0.03 to 0.44). Further, exercise interventions resulted in a decrease in fatigue from baseline to 12 weeks' follow-up (SMD -0.38; 95% CI -0.57 to -0.18) or when comparing difference in follow-up scores at follow-up of 12 weeks (SMD -0.73; 95% CI -1.14 to -0.31). Since there is consistency of findings on both types of measures (change scores and difference in follow-up scores) there is greater confidence in the robustness of these findings. When examining exercise effects by subgroups, exercise interventions had significantly greater reduction in anxiety for survivors with breast cancer than those with other types of cancer. Further, there was greater reduction in depression, fatigue, and sleep disturbances, and improvement in HRQoL, emotional wellbeing (EWB), physical functioning, and role function for cancer survivors diagnosed with cancers other than breast cancer but not for breast cancer. There were also greater improvements in HRQoL and physical functioning, and reduction in anxiety, fatigue, and sleep disturbances when prescribed a moderate or vigorous versus a mild exercise program. Results of the review need to be interpreted cautiously owing to the risk of bias. All the trials reviewed were at high risk for performance bias. In addition, the majority of trials were at high risk for detection, attrition, and selection bias. This systematic review indicates that exercise may have beneficial effects at varying follow-up periods on HRQoL and certain HRQoL domains including physical functioning, role function, social functioning, and fatigue. Positive effects of exercise interventions are more pronounced with moderate- or vigorous-intensity versus mild-intensity exercise programs. The positive results must be interpreted cautiously because of the heterogeneity of exercise programs tested and measures used to assess HRQoL and HRQoL domains, and the risk of bias in many trials. Further research is required to investigate how to sustain positive effects of exercise over time and to determine essential attributes of exercise (mode, intensity, frequency, duration, timing) by cancer type and cancer treatment for optimal effects on HRQoL and its domains.

People with cancer undergoing treatment often have many psychological and physical adverse effects as a result of their cancer and the treatment for it. They also experience poorer quality of life because of the disease and its treatment. Some studies have suggested that exercise may be helpful in reducing negative outcomes and improving the quality of life of people with cancer who are undergoing treatment. Also, a better quality of life may predict longer life. This review looked at the effect of exercise on health-related quality of life and areas of life that make up quality of life (e.g. tiredness, anxiety, emotional health) among people with cancer who are undergoing treatment. The review included 56 trials with a total of 4826 participants. The results suggest that exercise may improve overall quality of life right after the exercise program is completed. Exercise may also improve the person's physical ability and the way the person can function in society. Exercise also reduced tiredness at different times during and after the exercise program. The positive effects of exercise were greater when the exercise was more intense. No effects of exercise was found in the way a person views his or her body, on the person's ability to think clearly, the person's mood, feeling of pain, and on the way the person views his or her spiritual health. However, these findings need to be viewed with caution because this review looked at many different types of exercise programs, which varied by type of setting, length of the program, and how hard the trial participants had to exercise. Also, the investigators used a number of different ways to measure quality of life. There is a need for more research to understand how to maintain the positive effects of exercise over a longer period of time after the exercise program is completed, and to determine which parts of the exercise program are necessary (i.e. when to start the program, type of exercise, length of the program or exercise session, how hard to exercise). It is also important to find out if one type of exercise is better for a specific cancer type than another for the maximum effect on quality of life.

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We included six studies (373 workers), four parallel RCTs, one cross-over RCT, and one combined parallel plus cross-over RCT. At least 295 of the employees were female and at least 39 male; for the remaining 39 employees, the sex was not specified in the study trial. The studies investigated different work-break frequencies (five studies) and different work-break types (two studies). None of the studies investigated different work-break durations. We judged all studies to have a high risk of bias. The quality of the evidence for the primary outcomes of self-reported musculoskeletal pain, discomfort and fatigue was low; the quality of the evidence for the primary outcomes of productivity and work performance was very low. The studies were executed in Europe or Northern America, with none from low- to middle-income countries. One study could not be included in the data analyses, because no detailed results have been reported. Changes in the frequency of work breaks There is low-quality evidence that additional work breaks may not have a considerable effect on musculoskeletal pain, discomfort or fatigue, when compared with no additional work breaks (standardised mean difference (SMD) -0.08; 95% CI -0.35 to 0.18; three studies; 225 participants). Additional breaks may not have a positive effect on productivity or work performance, when compared with no additional work breaks (SMD -0.07; 95% CI -0.33 to 0.19; three studies; 225 participants; very low-quality evidence). We found low-quality evidence that additional work breaks may not have a considerable effect on participant-reported musculoskeletal pain, discomfort or fatigue (MD 1.80 on a 100-mm VAS scale; 95% CI -41.07 to 64.37; one study; 15 participants), when compared to work breaks as needed (i.e. microbreaks taken at own discretion). There is very low-quality evidence that additional work breaks may have a positive effect on productivity or work performance, when compared to work breaks as needed (MD 542.5 number of words typed per 3-hour recording session; 95% CI 177.22 to 907.78; one study; 15 participants). Additional higher frequency work breaks may not have a considerable effect on participant-reported musculoskeletal pain, discomfort or fatigue (MD 11.65 on a 100-mm VAS scale; 95% CI -41.07 to 64.37; one study; 10 participants; low-quality evidence), when compared to additional lower frequency work breaks. We found very low-quality evidence that additional higher frequency work breaks may not have a considerable effect on productivity or work performance (MD -83.00 number of words typed per 3-hour recording session; 95% CI -305.27 to 139.27; one study; 10 participants), when compared to additional lower frequency work breaks. Changes in the duration of work breaks No trials were identified that assessed the effect of different durations of work breaks. Changes in the type of work break We found low-quality evidence that active breaks may not have a considerable positive effect on participant-reported musculoskeletal pain, discomfort and fatigue (MD -0.17 on a 1-7 NRS scale; 95% CI -0.71 to 0.37; one study; 153 participants), when compared to passive work breaks. Relaxation work breaks may not have a considerable effect on participant-reported musculoskeletal pain, discomfort or fatigue, when compared to physical work breaks (MD 0.20 on a 1-7 NRS scale; 95% CI -0.43 to 0.82; one study; 97 participants; low-quality evidence). We found low-quality evidence that different work-break frequencies may have no effect on participant-reported musculoskeletal pain, discomfort and fatigue. For productivity and work performance, evidence was of very low-quality that different work-break frequencies may have a positive effect. For different types of break, there may be no effect on participant-reported musculoskeletal pain, discomfort and fatigue according to low-quality evidence. Further high-quality studies are needed to determine the effectiveness of frequency, duration and type of work-break interventions among workers, if possible, with much higher sample sizes than the studies included in the current review. Furthermore, work-break interventions should be reconsidered, taking into account worker populations other than office workers, and taking into account the possibility of combining work-break intervention with other interventions such as ergonomic training or counselling, which may may possibly have an effect on musculoskeletal outcomes and work performance.

We searched the literature until 2 May 2019 to find randomised controlled trials (RCTs), quasi-RCTs, cluster-RCTs and cross-over RCTs of work-break interventions aimed at preventing work-related musculoskeletal disorders at work. We analysed all relevant studies to answer the research question and found six studies involving 373 workers, the majority of whom were female (≥ 78%), with a follow-up period of two to 10 weeks. Key results Effect of different work-break frequencies Five of the six studies evaluated different work-break frequencies. The implementation of additional work breaks (three studies) may not have an effect on musculoskeletal pain, discomfort or fatigue when compared to no additional work breaks or work breaks taken as needed. Additional work breaks (three studies) may have a positive effect on productivity and work performance when compared to a conventional work-break schedule. Additional higher frequency work breaks have been compared with additional lower frequency work breaks in one study, which resulted in no differences in participant-reported musculoskeletal pain, discomfort and fatigue, nor in productivity and work performance. Effect of different work-break durations None of the studies evaluated the effect of duration of work breaks. Effect of different work-break types Two of the six studies evaluated different work-break types. Active work breaks (one study) may not reduce nor increase the incidence of participant-reported musculoskeletal pain, discomfort and fatigue, or productivity and work performance. Similarly, different active work breaks have been compared with one another (one study), i.e. relaxation and physical active work breaks, which revealed no differences in participant-reported musculoskeletal pain, discomfort and fatigue, nor in productivity and work performance. Conclusions At present, we conclude that there is very low- to low-quality evidence that different work-break frequencies and types may not considerably reduce the incidence of musculoskeletal disorders. Although the results suggest that there may be a positive effect of different work-break frequencies on productivity and work performance, there is a need for high-quality studies with large enough sample sizes to assess the effectiveness of different work-break interventions. Furthermore, work-break interventions should be reconsidered, taking into account worker populations other than office workers and the possibility of combining work-break interventions with other interventions such as ergonomic training or counselling, which may possibly prevent musculoskeletal disorders.

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Only two small trials comparing continuous vs. bolus indomethacin were eligible. Analysis of these studies showed that there were no statistically significant differences in PDA closure at day 2 (RR 1.57, 95% CI 0.54, 4.60) and at day 5 (RR 2.77, 95% CI 0.33, 23.14). There was no statistical difference between the bolus and continuous groups for the secondary outcomes of reopening of PDA, neonatal mortality, intraventricular hemorrhage and necrotizing enterocolitis. None of the trials reported on outcomes such as requirement for retreatment with indomethacin or surgical ligation, mortality, bronchopulmonary dysplasia, retinopathy of prematurity, neurodevelopmental outcome and isolated intestinal perforation. The review demonstrated that there was a decrease in cerebral blood flow velocity after bolus injections and that the difference between the bolus and continuous infusion groups remained significant for 12 - 24 hours. Similar decrease in blood flow to the renal and mesenteric circulations following bolus administration was reported in one study (Christmann 2002). None of the trials detected predefined levels of decreased urine output and increased levels of BUN and creatinine. The available data is insufficient to draw conclusions regarding the efficacy of continuous indomethacin infusion vs. bolus injections for the treatment of PDA. Although continuous indomethacin seems to cause less alterations in cerebral, renal and mesenteric circulations, the clinical meaning of this effect is unclear. Definitive recommendations about the preferred method of indomethacin administration in premature infants cannot be made based on the current findings of this review.

In this review, the analysis of the two eligible trials found that the data was insufficient to reach a conclusion regarding the effectiveness of the 36-hr continuous infusion method. The blood flow lowering side-effects of indomethacin were reduced by the continuous infusion method, but there was insufficient data to recommend this administration method versus the traditional method.

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Twenty-three randomised controlled trials met the inclusion criteria for this review. Five trials assessed a cognitive/behavioural intervention and eighteen assessed a pharmacological adjunct. In terms of prevention, two cognitive/behavioural trials showed significant treatment effect (mean weight change) at end of treatment (n=104, 2 RCTs, WMD -3.38 kg CI -4.2 to -2.0). Pharmacological adjunct treatments were significant with a modest prevention of weight gain (n=274, 6 RCTs, WMD - 1.16 kg CI -1.9 to -0.4). In terms of treatments for weight loss, we found significantly greater weight reduction in the cognitive behavioural intervention group (n=129, 3 RCTs, WMD -1.69 kg CI -2.8 to -0.6) compared with standard care. Modest weight loss can be achieved with selective pharmacological and non pharmacological interventions. However, interpretation is limited by the small number of studies, small sample size, short study duration and by variability of the interventions themselves, their intensity and duration. Future studies adequately powered, with longer treatment duration and rigorous methodology will be needed in further evaluating the efficacy and safety of weight loss interventions for moderating weight gain. At this stage, there is insufficient evidence to support the general use of pharmacological interventions for weight management in people with schizophrenia.

In this review we are able to show that small weight loss is possible with selective pharmacological or non-pharmacological interventions but it is difficult to be sure of the results because the studies were small and compared different interventions over different time periods.

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Fifteen studies were included in the previous version of the review, and we included two new studies in this update, although we were unable to pool new data. Overall, the quality of the studies was moderate; concealment of allocation was assessed as clearly adequate in only seven (45%) of the trials. There was significant clinical heterogeneity between studies as the doses of aminophylline and other medications and the severity of the acute asthma varied between studies. There was no statistically significant advantage when adding intravenous aminophylline with respect to hospital admissions (OR 0.58; 95% CI 0.30 to 1.12; 6 studies; n = 315). In 2000 it was found that there was no statistically significant effect of aminophylline on airflow outcomes at any time period; the addition of two trials in 2012 has not challenged this conclusion. People treated with aminophylline and beta2-agonists had similar peak expiratory flow (PEF) values compared to those treated with beta2-agonists alone at 12 h (MD 8.30 L/min; 95% CI -20.69 to 37.29 L/min) or (MD -1.21% predicted; 95% CI -14.21% to 11.78% predicted) and 24 h (MD 22.20 L/min; 95% CI -56.65 to 101.05 L/min). Two subgroup analyses were performed by grouping studies according to mean baseline airflow limitation (11 studies) and the use of any corticosteroids (nine studies). There was no relationship between baseline airflow limitation or the use of corticosteroids on the effect of aminophylline. Aminophylline-treated patients reported more palpitations/arrhythmias (OR 3.02; 95% CI 1.15 to 7.90; 6 studies; n = 249) and vomiting (OR 4.21; 95% CI 2.20 to 8.07; 7 studies; n = 321); however, no significant difference was found in tremor (OR 2.60; 95% CI 0.62 to 11.02; 5 studies; n = 249). The use of intravenous aminophylline did not result in significant additional bronchodilation compared to standard care with inhaled beta2-agonists in patients experiencing an asthma exacerbation in the ED setting, or in a significant reduction in the risk of hospital admission. For every 100 people treated with aminophylline an additional 20 people had vomiting and 15 people arrhythmias or palpitations. No subgroups in which aminophylline might be more effective were identified. Our update in 2012 is consistent with the original conclusions that the risk-benefit balance of intravenous aminophylline is unfavourable.

The drug aminophylline has also been used intravenously (injected into the veins) for many years; however, this review of trials found that aminophylline is not significantly better than other bronchodilator drugs, and has more adverse effects. For every 100 people treated with aminophylline an additional 20 people had vomiting and 15 people arrhythmias or palpitations. This review was first published in 2000 and was updated in 2012 and the addition of two trials in 2012 did not alter the original conclusions.

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Twenty-five trials were included. Only two studies reported live births. The odds ratios (OR) for pregnancy following ovulation suppression versus placebo or no treatment was 0.97 (95% confidence interval (CI) 0.68 to 1.34, P = 0.8) for all women randomised, and 1.02 (95% CI 0.70 to 1.52, P = 0.82) for subfertile couples only despite the use of a variety of suppression agents. There was no evidence of benefit from the treatment. The common OR for pregnancy following all agents versus danazol was 1.38 (95% CI 1.05 to 1.82, P = 0.02) for all women randomised, and 1.37 (95% CI 0.94 to 1.99, P = 0.10) for subfertile couples only. When GnRHa and danazol were directly compared, the OR was 1.45 (95% CI 1.08 to 1.95, P = 0.01) for all women randomised, and 1.63 (95% CI 1.12 to 2.37, P = 0.01) for subfertile couples only, in favour of GnRHa. No effect was observed for GnRHa compared with oral contraception (OR 0.93, 95% CI 0.41 to 2.12, P = 0.86 for all women randomised; OR 0.83, 95% CI 0.34 to 2.05, P = 0.69 for subfertile couples only). There is no evidence of benefit in the use of ovulation suppression in subfertile women with endometriosis who wish to conceive.

This review of 23 trials involving 3043 women with endometriosis has shown that there no evidence of benefit with the use of ovulation suppression for women with endometriosis and infertility. Endometriosis is caused by the lining of the uterus (endometrium) spreading to a site outside the uterus. It is associated with subfertility and can cause pain during both sexual intercourse and menstruation. The hormone oestrogen stimulates the growth of endometriosis. For many years, the use of drugs such as danazol to stop ovulation and the production of oestrogen has been standard practice in the treatment of pain and subfertility caused by endometriosis. This works well for pain, but does not appear to improve fertility. In fact, as ovulation and periods are stopped for the time of treatment, fertility may be reduced by this approach.

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Twenty-five trials met the inclusion criteria. Twelve included rapid smoking and nine used other aversion methods. Ten trials included two or more conditions allowing assessment of a dose-response to aversive stimulation. The odds ratio (OR) for abstinence following rapid smoking compared to control was 2.01 (95% confidence intervals (CI): 1.36 to 2.95). Several factors suggest that this finding should be interpreted cautiously. A funnel plot of included studies was asymmetric, due to the relative absence of small studies with negative results. Most trials had a number of serious methodological problems likely to lead to spurious positive results. The only trial using biochemical validation of all self reported cessation gave a non-significant result. Other aversion methods were not shown to be effective (OR 1.15, 95% CI 0.73 to 1.82). There was a borderline dose-response to the level of aversive stimulation (OR 1.67, 95% CI 0.99 to 2.81). The existing studies provide insufficient evidence to determine the efficacy of rapid smoking, or whether there is a dose-response to aversive stimulation. Milder versions of aversive smoking seem to lack specific efficacy. Rapid smoking is an unproven method with sufficient indications of promise to warrant evaluation using modern rigorous methodology.

The results of the existing trials suggest that this may be effective, but the evidence is not conclusive because most of the studies of this approach have methodological problems. A recent laboratory study also suggests that the method has an active ingredient. Further research may be worthwhile.

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Nine studies (484 patients) met the pre-specified inclusion criteria (Kappa 1.00). Six studies were rated as low risk of bias. Three studies were rated as high risk of bias due to blinding (two open label and one single-blind). The total daily dose of rectal 5-ASA ranged from 0.5 g to 4 g, and dose frequency ranged from once to three times daily. 5-ASA was delivered as liquid enema in five studies or as a suppository in four studies. Follow-up ranged from 6 to 24 months. Rectal 5-ASA was significantly superior to placebo for maintenance of symptomatic remission over a period of 12 months.Sixty-two per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 30% of patients in the placebo group (4 studies; 301 patients; RR 2.22, 95% CI 1.26 to 3.90; I2 = 67%; P < 0.01). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 144 events) and inconsistency (i.e. unexplained heterogeneity). Rectal 5-ASA was significantly superior to placebo for maintenance of endoscopic remission over a 12 month period. Seventy-five per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 15% of patients in the placebo group (1 study; 25 patients; RR 4.88, 95% CI 1.31 to 18.18; P < 0.05). There was no statistically significant difference in the proportion of patients who experienced at least one adverse event. Sixteen per cent of patients in the rectal 5-ASA group experienced at least one adverse compared to 12% of placebo patients (2 studies; 160 patients; RR 1.35, 95% CI 0.63 to 2.89; I2 = 0%; P = 0.44). The most commonly reported adverse events were anal irritation and abdominal pain. No statistically significant differences between rectal and oral 5-ASA were identified for either symptomatic or endoscopic remission over a period of six months. Eighty per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 65% of patients in the oral 5-ASA group (2 studies; 69 patients; RR 1.24, 95% CI 0.92 to 1.66; I2 = 0%; P = 0.15). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 50 events) and high risk of bias (i.e. both studies in the pooled analysis were open label). Eighty per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 70% of patients in the oral 5-ASA group (2 studies; 91 patients; RR 1.14, 95% CI 0.90 to 1.45; I2 = 0%; P = 0.26). In two small trials, one comparing 2 g/day 5-ASA enemas to 4 g/day 5-ASA enemas and the other comparing 0.5 g/day 5-ASA suppositories to 1 g/day 5-ASA suppositories no dose response relationship was observed. The limited data available suggest that rectal 5-ASA is effective and safe for maintenance of remission of mild to moderately active distal UC. Well designed randomized trials are needed to establish the optimal dosing regimen for rectal 5-ASA, to compare rectal 5-ASA with rectal corticosteroids and to identify subgroups of patients who are more or less responsive to specific rectal 5-ASA regimens. The combination of oral and rectal 5-ASA appears to be more effective than either oral or rectal monotherapy for induction of remission. The efficacy of combination therapy for maintenance of remission has not been assessed and could be evaluated in future trials.

This review includes nine randomized trials with a total of 484 participants. The limited data available suggest that rectal 5-ASA is effective and safe for maintenance of remission in UC. Rectal 5-ASA was found to be superior to placebo (e.g. enema or suppository with no active medicine). There was no difference in the incidence of side effects between rectal 5-ASA and placebo groups. Side effects were generally mild in nature and common side effects included anal irritation and abdominal pain. Studies comparing rectal 5-ASA with oral 5-ASA (pills) found no differences in effectiveness for maintenance therapy. Well designed randomized trials are needed to investigate different doses of rectal 5-ASA for maintenance therapy, Future studies should assess the effectiveness of combination therapy of oral 5-ASA with rectal 5-ASA as this has been found to be effective in active UC and has not been investigated for maintenance therapy. Future studies should also compare rectal 5-ASA with rectal corticosteroids.

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We included 66 studies with 7840 participants in the review, though most analyses were based on data from fewer participants. In total there are 17 studies awaiting classification. No studies were at a low risk of bias. We noted substantial statistical and clinical heterogeneity between trials. Most of the studies reported the primary outcome pain as assessed by verbal response from participants in an awake state but some trials reported withdrawal of the injected limb as a proxy for pain after induction of anaesthesia in response to rocuronium administration. Few studies reported adverse events and no study reported heart rate and blood pressure changes after administration of rocuronium. Lidocaine was the most commonly studied intervention drug, used in 29 trials with 2256 participants. The risk ratio (RR) of pain on injection if given lidocaine compared to placebo was 0.23 (95% confidence interval (CI) 0.17 to 0.31; I² = 65%, low quality of evidence). The RR of pain on injection if fentanyl and remifentanil were given compared to placebo was 0.42 (95% CI 0.26 to 0.70; I² = 79%, low quality of evidence) and (RR 0.10, 95% CI 0.04 to 0.26; I² = 74%, low quality of evidence), respectively. Pain on injection of intervention drugs was reported with the use of lidocaine and acetaminophen in one study. Cough was reported with the use of fentanyl (one study), remifentanil (five studies, low quality evidence) and alfentanil (one study). Breath holding and chest tightness were reported with the use of remifentanil in two studies (very low quality evidence) and one study (very low quality evidence), respectively. The overall rate of complications was low. The evidence to suggest that the most commonly investigated pharmacological interventions reduce pain on injection of rocuronium is of low quality due to risk of bias and inconsistency. There is low or very low quality evidence for adverse events, due to risk of bias, inconsistency and imprecision of effect. We did not compare the various interventions with one another and so cannot comment on the superiority of one intervention over another. Complications were reported more often with use of opioids.

We included trials up to July 2013 in our review. We re-ran the searches in February 2015. In total there are 17 studies awaiting classification. We included 66 studies with 7840 participants, both male and female, and including children and adults. Most of these participants were undergoing various planned surgical procedures in hospitals in several countries including Korea, Turkey and India. The trials compared an intervention aiming to reduce pain on injection with a placebo to ascertain whether any intervention was effective at reducing pain. The outcome was assessed by recording the level of pain reported by patients when injected with rocuronium bromide. The most studied treatments were injection of the local anaesthetic lidocaine, or the painkillers fentanyl or remifentanil, into the vein before injecting rocuronium. These treatments may reduce the pain associated with injecting rocuronium, but the evidence is of low quality. Some interventions, for example using painkillers such as fentanyl, may increase cough, chest tightness and breath holding. These are recognized side effects of these drugs. The low quality of the evidence for the assessment of changes in the level of pain was due to inadequate reporting of study design and variation in the study results. In addition to these limitations, for some adverse event outcomes we did not have enough information to be certain about the average effect. Further research is needed with high quality, well designed studies to determine whether pain on injection of rocuronium bromide can be reduced by using an appropriate intervention.

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We included 13 studies, involving 1622 women. All were comparisons of single-dose treatment with short-course (four- to seven-day) treatments. The risk of bias of trials included in this review was largely unclear, and most trials were at high risk of performance bias. The quality of the evidence was assessed using the GRADE approach. When the any antibiotic agent was used, the 'no cure' rate for asymptomatic bacteriuria in pregnant women was slightly lower for the short-course treatment over the single-dose treatment, although there was evidence of statistical heterogeneity (average risk ratio (RR) 1.28, 95% confidence interval (CI) 0.87 to 1.88; women = 1502, studies = 13; I² = 56%; very low quality evidence). Data from only good quality trials also showed better cure rates with short (four- to seven-day) regimens of the same microbial agent (average RR 1.72, 95% CI 1.27 to 2.33; women = 803, studies = two; I² = 0%; high quality evidence). There was no clear difference in the recurrence of asymptomatic bacteriuria rate between treatment and control groups, whether the same or different microbial agents were used (RR 1.13, 95% CI 0.77 to 1.66; 445 women studies = eight; I² = 0%; very low quality evidence). Differences were detected for low birthweight babies, favoring a short course (four- to seven-day treatment) of the same microbial agent, although the data come from a single trial (RR 1.65, 95% CI 1.06 to 2.57; 714 women; high quality evidence), but no differences were observed for preterm delivery (RR 1.17, 95% CI 0.77 to 1.78; women = 804; studies = three; I² = 23%; moderate quality) or pyelonephritis (RR 3.09, 95% CI 0.54 to 17.55; women = 102; studies = two; I² = 0%; very low quality evidence). Finally, single-dose treatment of any microbial agent was associated with a decrease in reports of 'any side effects' (RR 0.70, 95% CI 0.56 to 0.88; 1460 women, studies = 12; I² = 9%; low quality evidence). Evidence was downgraded for risk of bias concerns in trials contributing data and for imprecise effect estimates (wide confidence intervals crossing the line of no effect, and in some cases, small studies with few events). A single-dose regimen of antibiotics may be less effective than a short-course (four- to seven-day) regimen, but more evidence is needed from large trials measuring important outcomes, such as cure rate. Women with asymptomatic bacteriuria in pregnancy should be treated by the standard regimen of antibiotics until more data become available testing seven-day treatment compared with shorter courses of three- or five-day regimens.

This review aimed to identify whether single-dose antibiotic treatments are as effective as longer ones for maternal and newborn outcomes. In general, the risk of bias of trials included in this review was largely unclear. The overall quality of the evidence was assessed using the GRADE approach. The review of 13 studies, involving over 1622 women, found that a seven-day regimen is more effective than a one-day course, especially for the outcome of low birthweight (high quality evidence), but this result is based on just one study. There were no clear differences between a single dose and a four- to seven-day short course of antibiotics for other review outcomes, including kidney infection (very low quality evidence) and preterm birth (moderate quality evidence). Women with a single-dose regimen reported fewer side effects (low quality evidence). More trials are needed to confirm which length of treatment is best for women and babies.

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We included eight RCTs with 1157 patient participants and 943 carer participants. We found no quasi-RCTs. We identified seven studies that await classification, and three ongoing studies. Three studies designed an intervention targeted at patients, four at carers, and one at both patients and carers. Studies included varied information: standardised or tailored, presented once or several times, and that included verbal or written information, audio recordings, multimedia information, and interactive information packs. Five studies reported robust methods of randomisation and allocation concealment. We noted high attrition rates in five studies. It was not feasible to blind participants, and we rated all studies as at high risk of performance bias, and at unclear risk of detection bias because most outcomes required self reporting. We attempted to pool data statistically, however this was not always possible due to high levels of heterogeneity. We calculated mean differences (MDs) using data reported from individual study authors where possible, and narratively synthesised the results. We reported the following two comparisons. Information or education intervention versus no information or education intervention (4 studies) For patient anxiety, we did not pool data from three studies (332 participants) owing to unexplained substantial statistical heterogeneity and possible clinical or methodological differences between studies. One study reported less anxiety when an intervention was used (MD -3.20, 95% confidence interval (CI) -3.38 to -3.02), and two studies reported little or no difference between groups (MD -0.40, 95% CI -4.75 to 3.95; MD -1.00, 95% CI -2.94 to 0.94). Similarly, for patient depression, we did not pool data from two studies (160 patient participants). These studies reported less depression when an information or education intervention was used (MD -2.90, 95% CI -4.00 to -1.80; MD -1.27, 95% CI -1.47 to -1.07). However, it is uncertain whether information or education interventions reduce patient anxiety or depression due to very low-certainty evidence. It is uncertain whether information or education interventions improve health-related quality of life due to very low-certainty evidence from one study reporting little or no difference between intervention groups (MD -1.30, 95% CI -4.99 to 2.39; 143 patient participants). No study reported adverse effects, knowledge acquisition, PTSD severity, or patient or carer satisfaction. We used the GRADE approach and downgraded certainty of the evidence owing to study limitations, inconsistencies between results, and limited data from few small studies. Information or education intervention as part of a complex intervention versus a complex intervention without information or education (4 studies) One study (three comparison groups; 38 participants) reported little or no difference between groups in patient anxiety (tailored information pack versus control: MD 0.09, 95% CI -3.29 to 3.47; standardised general ICU information versus control: MD -0.25, 95% CI -4.34 to 3.84), and little or no difference in patient depression (tailored information pack versus control: MD -1.26, 95% CI -4.48 to 1.96; standardised general ICU information versus control: MD -1.47, 95% CI -6.37 to 3.43). It is uncertain whether information or education interventions as part of a complex intervention reduce patient anxiety and depression due to very low-certainty evidence. One study (175 carer participants) reported fewer carer participants with poor comprehension among those given information (risk ratio 0.28, 95% CI 0.15 to 0.53), but again this finding is uncertain due to very low-certainty evidence. Two studies (487 carer participants) reported little or no difference in carer satisfaction; it is uncertain whether information or education interventions as part of a complex intervention increase carer satisfaction due to very low-certainty evidence. Adverse effects were reported in only one study: one participant withdrew because of deterioration in mental health on completion of anxiety and depression questionnaires, but the study authors did not report whether this participant was from the intervention or comparison group. We downgraded certainty of the evidence owing to study limitations, and limited data from few small studies. No studies reported severity of PTSD, or health-related quality of life. We are uncertain of the effects of information or education interventions given to adult ICU patients and their carers, as the evidence in all cases was of very low certainty, and our confidence in the evidence was limited. Ongoing studies may contribute more data and introduce more certainty when incorporated into future updates of the review.

The evidence is current up to 10 April 2017. We included eight studies with 1157 ICU patients and 943 carers of ICU patients. Seven studies are awaiting classification because we could not assess their eligibility, and three studies are ongoing. We included studies that assessed information given to patients or their carers compared to no information, and studies that assessed information as part of a more complex intervention compared to a complex intervention that did not include information or education. Studies included varied information: standardised or tailored to the individual, given regularly or on a single occasion, and that included verbal or written information, audio recordings, multimedia information, and interactive information packs. Overall, it is uncertain whether information or education (given alone or as part of a more complex intervention) improves outcomes for patients and their carers following a stay in the ICU. For patients, it is uncertain whether or not information or education reduces anxiety or depression, or improves health-related quality of life. One patient asked to withdraw from the study because they believed that their mental health worsened when they completed a questionnaire to assess anxiety and depression, but it is not clear whether this person received the information intervention or not. No studies reported PTSD in patients. For carers, it is uncertain whether or not information or education reduces anxiety or depression or improves carers' knowledge acquisition or their satisfaction with information provided. It was not possible for researchers to mask patients and carers to the intervention they received, and it was unclear whether this would affect the results, which relied on self assessments. Study authors did not consistently report rigorous methods for carrying out randomised trials, and we noted some losses of patients and carers during the studies. We found few small studies for this review, reporting limited data for many outcomes of interest. It is uncertain whether information or education is effective due to very low-certainty evidence. We are uncertain about the effects of information or education interventions given to adult ICU patients and their carers. The evidence was of very low certainty, and our confidence in the evidence was limited. We are aware of three ongoing studies and seven studies that were recently completed but not yet published. These studies may provide additional evidence or improve the certainty in the findings in future updates of the review.

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Four RCTs enrolling 2177 participants met our inclusion criteria. Of these, three compared ACEi with placebo and one compared ACEi with ARB. Two studies had an overall low risk of bias, and the other two were considered to be at moderate to high risk of bias. Low to moderate quality of evidence (from two studies representing 1906 patients) suggested that ACEi had no impact on all-cause mortality (RR 1.80, 95% CI 0.17 to 19.27, P = 0.63) or cardiovascular events (RR 0.87, 95% CI 0.66 to 1.14, P = 0.31) in people with stage 3 CKD. For all-cause mortality, there was substantial heterogeneity in the results. One study (quality assessment: low risk of bias) reported no difference in the risk of end-stage kidney disease in those with an eGFR > 45 mL/min/1.74 m² treated with ACEi versus placebo (RR 1.00, 95% CI 0.09 to 1.11, P = 0.99). The (high risk of bias) study that compared ACEi with ARB reported little difference in effect between the treatments when urinary protein, blood pressure or creatinine clearance were compared. No published studies comparing ARB with placebo or ACEi and ARB with placebo were identified. Our review demonstrated that there is currently insufficient evidence to determine the effectiveness of ACEi or ARB in patients with stage 1 to 3 CKD who do not have diabetes mellitus. We have identified an area of significant uncertainty for a group of patients who account for most of those labelled as having CKD.

This review identified four studies (enrolling 2177 people). Three studies compared ACEi to placebo or no treatment and one study compared ACEi to ARB. There is not enough evidence in the published literature at present to determine how effective drugs in the ACEi or ARB families are for treating patients with early (stage 1 to 3) CKD who do not have diabetes.

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Seventeen trials were included. These involved 1433 people, mostly young physically active adults. All included trials had methodological weaknesses and were at risk of bias, notably selection bias from inadequate or lack of allocation concealment. Data for pooling individual outcomes were available for a maximum of nine trials and 54% of participants. There were no statistically or clinically significant differences between double-bundle and single-bundle reconstruction in the subjective functional knee scores (subjective IKDC score, Tegner activity score, Lysholm score) in the intermediate (six months up to two years since surgery) or long term (two to five years from surgery). For example, the long term results for the Lysholm score (0 to 100: best score) were: mean difference (MD) 0.12, 95% confidence interval (CI) -1.50 to 1.75; 5 trials, 263 participants). The only trial reporting on long term knee pain found no statistically significant differences between the two groups. There were no significant differences between the two groups in adverse effects and complications (e.g. infection reported by nine trials (7/285 versus 7/393; risk ratio (RR) 1.14, 95% CI 0.46 to 2.81); graft failure reported by six trials (1/169 versus 4/185; RR 0.45; 95% CI 0.07 to 2.90). Limited data from five trials found a better return to pre-injury level of activity after double-bundle reconstruction (147/162 versus 208/255; RR 1.15, 95% CI 1.07 to 1.25). At long term follow-up, there were statistically significant differences in favour of double-bundle reconstruction for IKDC knee examination (normal or nearly normal categories: 325/344 versus 386/429; RR 1.05, 95% CI 1.01 to 1.08; 9 trials), knee stability measured with KT-1000 arthrometer (MD -0.74 mm, 95% CI -1.10 to -0.37; 5 trials, 363 participants) and rotational knee stability tested by the pivot-shift test (normal or nearly normal categories: 293/298 versus 382/415; RR 1.06, 95% CI 1.02 to 1.09; 9 trials). There were also statistically significant differences in favour of double-bundle reconstruction for newly occurring meniscal injury (9/240 versus 24/358; RR 0.46, 95% CI 0.23 to 0.92; 6 trials) and traumatic ACL rupture (1/120 versus 8/149; RR 0.17, 95% CI 0.03 to 0.96; 3 trials). There were no statistically significant differences found between the two groups in range of motion (flexion and extension) deficits. There is insufficient evidence to determine the relative effectiveness of double-bundle and single-bundle reconstruction for anterior cruciate ligament rupture in adults, although there is limited evidence that double-bundle ACL reconstruction has some superior results in objective measurements of knee stability and protection against repeat ACL rupture or a new meniscal injury. High quality, large and appropriately reported randomised controlled trials of double-bundle versus single-bundle reconstruction for anterior cruciate ligament rupture in adults appear justified.

Seventeen trials were included. These involved 1433 patients, who were mostly young physically active adults. All included trials had methodological weaknesses that are likely to undermine the reliability of their results. Data for pooling individual outcomes were available for a maximum of nine trials. There was not enough evidence of differences between two groups in terms of functional knee scores, adverse effects and complications (infection, hardware problem such as pain from fixation device, graft failure), range of motion (flexion and extension deficit). At long term follow-up, some clinician-assessed measures of knee stability and repeated rupture rate or occurrence of new meniscal injuries were better after double-bundle reconstruction. We concluded that there was not enough evidence to say whether double-bundle reconstruction gives better results than single-bundle reconstruction for anterior cruciate ligament rupture in adults. However, there is limited evidence that double-bundle ACL reconstruction has some superior results for knee stability and protection against repeat ACL rupture or newly occurring meniscal injury.

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One single trial was eligible for inclusion. This non-randomised, unblinded, controlled trial undertaken in Bangladesh involved 117 tetanus patients. Vitamin C at a dosage of 1 g/day was administered intravenously alongside conventional treatment. At recruitment, the participants were stratified into two age groups and the results were reported by age. There was a significant difference in the vitamin C effect between the two age groups (P = 0.01). In the tetanus patients aged 1 to 12 years (n = 62), vitamin C treatment was associated with a 100% reduction in case fatality rate (95% CI from -100% to -94%). In patients aged 13 to 30 years (n = 55), vitamin C treatment was associated with a 45% reduction in case fatality rate (95% CI from -69% to -5%). A single, non-randomised, poorly reported trial of vitamin C as a treatment for tetanus suggests a considerable reduction in mortality. However, concerns about trial quality mean that this result must be interpreted with caution and vitamin C cannot be recommended as a treatment for tetanus on the basis of this evidence. New trials should be carried out to examine the effect of vitamin C on tetanus treatment.

We found one controlled trial that examined whether one gram per day of intravenous vitamin C would help in the treatment of tetanus patients. Vitamin C was used alongside standard treatments for tetanus. Intravenous vitamin C reduced the mortality of children aged between 1 and 12 with tetanus by 100% and that of 13 to 30 year old patients by 45%. The trial was not properly conducted and caution is required in the interpretation of the findings. Vitamin C cannot be recommended as a treatment for tetanus on the basis of this single study. Further investigation of the role of vitamin C in tetanus treatment is warranted.

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We did not find any trials that investigated the role of AEDs in preventing seizures among people with neurocysticercosis, presenting with symptoms other than seizures. We did not find any trials that evaluated evaluating individual AEDs in people with neurocysticercosis. We found one trial, comparing two AEDs in people with solitary neurocysticercosis with seizures. However, we excluded this study from the review as it was of poor quality. We found four trials that compared the efficacy of short term versus longer term AED treatment for people with solitary neurocysticercosis (identified on computed tomography (CT) scan) presenting with seizures. In total, 466 people were enrolled. These studies compared various AED treatment durations, six, 12 and 24 months. The risk of seizure recurrence with six months treatment compared with 12 to 24 months treatment was not statistically significant (odds ratio (OR) 1.34 (95% confidence interval (CI) 0.73 to 2.47; three studies, 360 participants; low-certainty evidence)). The risk of seizure recurrence with six to 12 months compared with 24 months treatment was not statistically significant (OR 1.36 (95% CI 0.72 to 2.57; three studies, 385 participants; low-certainty evidence)). Two studies co-related seizure recurrence with CT findings and suggested that persistent and calcified lesions had a higher recurrence risk and suggest longer duration of treatment with AEDs. One study reported no side effects, while the rest did not comment on side effects of drugs. None of the studies addressed the quality of life of the participants.These studies had certain methodological deficiencies such as a small sample size and a possibility of bias due to lack of blinding, which affect the results of this review. Despite neurocysticercosis being the most common cause of epilepsy worldwide, there is currently no evidence available regarding the use of AEDs as seizure prophylaxis among people presenting with symptoms other than seizures. For those presenting with seizures, there is no reliable evidence regarding the duration of treatment required. There is therefore a need for large scale randomised controlled trials to address these questions.

Four trials with a total of 466 participants were reviewed, focusing on the comparison of 'short duration' and 'long duration' of AEDs drugs in people with a single cerebral lesion. These trials compared various durations of AED therapy: six to 12 months as short duration and 12 to 24 months as long-duration therapy. No statistically significant benefit of one duration of AED over the other (six, 12 or 24 months) could be demonstrated. In people with calcified cysts, longer duration of therapy may be preferable. All four included trials, enrolled people with a single brain lesion. The findings of our review cannot be extrapolated to people with multiple cysts or with cysts in unusual parts of the brain. The evidence is current to July 2019.

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Two eligible studies of a total of 273 infants were included. Both studies were randomized controlled trials. One study treated 63 infants with vidarabine or placebo (Whitley 1980) and the other study treated 210 infants with aciclovir or vidarabine (Whitley 1991). In the study comparing vidarabine with placebo (Whitley 1980), infants with all forms of neonatal HSV disease were included [disseminated disease, central nervous system (CNS) disease alone, and skin, eye and mouth (SEM) disease].There was no significant reduction in the risk of mortality when analyzed as an entire group; however, mortality was significantly reduced when data from infants with CNS disease or disseminated disease were combined. There was no difference in the rate of neurological abnormalities in survivors at one year when analyzed as an entire group or by disease category. There was no difference between aciclovir and vidarabine (Whitley 1991) in preventing mortality from neonatal HSV disease, in preventing disease progression, in reducing the incidence of neurological abnormality at one year, or in the incidence of drug-induced renal or bone marrow toxicity. In infants with SEM disease, there was no significant difference in neurological outcome with aciclovir compared vidarabine treatment. Both drugs were well tolerated in the newborn period. There is insufficient trial evidence to evaluate the effects of antiviral agents with controls or with each other. The rarity of the condition makes effectively powered clinical trials difficult to perform. The efficacy of newer antiviral agents with better bioavailability (e.g. valaciclovir, valganciclovir) for the treatment of neonatal disease needs to be evaluated in randomised trials. The efficacy of oral formulations need to be evaluated as they may be useful for infants with skin, eye or mouth HSV disease or in the treatment of infants with recurrences after the neonatal period.

We reviewed five studies conducted to assess the effects of antiviral agents (medications that reduce the spread of virus in the body) on mortality and long-term complications of herpes disease in the newborn. Antiviral agents were shown to reduce mortality from the condition, but the reduction was not statistically significant due to the small number of infants in the study. There was insufficient trial data to guide caregivers regarding the duration of antiviral therapy or dose.

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Nine RCTs, one with two reports, (N = 531 participants, 469 included in analyses) investigated a variety of telerehabilitation interventions in adults with MS. The mean age of participants varied from 41 to 52 years (mean 46.5 years) and mean years since diagnosis from 7.7 to 19.0 years (mean 12.3 years). The majority of the participants were women (proportion ranging from 56% to 87%, mean 74%) and with a relapsing-remitting course of MS. These interventions were complex, with more than one rehabilitation component and included physical activity, educational, behavioural and symptom management programmes. All studies scored 'low' on the methodological quality assessment. Overall, the review found 'low-level' evidence for telerehabilitation interventions in reducing short-term disability and symptoms such as fatigue. There was also 'low-level' evidence supporting telerehabilitation in the longer term for improved functional activities, impairments (such as fatigue, pain, insomnia); and participation measured by quality of life and psychological outcomes. There were limited data on process evaluation (participants'/therapists' satisfaction) and no data available for cost effectiveness. There were no adverse events reported as a result of telerehabilitation interventions. There is currently limited evidence on the efficacy of telerehabilitation in improving functional activities, fatigue and quality of life in adults with MS. A range of telerehabilitation interventions might be an alternative method of delivering services in MS populations. There is insufficient evidence to support on what types of telerehabilitation interventions are effective, and in which setting. More robust trials are needed to build evidence for the clinical and cost effectiveness of these interventions.

This review looked for evidence on how telerehabilitation interventions work in adults with MS. We searched widely for randomised controlled trials (RCTs), a particular kind of study where participants are placed in treatment groups by chance (that is, randomly) because in most settings these provide the highest quality evidence. We were interested in studies that compared a telerehabilitation programme with standard or minimal care, or with different kinds of rehabilitation programmes. We found nine relevant RCTs covering 531 participants (469 included in the analyses), evaluating a wide variety of telerehabilitation interventions in persons with MS. The telerehabilitation interventions evaluated were complex, with more than one rehabilitation component and included physical activity, educational, behavioural and symptom management programmes. These interventions had different purposes and used different technologies, so a single overall definite conclusion was not possible. The methodological quality of the included studies is low and varied among the studies. There was 'low-quality' evidence from the included RCTs to support the benefit of telerehabilitation in reducing short-term disability and managing symptoms such as fatigue in adults with MS. We found limited evidence to support the benefit of telerehabilitation interventions in improving disability, reducing symptoms and improving quality of life in the longer term. Furthermore, the interventions and outcomes being investigated in the included studies were different to each other. No studies reported any serious harm from telerehabilitation and there was no information on the associated costs. There is a need for further research to assess the effects of the range of telerehabilitation techniques and to establish the clinical and cost effectiveness of these interventions in people with MS. The evidence in this review is up to date to July 2014.

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We included two RCTs that randomised 20 participants to NPPV and 20 participants to control. We assessed both studies as having high risk of bias; both trials assessed effects of bilateral positive airway pressure (BiPAP). Neither trial used continuous positive airway pressure (CPAP). Controls received standard care. Investigators reported no deaths and no serious adverse events (Grades of Recommendation, Assessment, Development and Evaluation (GRADE): very low quality of evidence due to serious risk of bias and serious imprecision of results). Both trials showed a statistically significant reduction in symptom score. One trial did not report a standard deviation (SD), but by using an estimated SD, we found a statistically significantly reduced asthma symptom score (mean difference (MD) ‐2.50, 95% confidence interval (CI) ‐4.70 to ‐0.30, P = 0.03, 19 participants, GRADE: very low quality of evidence). In the other trial, NPPV was associated with a lower total symptom score (5.6 vs 1.9, 16 participants, very low quality of evidence) before cross‐over, but investigators did not report an SD, nor could it be estimated from the first phase of the trial, before the cross‐over. These gains could be clinically relevant, as a reduction of three or more points in symptom score is considered a clinically meaningful change. Researchers documented five dropouts (12.5%), four of which were due to intolerance to NPPV, and one to respiratory failure requiring intubation. Owing to insufficient reporting in the latter trial and use of different scoring systems, it was not possible to conduct a meta‐analysis nor a Trial Sequential Analysis. Current evidence does not permit confirmation or rejection of the effects of NPPV for acute asthma in children. Large RCTs with low risk of bias are warranted.

The evidence is current to August 2016. We included two trials, with 40 participants. Included trials assessed the effects of one type of NPPV called bilevel positive airway pressure, which lasted for two and 24 hours, respectively, in the two trials. Overall, we found that NPPV compared with no additional treatment, treatment as usual or placebo did not result in any benefit or harm regarding death from all causes, serious adverse events (i.e. major complications) or improvement in asthma symptoms. Five study participants did not tolerate the treatment, four because of discomfort and one because intubation was required. Current evidence cannot confirm or reject the effects of NPPV for treatment of children with acute asthma. Larger randomised clinical trials are warranted. The evidence behind our conclusions is of very low quality. The two studies had high risk of bias (i.e. the studies were conducted in a way that may skew results to the positive side). In addition, the two studies included few participants, making results of this review imprecise.

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We identified 10 trials, which included 375 women having six different types of needle suspension procedures and 489 who received comparison interventions. Needle suspensions were more likely to fail than open abdominal retropubic suspension. There was a higher subjective failure rate after the first year (91/313 (29%) failed versus 47/297 (16%) failed after open abdominal retropubic suspension). The risk ratio (RR) was 2.00 (95% confidence interval (CI) 1.47 to 2.72), although the difference in peri-operative complications was not significant (17/75 (23%) versus 12/77 (16%); RR 1.44, 95% CI 0.73 to 2.83). There were no significant differences for the other outcome measures. This effect was seen in both women with primary incontinence and women with recurrent incontinence after failed primary operations. Needle suspensions may be as effective as anterior vaginal repair (50/156 (32%) failed after needle suspension versus 64/181 (35%) after anterior repair; RR 0.86, 95% CI 0.64 to 1.16), but there was little information about morbidity. Data for comparison with suburethral slings were inconclusive because they came from a small and atypical population. No trials compared needle suspensions with conservative management, peri-urethral injections, or sham or laparoscopic surgery. Bladder neck needle suspension surgery is probably not as good as open abdominal retropubic suspension for the treatment of primary and secondary urodynamic stress incontinence because the cure rates were lower in the trials reviewed. However, the reliability of the evidence was limited by poor quality and small trials. There was not enough information to comment on comparisons with suburethral sling operations. Although cure rates were similar after needle suspension compared with after anterior vaginal repair, the data were insufficient to be reliable and inadequate to compare morbidity. A Brief Economic Commentary (BEC) identified no cost-effectiveness studies comparing bladder neck needle suspension with other surgeries.

The review found 10 trials, which studied 375 women having six different types of needle suspension operations and compared them with 489 women who received other treatments. Most of the trials were small or of poor quality, making their results less reliable. More women were cured after abdominal operations such as colposuspension (84%) than after needle suspension (71%): both women who had and had not had a previous operation for incontinence. There was not enough evidence about complications, or how needle suspension compares with other operations. Needle suspension operations were not compared with conservative treatments such as pelvic floor exercises or drugs. In summary, needle suspension surgery appears to be less effective for urinary incontinence than abdominal surgery, and there is not enough evidence to compare it to other treatments.

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We included four trials of good methodological quality involving 656 women in the review. The four included trials evaluated five different interventions including glycerine pads, lanolin with breast shells, lanolin alone, expressed breast milk, and an all-purpose nipple ointment. All studies included education to position the infant at the breast correctly as part of routine postpartum care to both treatment and control groups. Pooled data existed only for the comparison of lanolin versus usual care. We did not pool data for other outcomes due to either heterogeneity in outcome measures or differing interventions. There was no evidence that glycerine gel dressings or breast shells with lanolin significantly improved nipple pain. One trial found no clear differences in nipple pain (at one to three days, four to five days, or six to seven days' post-treatment) between women who applied lanolin or nothing to their nipples. In contrast, the same trial found that women who applied expressed breast milk had significantly lower perceptions of nipple pain following four to five days of treatment than women who applied lanolin. However, this beneficial effect was not maintained after six to seven days of treatment. There were no group differences in nipple pain perceptions at any assessment between women who applied expressed breast milk and women who applied nothing. Women who applied an "all-purpose nipple ointment", in comparison to women who applied lanolin, had no improvement in nipple pain after seven days of treatment. There was insufficient evidence that glycerine gel dressings, lanolin with breast shells, lanolin alone, expressed breast milk, or all-purpose nipple ointment improved maternal perceptions of nipple pain. Overall, there was insufficient evidence to recommend any intervention for the treatment of nipple pain. However, one important finding was that regardless of the treatment used, for most women nipple pain reduced to mild levels after approximately seven to 10 days' postpartum. The provision of anticipatory guidance regarding usual time to pain reduction may be a useful strategy in assisting women to continue to breastfeed and to do so exclusively. The overall quality of the evidence for the primary outcome of nipple pain as assessed using GRADE was of low quality, mainly because single studies with few participants contributed data for analysis. There was insufficient evidence that glycerine gel dressings, breast shells with lanolin, lanolin alone, or the all-purpose nipple ointment significantly improved maternal perceptions of nipple pain. The results from these four trials of good methodological quality suggested that applying nothing or just expressed breast milk may be equally or more beneficial in the short-term experience of nipple pain than the application of an ointment such as lanolin. The quality of the evidence for this review did not lead to robust conclusions regarding the objectives assessed. We included only four trials, incorporating 656 women, in the review and all four trials compared varying interventions, participants, study outcome measures, and standards of usual care. The methodological quality of the included studies was good but the overall quality of the evidence for the primary outcome of nipple pain was of low quality, mainly because single studies with few participants contributed data for analysis.

We searched the Cochrane Pregnancy and Childbirth Group's Trials database for clinical trials assessing methods (interventions) of improving nipple pain among breastfeeding women in September 2014. We also looked at healing and infection of nipples, length of breastfeeding, if infants only received breast milk, and if mothers were happy with treatment for nipple problems and breastfeeding in general. Interventions included drug treatments (against bacteria given by mouth, spray, ointment; against fungal infections), non-drug treatments (lanolin, petroleum jelly, peppermint oil, glycerine), dressings, nipple protectors (breast shields or shells), light treatment, or applying expressed breast milk. Interventions were compared with each other or usual care (control). We found four trials of good methodological quality involving 656 women, which evaluated five different interventions including glycerine pads, lanolin with breast shells, lanolin alone, expressed breast milk, and an all-purpose nipple ointment. All studies included education to position the infant at the breast correctly as part of routine care to both intervention and control groups. Currently, there is not enough evidence to recommend any specific type of treatment for painful nipples among breastfeeding women. These results suggest that applying nothing or expressed breast milk may be equally or more beneficial in the short-term experience of nipple pain than the application of an ointment such as lanolin. One important finding in this review was that regardless of the treatment used, for most women, nipple pain reduced to mild levels approximately seven to 10 days' after giving birth (postpartum). The quality of the evidence for this review did not allow robust conclusions regarding treating nipple pain. We found only four small trials and all four trials compared varying interventions, participants, what was measured, and standards of usual care. While the methodological quality of the included studies was good, the overall quality of the evidence for the primary outcome of nipple pain was of low quality, mainly due to single studies with few participants contributed data for analysis.

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One new trial was included in this update. In all, 11 trials (six were randomised and five were quasi-randomised), involving a total of 1654 predominantly elderly patients with hip fractures, are included in the review. Most trials were at risk of bias, particularly that resulting from inadequate allocation concealment, lack of assessor blinding and incomplete outcome assessment. Only very limited data pooling was possible. Ten trials compared predominantly skin traction with no traction. The available data provided no evidence of benefit from traction either in the relief of pain (pain soon after immobilisation (visual analogue score 0: none to 10: worst pain): mean difference 0.11, 95% CI -0.27 to 0.50; 3 trials), ease of fracture reduction or quality of fracture reduction at time of surgery. There were inconclusive data for pressures sores and other complications, including fracture fixation failure. Three minor adverse effects (sensory disturbance and skin blisters) related to skin traction were reported. One of the above trials included both skin and skeletal traction groups. This trial and one other compared skeletal traction with skin traction and found no important differences between these two methods, although the initial application of skeletal traction was noted as being more painful and more costly. From the evidence available, the routine use of traction (either skin or skeletal) prior to surgery for a hip fracture does not appear to have any benefit. However, the evidence is also insufficient to rule out the potential advantages for traction, in particular for specific fracture types, or to confirm additional complications due to traction use. Given the increasing lack of evidence for the use of pre-operative traction, the onus should now be on clinicians who persist in using pre-operative traction to either stop using it or to use it only in the context of a well-designed randomised controlled trial.

This review summarising the evidence from randomised controlled trials included 11 trials with 1654 participants. Consistent with the general hip fracture population, most of the trial participants were older persons of around 80 years of age and the majority were female. Ten trials compared traction versus no traction and two trials, including one of the preceding 10 trials, compared skin and skeletal traction. As well as limitations in the trial methods, there were very limited data for pooling and a lack of information about the longer-term consequences of applying or not applying traction. Nonetheless, the evidence from the 10 trials consistently showed no evidence to support the supposed advantages of traction described above. There were inconclusive data for pressures sores (skin ulcers) and other complications. One trial reported three adverse effects (sensory disturbance and skin blisters) related to skin traction; all were minor.

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Five RCTs with a total of 341,342 participants were included in this review. All involved prostate-specific antigen (PSA) testing, with or without digital rectal examination (DRE), though the interval and threshold for further evaluation varied across trials. The age of participants ranged from 45 to 80 years and duration of follow-up from 7 to 20 years. Our meta-analysis of the five included studies indicated no statistically significant difference in prostate cancer-specific mortality between men randomised to the screening and control groups (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.86 to 1.17). The methodological quality of three of the studies was assessed as posing a high risk of bias. The European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial were assessed as posing a low risk of bias, but provided contradicting results. The ERSPC study reported a significant reduction in prostate cancer-specific mortality (RR 0.84, 95% CI 0.73 to 0.95), whilst the PLCO study concluded no significant benefit (RR 1.15, 95% CI 0.86 to 1.54). The ERSPC was the only study of the five included in this review that reported a significant reduction in prostate cancer-specific mortality, in a pre-specified subgroup of men aged 55 to 69 years of age. Sensitivity analysis for overall risk of bias indicated no significant difference in prostate cancer-specific mortality when referring to the meta analysis of only the ERSPC and PLCO trial data (RR 0.96, 95% CI 0.70 to 1.30). Subgroup analyses indicated that prostate cancer-specific mortality was not affected by the age at which participants were screened. Meta-analysis of four studies investigating all-cause mortality did not determine any significant differences between men randomised to screening or control (RR 1.00, 95% CI 0.96 to 1.03). A diagnosis of prostate cancer was significantly greater in men randomised to screening compared to those randomised to control (RR 1.30, 95% CI 1.02 to 1.65). Localised prostate cancer was more commonly diagnosed in men randomised to screening (RR 1.79, 95% CI 1.19 to 2.70), whilst the proportion of men diagnosed with advanced prostate cancer was significantly lower in the screening group compared to the men serving as controls (RR 0.80, 95% CI 0.73 to 0.87). Screening resulted in a range of harms that can be considered minor to major in severity and duration. Common minor harms from screening include bleeding, bruising and short-term anxiety. Common major harms include overdiagnosis and overtreatment, including infection, blood loss requiring transfusion, pneumonia, erectile dysfunction, and incontinence. Harms of screening included false-positive results for the PSA test and overdiagnosis (up to 50% in the ERSPC study). Adverse events associated with transrectal ultrasound (TRUS)-guided biopsies included infection, bleeding and pain. No deaths were attributed to any biopsy procedure. None of the studies provided detailed assessment of the effect of screening on quality of life or provided a comprehensive assessment of resource utilization associated with screening (although preliminary analyses were reported). Prostate cancer screening did not significantly decrease prostate cancer-specific mortality in a combined meta-analysis of five RCTs. Only one study (ERSPC) reported a 21% significant reduction of prostate cancer-specific mortality in a pre-specified subgroup of men aged 55 to 69 years. Pooled data currently demonstrates no significant reduction in prostate cancer-specific and overall mortality. Harms associated with PSA-based screening and subsequent diagnostic evaluations are frequent, and moderate in severity. Overdiagnosis and overtreatment are common and are associated with treatment-related harms. Men should be informed of this and the demonstrated adverse effects when they are deciding whether or not to undertake screening for prostate cancer. Any reduction in prostate cancer-specific mortality may take up to 10 years to accrue; therefore, men who have a life expectancy less than 10 to 15 years should be informed that screening for prostate cancer is unlikely to be beneficial. No studies examined the independent role of screening by DRE.

This review identified five relevant studies, comprised of 341,342 participants in total. Two of the studies were assessed to be of low risk of bias, whilst the remaining three had more substantive methodological weaknesses. Meta-analysis of all five included studies demonstrated no statistically significant reduction in prostate cancer-specific mortality (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.86 to 1.17). Meta-analysis of the two low risk of bias studies indicated no significant reduction in prostate cancer-specific mortality (RR 0.96, 95% CI 0.70 to 1.30). Only one study included in this review (ERSPC) reported a significant 21% relative reduction (95% CI 31% to 8%) in prostate cancer-specific mortality in a pre-specified subgroup of men. These results were primarily driven by two countries within the ERSPC study that had very high prostate cancer mortality rates and unusually large reduction estimates. Among men aged 55 to 69 years in the ERSPC study, the study authors reported that 1055 men would need to be screened to prevent one additional death from prostate cancer during a median follow-up duration of 11 years. Harms included overdiagnosis and harms associated with overtreatment, including false-positive results for the PSA test, infection, bleeding, and pain associated with subsequent biopsy.

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A total of 12 studies including 1020 participants were incorporated into the review. These studies had low to moderate risk of bias, mainly because allocation concealment or methods of sequence generation were not adequately reported. In addition, it was not clear whether follow-up was similar for the treatment groups. The index test was incorporated as a reference standard in the laparoscopy group, and differential verification or partial verification bias may have occurred in most RCTs. Overall the quality of the evidence was low to moderate for most outcomes, as per the GRADE approach. Laparoscopy was compared with open appendicectomy in eight RCTs. Laparoscopy was associated with an increased rate of specific diagnoses (seven RCTs, 561 participants; odds ratio (OR) 4.10, 95% confidence interval (CI) 2.50 to 6.71; I2 = 18%), but no evidence was found of reduced rates for any adverse events (eight RCTs, 623 participants; OR 0.46, 95% CI 0.19 to 1.10; I2 = 0%). A meta-analysis of seven studies found a significant difference favouring the laparoscopic procedure in the rate of removal of normal appendix (seven RCTs, 475 participants; OR 0.13, 95% CI 0.07 to 0.24; I2 = 0%). Laparoscopic diagnosis versus a 'wait and see' strategy was investigated in four RCTs. A significant difference favoured laparoscopy in terms of rate of specific diagnoses (four RCTs, 395 participants; OR 6.07, 95% CI 1.85 to 29.88; I2 = 79%), but no evidence suggested a difference in rates of adverse events (OR 0.87, 95% CI 0.45 to 1.67; I2 = 0%). We found that laparoscopy in women with acute lower abdominal pain, non-specific lower abdominal pain or suspected appendicitis led to a higher rate of specific diagnoses being made and a lower rate of removal of normal appendices compared with open appendicectomy only. Hospital stays were shorter. No evidence showed an increase in adverse events when any of these strategies were used.

Twelve studies were identified with 1020 women from 11 countries. Eight studies compared laparoscopy versus open appendicectomy, and four compared laparoscopy using a wait and see approach. The evidence is current to October 2013. In this review of randomised controlled trials, laparoscopy was found to be superior to both open appendicectomy alone and a wait and see strategy, as more specific diagnoses were made before discharge, and shorter hospital stays and earlier return to work (when compared with open appendicectomy only) were reported. No evidence was found of an increase in adverse events when any of these strategies was applied. The rate of removal of normal appendices was reduced with the laparoscopic approach compared with open appendicectomy but was greater when a laparoscopic approach was compared with a wait and see strategy. The quality of the evidence was ranked as low to moderate for most outcomes, mainly because many of the studies had methodological limitations and imprecision was noted for some outcomes.

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Thirteen studies, most including adult patients, met the eligibility criteria. We found no clear evidence of an effect of leukoreduced PRBC versus non-leukoreduced PRBC in patients that were randomised to receive transfusion for the following outcomes: TRALI: RR 0.96, 95% CI 0.67 to 1.36, P = 0.80 from one trial reporting data on 1864 trauma patients. The accrued information of 1864 participants constituted only 28.5% of the diversity-adjusted required information size (DARIS) of 6548 participants. The quality of evidence was low. Death from any cause: RR 0.81, 95% CI 0.58 to 1.12, I² statistic = 63%, P = 0.20 from nine trials reporting data on 6485 cardiovascular surgical patients, gastro-oncology surgical patients, trauma patients and HIV infected patients. The accrued information of 6485 participants constituted only 55.3% of the DARIS of 11,735 participants. The quality of evidence was very low. Infection from any cause: RR 0.80, 95% CI 0.62 to 1.03, I² statistic = 84%, P = 0.08 from 10 trials reporting data on 6709 cardiovascular surgical patients, gastro-oncology surgical patients, trauma patients and HIV infected patients. The accrued information of 6709 participants constituted only 60.6% of the DARIS of 11,062 participants. The quality of evidence was very low. Adverse events: The only adverse event reported as an adverse event was fever (RR 0.81, 95% CI 0.64 to 1.02; I² statistic= 0%, P = 0.07). Fever was reported in two trials on 634 cardiovascular surgical and gastro-oncology surgical patients. The accrued information of 634 participants constituted only 84.4% of the DARIS of 751 participants. The quality of evidence was low. Incidence of other non-infectious complications: This outcome was not assessed in any included trial. There is no clear evidence for supporting or rejecting the routine use of leukoreduction in all patients requiring PRBC transfusion for preventing TRALI, death, infection, non-infectious complications and other adverse events. As the quality of evidence is very low to low, more evidence is needed before a definitive conclusion can be drawn.

We searched medical journals for reports of clinical trials which examined the effects of removing white blood cells from donated blood. We were interested in finding out whether the removal of white blood cells from donated blood resulted in patients receiving a blood transfusion having few complications such as transfusion-related acute lung injury, death, infectious and non-infectious complications, or any other adverse event. We included people of any age or sex, who received a blood transfusion for any reason. The evidence is based on studies retrieved up to 05 December 2014. We found 13 studies which included people who received a blood transfusion during heart or cancer surgery, or because they were injured, had cancer, HIV or sepsis. We found no clear evidence showing either benefits or harms for removing white blood cells from donated blood. For all of the outcomes examined (transfusion-related acute lung injury, death from any cause, infection from any cause, non-infectious complication or any other adverse event), there was no sign of benefit or harm. The overall quality of evidence of the included studies ranges from very low to low. None of the studies included enough people to give a definitive answer about the usefulness of removing white blood cells from donated blood. New high-quality studies, involving a few thousand people, are needed to enable us to know the true benefits and harms of this procedure.

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We included 62 trials (6428 women). Twenty-two trials did not contribute data to the meta-analyses. The trials were generally small and of limited quality. Three trials (107 women) indicated that bromocriptine significantly reduced the proportion of women lactating compared with no treatment at or within seven days postpartum (three trials, 107 women; risk ratio (RR) 0.36, 95% confidence interval (CI) 0.24 to 0.54). Seven trials involving oestrogen preparations (diethylstilbestrol, quinestrol, chlorotrianisene, hexestrol) suggested that they significantly reduced the proportion of lactating women compared with no treatment at or within seven days postpartum (RR 0.40, 95% CI 0.29 to 0.56). We found no trials comparing non-pharmacologic methods with no treatment. Trials comparing bromocriptine with other pharmacologic agents such as methergoline, prostaglandins, pyridoxine, carbegoline, diethylstilbestrol and cyclofenil suggested similarity in their effectiveness. Side effects were poorly reported in the trials and no case of thromboembolism was recorded in the four trials that reported it as an outcome. There is weak evidence that some pharmacologic treatments (most of which are currently unavailable to the public) are better than no treatment for suppressing lactation symptoms in the first postpartum week. No evidence currently exists to indicate whether non-pharmacologic approaches are more effective than no treatment. Presently, there is insufficient evidence to address the side effects of methods employed for suppressing lactation. When women desire treatment, bromocriptine may be considered where it is registered for lactation suppression in those without predisposition to its major side effects of public concerns. Many trials did not contribute data that could be included in analyses. Large randomised trials are needed to compare the effectiveness of pharmacologic (especially bromocriptine) and non-pharmacologic methods with no treatment. Such trials should consider the acceptability of the intervention and lactation symptoms of concern to women and be large enough to detect clinically important differences in major side effects between comparison groups.

The evidence to support treatments for preventing lactation is limited. The review authors identified 62 controlled trials that randomised a total of 6428 mothers to receive the treatment under investigation, no treatment or another treatment. Twenty-two trials did not contribute data to the meta-analyses. The trials were generally of limited quality and most were conducted among healthy women who chose not to breastfeed for personal reasons at hospitals in industrialised countries before 1980. Half of the trials involved bromocriptine. Two trials (107 women) reported that taking bromocriptine was better than no treatment in suppressing lactation in the first week after giving birth. The 11 trials using oestrogen preparations (diethylstilbestrol, quinestrol, chlorotrianisene, hexestrol) also showed suppression of lactation. A combination of testosterone and oestrogen preparations was of some benefit in reducing symptoms in three trials (436 women). Other pharmacologic agents (clomiphene, tamoxifen, prostaglandins, pyridoxine, oxytocin, L-dopa and homeopathic preparation) were tested in single small trials. Generally, side effects were poorly reported and no case of thromboembolism was recorded among trials that included it as an adverse treatment outcome. Most of the drugs tested are currently not available or registered for suppressing lactation. No trials compared non-drug approaches with no treatment and none of the included trials provided reliable data on women’s satisfaction with the treatment.

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We included 35 studies (including seven from the previous version of the review), which included 2565 participants in total. All studies used a parallel RCT design, and 33 studies (94%) only targeted T2DM patients. There was variation between studies with regards to included age groups (ages 18 to 80), duration of follow-up (3 to 12 months), use of antidiabetic therapy, and included participants' baseline HbA1c levels (from 5.5% to 13.1%). We assessed 29 studies (83%) as being at high risk of bias, two studies (6%) as being at low risk of bias, and four studies (11%) as unclear. Thirty-four of the studies provided data suitable for analysis under one or both of the two comparisons. Comparison 1: low quality evidence from 14 studies (1499 participants) comparing periodontal therapy with no active intervention/usual care demonstrated that mean HbA1c was 0.29% lower (95% confidence interval (CI) 0.48% to 0.10% lower) 3 to 4 months post-treatment, and 0.02% lower after 6 months (five studies, 826 participants; 95% CI 0.20% lower to 0.16% higher). Comparison 2: 21 studies (920 participants) compared different periodontal therapies with each other. There was only very low quality evidence for the multiple head-to-head comparisons, the majority of which were unsuitable to be pooled, and provided no clear evidence of a benefit for one periodontal intervention over another. We were able to pool the specific comparison between scaling and root planing (SRP) plus antimicrobial versus SRP and there was no consistent evidence that the addition of antimicrobials to SRP was of any benefit to delivering SRP alone (mean HbA1c 0.00% lower: 12 studies, 450 participants; 95% CI 0.22% lower to 0.22% higher) at 3-4 months post-treatment, or after 6 months (mean HbA1c 0.04% lower: five studies, 206 patients; 95% CI 0.41% lower to 0.32% higher). Less than half of the studies measured adverse effects. The evidence was insufficient to conclude whether any of the treatments were associated with harm. No other patient-reported outcomes (e.g. quality of life) were measured by the included studies, and neither were cost implications or diabetic complications. Studies showed varying degrees of success with regards to achieving periodontal health, with some showing high levels of residual inflammation following treatment. Statistically significant improvements were shown for all periodontal indices (BOP, CAL, GI, PI and PPD) at 3-4 and 6 months in comparison 1; however, this was less clear for individual comparisons within the broad category of comparison 2. There is low quality evidence that the treatment of periodontal disease by SRP does improve glycaemic control in people with diabetes, with a mean percentage reduction in HbA1c of 0.29% at 3-4 months; however, there is insufficient evidence to demonstrate that this is maintained after 4 months. There was no evidence to support that one periodontal therapy was more effective than another in improving glycaemic control in people with diabetes mellitus. In clinical practice, ongoing professional periodontal treatment will be required to maintain clinical improvements beyond 6 months. Further research is required to determine whether adjunctive drug therapies should be used with periodontal treatment. Future RCTs should evaluate this, provide longer follow-up periods, and consider the inclusion of a third 'no treatment' control arm. Larger, well conducted and clearly reported studies are needed in order to understand the potential of periodontal treatment to improve glycaemic control among people with diabetes mellitus. In addition, it will be important in future studies that the intervention is effective in reducing periodontal inflammation and maintaining it at lowered levels throughout the period of observation.

This review of existing clinical trials was carried out by authors working with the Cochrane Oral Health Group and updates the previous version published in 2010. The evidence is current up to 31 December 2014. In this review there are 35 trials (including 2565 participants), published between 1997 and 2014, where people randomly received a type of gum disease treatment (including scaling and root planing (SRP) and SRP combined with other types of treatment), or usual care/no active treatment. The trials included in this review used SRP with, or without, an additional treatment. Additional treatments included instructions for cleaning teeth properly (known as oral hygiene instruction (OHI)), and other gum treatments (for example, antimicrobials, which are used to treat infections). We found 35 trials that were suitable for inclusion in this review. Thirty-four of those studies provided results that could be included in at least one of the two comparisons. 1. The evidence from 14 trials (1499 participants) showed that SRP reduces blood sugar levels in diabetic patients by 0.29% up to 4 months after receiving care when compared with usual care/no active treatment. After 6 months, there was no evidence that this reduction was sustained. 2. The evidence from 21 trials (920 participants) investigating different types of gum disease treatments failed to show that one treatment was better than another. There were not enough studies measuring side effects to be able to show if gum disease treatments cause any harm. Currently there is low quality evidence to support using scaling and root planing for controlling blood sugar levels up to 4 months after receiving treatment. Ongoing gum disease treatment is advised to maintain improvements in blood sugar levels.

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Two studies, involving a total of 122 participants who had experienced adductor-related groin pain for at least two months, were included in this review. All but one of the participants were male athletes aged between 18 and 50 years old. Both studies were assessed as 'high risk of bias' for at least one source of bias domain. The 'successful treatment' outcome reported in both studies was based primarily on pain measures. One study, based on an intention-to-treat analysis, found a significant difference favouring exercise therapy (strengthening with an emphasis on the adductor and abdominal muscles and training muscular co-ordination) compared with 'conventional' physiotherapy (stretching exercises, electrotherapy and transverse friction massage) in successful treatment at 16-week follow-up (25/34 (74%) versus 10/34 (29%); risk ratio (RR) 2.50, 95% CI 1.43 to 4.37, P = 0.001). Similarly, of those followed-up significantly more athletes treated by exercise therapy returned to sport at the same level (23/29 (79%) versus 4/30 (13%); RR 5.95, 95% CI 2.34 to 15.09, P = 0.0002). Although still favouring the exercise group, the differences between the two groups in patients' subjective global assessment at 16 weeks and successful treatment at 8 to 12 years follow-up were not statistically significant. The second study (54 participants) found no significant differences at 16-week follow-up between a multi-modal treatment (heat, manual therapy and stretching) and exercise therapy (the same intervention as in the above study) for the outcomes of successful treatment (14/26 (54%) versus 12/22 (55%); RR 0.99, 95% CI 0.59 to 1.66, P = 0.96) and return to full sports participation (13/26 (50%) versus 12/22 (55%); RR 0.92, 95% CI 0.53 to 1.58, P = 0.75). Those returning to full sports participation returned on average 4.5 weeks earlier after receiving multi-modal therapy (mean difference -4.50 weeks, 95% CI -8.60 to -0.40, P = 0.03) than those in the exercise therapy group. This study reported that there were no complications or side effects found in either intervention group. The available evidence from the randomized trials is insufficient to advise on any specific conservative modality for treating exercise-related groin pain. While still low quality, the best evidence is from one trial which found that exercise therapy (strengthening of hip and abdominal muscles) in athletes improves short-term outcomes (based primarily on pain measures) and return to sports compared with physiotherapy consisting of passive modalities. Given the low quality of the available evidence from both included trials, further randomized trials are necessary to reinforce their findings.

Two randomized controlled trials, involving a total of 122 athletes with exercise-related groin pain, were included in this review. Participants were aged between 18 and 50 years and all but one were male. They had had groin pain for at least two months. One trial demonstrated positive results in athletes treated by exercise therapy (strengthening of hip and abdominal muscles, and training muscular co-ordination) in comparison with 'conventional' physiotherapy consisting of passive modalities (stretching exercises, electrotherapy and transverse friction massage) 16 weeks after the end of treatment, for 'successful treatment' (based primarily on pain measures) and for the rate of return to sports at the same level without groin pain. The second study compared multi-modal treatment (heat, manual therapy and stretching) with exercise therapy and found no significant difference between groups for 'successful treatment' and return to sports, but did show an earlier return to sport for those athletes who achieved this outcome following the multi-modal treatment. The available evidence is exclusively related to athletes and is limited because of the low number of studies and low number of participants for each outcome. Further randomized controlled trials are needed to ratify these results.

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We included six randomised controlled trials involving 899 children; we added three studies (331 children) in this update. We assessed two studies as at high risk of performance and detection bias; three studies as at unclear risk of attrition bias; and three studies as at unclear risk of other bias. Studies compared honey with dextromethorphan, diphenhydramine, salbutamol, bromelin (an enzyme from the Bromeliaceae (pineapple) family), no treatment, and placebo. Five studies used 7-point Likert scales to measure symptomatic relief of cough; one used an unclear 5-point scale. In all studies, low score indicated better cough symptom relief. Using a 7-point Likert scale, honey probably reduces cough frequency better than no treatment or placebo (no treatment: mean difference (MD) -1.05, 95% confidence interval (CI) -1.48 to -0.62; I² = 0%; 2 studies; 154 children; moderate-certainty evidence; placebo: MD -1.62, 95% CI -3.02 to -0.22; I² = 0%; 2 studies; 402 children; moderate-certainty evidence). Honey may have a similar effect as dextromethorphan in reducing cough frequency (MD -0.07, 95% CI -1.07 to 0.94; I² = 87%; 2 studies; 149 children; low-certainty evidence). Honey may be better than diphenhydramine in reducing cough frequency (MD -0.57, 95% CI -0.90 to -0.24; 1 study; 80 children; low-certainty evidence). Giving honey for up to three days is probably more effective in relieving cough symptoms compared with placebo or salbutamol. Beyond three days honey probably had no advantage over salbutamol or placebo in reducing cough severity, bothersome cough, and impact of cough on sleep for parents and children (moderate-certainty evidence). With a 5-point cough scale, there was probably little or no difference between the effects of honey and bromelin mixed with honey in reducing cough frequency and severity. Adverse events included nervousness, insomnia, and hyperactivity, experienced by seven children (9.3%) treated with honey and two children (2.7%) treated with dextromethorphan (risk ratio (RR) 2.94, 95% Cl 0.74 to 11.71; I² = 0%; 2 studies; 149 children; low-certainty evidence). Three children (7.5%) in the diphenhydramine group experienced somnolence (RR 0.14, 95% Cl 0.01 to 2.68; 1 study; 80 children; low-certainty evidence). When honey was compared with placebo, 34 children (12%) in the honey group and 13 (11%) in the placebo group complained of gastrointestinal symptoms (RR 1.91, 95% CI 1.12 to 3.24; I² = 0%; 2 studies; 402 children; moderate-certainty evidence). Four children who received salbutamol had rashes compared to one child in the honey group (RR 0.19, 95% CI 0.02 to 1.63; 1 study; 100 children; moderate-certainty evidence). No adverse events were reported in the no-treatment group. Honey probably relieves cough symptoms to a greater extent than no treatment, diphenhydramine, and placebo, but may make little or no difference compared to dextromethorphan. Honey probably reduces cough duration better than placebo and salbutamol. There was no strong evidence for or against using honey. Most of the children received treatment for one night, which is a limitation to the results of this review. There was no difference in occurrence of adverse events between the honey and control arms.

We included six small trials involving 899 children aged 12 months to 18 years conducted in Iran, Israel, the USA, Brazil, and Kenya. This update included three new trials conducted between 2007 and 2016 that involved 331 children. Two studies were supported by pharmaceutical manufacturers; one by a university research centre; one by the Honey Board of Israel and non-government agencies; and one by USA National Honey Board. One study did not report funding sources. We compared honey to over-the-counter cough preparations, bromelin (a pineapple enzyme) mixed with honey, fake treatment (placebo), and no treatment. Honey probably reduces cough symptoms more than placebo and salbutamol (a drug that opens lung airways) when given for up to three days. Honey is probably more effective at providing cough relief and reducing the impact of cough on children's sleep at night than no treatment. There may be little or no difference between the effects of honey and dextromethorphan (an ingredient in over-the-counter cough remedies) or honey and bromelin with honey on all cough symptoms. Honey may be better than diphenhydramine (an antihistamine) at relieving and reducing children's cough. The parents of seven children given honey and two given dextromethorphan reported side effects in their children, such as not falling asleep easily, restlessness, and becoming overexcited. The parents of three children in the diphenhydramine group reported that their children were often sleepy. The parents of nine children given salbutamol, seven given honey, and six given placebo reported diarrhoea. The parents of four children who received salbutamol and one child given honey reported rash. We found no evidence for or against the use of honey to relieve cough in children. Using honey for infants aged up to 12 months is not advised because of poor immunity against bacteria that may be present, which can cause paralysis. Most of the children received honey for just one night, which is a limitation to the results of this review. Overall, evidence quality was low to moderate. Some studies did not blind participants.

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Five reviews, 114 studies, 7333 participants, satisfied criteria for inclusions. The outcomes considered were alcohol withdrawal seizures, adverse events and dropouts. Comparing the five treatments with placebo, benzodiazepines performed better for seizures, three studies, 324 participants, RR 0.16 (95% CI 0.04 to 0.69), moderate quality of evidence. Comparing each of the five treatments versus specific class of drugs, benzodiazepines performed better than antipsychotics for seizures, 4 studies, 633 participants, RR 0.24 (95% CI 0.07 to 0.88) high quality of the evidence. Comparing different benzodiazepines and anticonvulsants among themselves, 28 comparisons, results never reached statistical significance but chlordiazepoxide performed better. The quality of evidence was high for 3% of the results, moderate for 28%, low for 48% and very low for 20%. Among the treatments considered, benzodiazepines showed a protective benefit against seizures, when compared to placebo and a potentially protective benefit for many outcomes when compared with antipsychotics. Nevertheless, no definite conclusions about the effectiveness and safety of benzodiazepines were possible, because of the heterogeneity of the trials both in interventions and in the assessment of outcomes. Data on potential harms are sparse and fragmented. Results do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS, but anticonvulsants seem to have limited side effects. There is also not enough evidence of effectiveness and safety of baclofen, because only one study consider this treatment and of GHB for which no strong differences were observed in the comparisons with placebo, benzodiazepines and anticonvulsants.

Cochrane reviews of randomised controlled trials that examined the effectiveness and safety of medications for alcohol withdrawal syndrome were included in this overview. Participants in the review studies varied in age, gender, nationality, severity of symptoms and treatment as outpatients or inpatients. Five reviews, 114 studies, 7333 participants, were included. We considered the efficacy of the medication on alcohol withdrawal seizures, adverse events as a measure of safety and acceptability of the treatment as dropouts from the study. These outcomes were considered in 72 of the 114 studies. The treatments used were sedative benzodiazepines, anticonvulsants, baclofen, GHB and PAN. Baclofen and GHB mimic alcohol effects and can rapidly reduce symptoms. PAN (psychotropic analgesic nitrous oxide) involves administering low levels of nitrous oxide and oxygen gases so that the individual remains conscious and coherent. Comparing the five treatments with placebo, benzodiazepines performed better for seizures (three studies, 324 participants, moderate quality of evidence). This was the only treatment with statistically significant findings. Data on potential harms were sparse and fragmented in these studies. Benzodiazepines also performed better than antipsychotics for seizures (4 studies, 633 participants, high quality of evidence). For the majority of our results, further research is likely to have an important impact on confidence in the estimate of effect. We assessed the quality of the evidence in the included reviews using GRADE, which looks at the quality of evidence for each outcome, taking into consideration the magnitude of the effect, the relevance of the data to the clinical question being asked, the sample size in the relevant trials, the methodological quality of the trials and the consistency of the findings.

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Ten studies fulfilled the inclusion criteria. Six CBA studies reported on interventions relating to temporal flexibility: self-scheduling of shift work (n = 4), flexitime (n = 1) and overtime (n = 1). The remaining four CBA studies evaluated a form of contractual flexibility: partial/gradual retirement (n = 2), involuntary part-time work (n = 1) and fixed-term contract (n = 1). The studies retrieved had a number of methodological limitations including short follow-up periods, risk of selection bias and reliance on largely self-reported outcome data. Four CBA studies on self-scheduling of shifts and one CBA study on gradual/partial retirement reported statistically significant improvements in either primary outcomes (including systolic blood pressure and heart rate; tiredness; mental health, sleep duration, sleep quality and alertness; self-rated health status) or secondary health outcomes (co-workers social support and sense of community) and no ill health effects were reported. Flexitime was shown not to have significant effects on self-reported physiological and psychological health outcomes. Similarly, when comparing individuals working overtime with those who did not the odds of ill health effects were not significantly higher in the intervention group at follow up. The effects of contractual flexibility on self-reported health (with the exception of gradual/partial retirement, which when controlled by employees improved health outcomes) were either equivocal or negative. No studies differentiated results by socio-economic status, although one study did compare findings by gender but found no differential effect on self-reported health outcomes. The findings of this review tentatively suggest that flexible working interventions that increase worker control and choice (such as self-scheduling or gradual/partial retirement) are likely to have a positive effect on health outcomes. In contrast, interventions that were motivated or dictated by organisational interests, such as fixed-term contract and involuntary part-time employment, found equivocal or negative health effects. Given the partial and methodologically limited evidence base these findings should be interpreted with caution. Moreover, there is a clear need for well-designed intervention studies to delineate the impact of flexible working conditions on health, wellbeing and health inequalities.

Flexible working arrangements, such as flexitime and teleworking, are becoming more common in industrialised countries but the impacts of such flexibility on employee health and wellbeing are largely unknown. This review examined the health and wellbeing effects of flexible working arrangements which favour the worker as well as those dictated by the employer (for example, fixed-term contracts or mandatory overtime). Ten controlled before and after studies were found which evaluated the effects of six different types of flexible working arrangement on employee health and wellbeing: self-scheduling (n = 4); flextime (n = 1); overtime (n = 1); gradual retirement (n = 2); involuntary part-time (n = 1) and fixed-term contract (n = 1). Self-scheduling of shift interventions and employee controlled partial/early retirement were found to improve health (including systolic blood pressure and heart rate; tiredness; mental health, sleep duration, sleep quality and alertness; and self-rated health status) and/or wellbeing (co-workers' social support and sense of community) and no ill health effects were observed. The studies of overtime working, flexitime and fixed-term contracts found no significant effects on physical, mental or general health or on any of the wellbeing outcomes examined. Importantly, however, the study on overtime failed to provide detailed information on either the amount or duration of overtime worked, so it is therefore difficult to draw any conclusions regarding the effects of overtime on workers' health and wellbeing. Overall, these findings seem to indicate that flexibility in working patterns which gives the worker more choice or control is likely to have positive effects on health and wellbeing. However, given the small number of studies included in the review and their methodological limitations, caution should be applied to this conclusion. Well-designed studies are therefore needed to further explain the relationship between flexible working and health and wellbeing.

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Of 720 records screened, we included eight trials that randomised 1048 participants with type 2 diabetes (387 SSI participants and 615 participants in comparator groups were available for final analysis). We included non-critically ill medical and surgical adults with the diagnosis of diabetes mellitus. The mean follow-up time was measured by the mean length of hospital stay and ranged between five and 24 days. The mean age of participants was 44.5 years to 71 years. Overall, we judged the risk of bias on the trial level as unclear for selection bias, high for outcome-related performance and detection bias with regard to hypoglycaemic episodes, other adverse events, and mean glucose levels, and low for all-cause mortality and length of hospital stay. Attrition bias was low for all outcome measures. Six trials compared SSI with a basal-bolus insulin scheme, three of which investigating 64% of all participants in this category also applying an SSI approach in the bolus comparator part. One trial had a basal insulin-only comparator arm, and the remaining trial used continuous insulin infusion as the comparator. For our main comparison of SSI versus basal-bolus insulin, the results were as follows. Four trials reported mortality data. One out of 268 participants in the SSI group (0.3%) compared with two out of 334 participants in the basal-bolus group (0.6%) died (low-certainty evidence). Severe hypoglycaemic episodes, defined as blood glucose levels below 40 mg/dL (2.2 mmol/L), showed a risk ratio (RR) of 0.22, 95% confidence interval (CI) 0.05 to 1.00; P = 0.05; 5 trials; 667 participants; very low-certainty evidence. The 95% prediction interval ranged between 0.02 and 2.57. All nine severe hypoglycaemic episodes were observed among the 369 participants on basal-bolus insulin (2.4%). The mean length of hospital stay was 0.5 days longer for the SSI group, 95% CI -0.5 to 1.4; P = 0.32; 6 trials; 717 participants; very low-certainty evidence. The 95% prediction interval ranged between -1.7 days and 2.7 days. Adverse events other than hypoglycaemic episodes, such as postoperative infections, showed a RR of 1.16, 95% CI 0.25 to 5.37; P = 0.85; 3 trials; 481 participants; very low-certainty evidence. The mean blood glucose levels ranged across basal-bolus groups from 156 mg/dL (8.7 mmol/L) to 221 mg/dL (12.3 mmol/L). The mean blood glucose level in the SSI groups was 14.8 mg/dL (0.8 mmol/L) higher (95% CI 7.8 (0.4) to 21.8 (1.2); P < 0.001; 6 trials; 717 participants; low-certainty evidence). The 95% prediction interval ranged between -3.6 mg/dL (-0.2 mmol/L) and 33.2 mg/dL (1.8 mmol/L). No trial reported on diabetes-related mortality or socioeconomic effects. We are uncertain which insulin strategy (SSI or basal-bolus insulin) is best for non-critically hospitalised adults with diabetes mellitus. A basal-bolus insulin strategy in these patients might result in better short-term glycaemic control but could increase the risk for severe hypoglycaemic episodes. The certainty of the body of evidence comparing SSI with basal-bolus insulin was low to very low and needs to be improved by adequately performed, well-powered RCTs in different hospital environments with well-educated medical staff using identical short-acting insulins in both intervention and comparator arms to compare the rigid SSI approach with flexible insulin application strategies.

We found eight randomised controlled trials (studies in which participants are assigned to one of two or more treatment groups in a random manner) where 387 people on sliding scale insulin therapy and 615 on mainly basal-bolus insulin treatment with type 2 diabetes could be analysed. The average length of hospital stay was between five and 24 days. Six studies compared sliding scale insulin with basal-bolus insulin; one study compared sliding scale insulin with basal insulin only; and the remaining study used continuous insulin infusion as the control group. The average age of participants was 44.5 years to 71 years. The evidence is up to date as of December 2017. The main comparison was between sliding scale insulin and basal-bolus insulin therapy with the following results. Of the four studies reporting deaths, one out of 268 participants in the SSI group compared with two out of 334 participants in the basal-bolus group died. Severe hypoglycaemic episodes, defined as blood glucose levels below 40 mg/dL, occurred in 5 per 1000 people in the sliding scale insulin groups compared with 24 per 1000 people in the basal-bolus insulin groups. These data are uncertain because further analyses showed neither a positive nor a negative effect comparing both insulin strategies. The length of hospital stay in the sliding scale insulin groups compared with the basal-bolus insulin groups was 0.5 days longer, again with further analyses indicating that this information is uncertain. The results for adverse events other than hypoglycaemic episodes, such as postoperative infections, did not indicate an advantage or disadvantage of either strategy. The average blood glucose level during hospital stay in the sliding scale groups was 14.8 mg/dL higher compared with the basal-bolus groups. We are uncertain about these data because analyses showed neither a positive nor a negative effect comparing both insulin strategies. No trial reported on deaths caused by diabetes as such or socioeconomic effects like costs of the interventions or absence from work. Overall, our confidence in the results for all analysed outcomes was low or very low mainly due to the low number of studies and participants and because the results were not precise, that is they could change in any direction once new studies are published.

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We included four trials (three RCTs and one cross-over trial) involving 139 participants. Blinding of participants and physicians was well reported within all trials. We judged the overall risk of bias across trials as low. Only two trials (with 63 and 18 participants, respectively) provided sufficient information to be included in the meta-analysis. We found no clear effect of rPMS on activities of daily living at the end of treatment (mean difference (MD) -3.00, 95% confidence interval (CI) -16.35 to 10.35; P = 0.66; 1 trial; 63 participants; low-quality evidence) and at the end of follow-up (MD -2.00, 95% CI -14.86 to 10.86; P = 0.76; 1 trial; 63 participants; low-quality evidence) when comparing rPMS plus rehabilitation versus sham plus rehabilitation. We found no statistical difference in improvement of upper limb function at the end of treatment (MD 2.00, 95% CI -4.91 to 8.91; P = 0.57; 1 trial; 63 participants; low-quality evidence) and at the end of follow-up (MD 4.00, 95% CI -2.92 to 10.92; P = 0.26; 1 trial; 63 participants; low-quality evidence) when comparing rPMS plus rehabilitation versus sham plus rehabilitation. We observed a significant decrease in spasticity of the elbow at the end of follow-up (MD -0.48, 95% CI -0.93 to -0.03; P = 0.03; 1 trial; 63 participants; low-quality evidence) when comparing rPMS plus rehabilitation versus sham plus rehabilitation. In terms of muscle strength, rPMS treatment was not associated with improved muscle strength of the ankle dorsiflexors at the end of treatment (MD 3.00, 95% CI -2.44 to 8.44; P = 0.28; 1 trial; 18 participants; low-quality evidence) when compared with sham rPMS. No studies provided information on lower limb function or adverse events, including death. Based on the GRADE approach, we judged the quality of evidence related to the primary outcome as low, owing to the small sample size of the studies. Available trials provided insufficient evidence to permit any conclusions about routine use of rPMS for people after stroke. Additional trials with large sample sizes are needed to provide robust evidence for rPMS after stroke.

This is an update of the review published in 2017. We examined the evidence from four trials of rPMS (three individual RCTs and one cross-over trial) involving a total of 139 participants. Two studies compared rPMS against 'sham' stimulation (a very weak stimulation or a sound only). Two studies compared rPMS plus rehabilitation versus sham plus rehabilitation. We found little evidence for the use of rPMS to improve activities of daily living, muscle strength, upper limb function, and spasticity (unusual stiffness of muscles) in people after stroke. Although one trial reported that rPMS reduced spasticity of the upper limb, the effect was small and remains unclear. We classified the quality of the evidence as low for improving activities of daily living, mainly because one study had a small sample size. It remains unclear whether use of rPMS is useful for improving activities of daily living and functional ability in people after stroke. More trials involving larger numbers of participants are needed to determine the effects of rPMS.

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Nine small trials were identified. In total, 189 infants participated. Most participants were greater than 30 weeks gestational age at birth and were clinically stable. In eight of the studies, taurine was given enterally with formula milk. Only one small trial assessed parenteral taurine supplementation. Taurine supplementation increased intestinal fat absorption [weighted mean difference 4.0 (95% confidence interval 1.4, 6.6) percent of intake]. However, meta-analyses did not reveal any statistically significant effects on growth parameters assessed during the neonatal period or until three to four months chronological age [rate of weight gain: weighted mean difference -0.25 (95% confidence interval -1.16, 0.66) grams/kilogram/day; change in length: weighted mean difference 0.37 (95% confidence interval -0.23, 0.98) millimetres/week; change in head circumference: weighted mean difference 0.15 (95% confidence interval -0.19, 0.50) millimeters/week]. There are very limited data on the effect on neonatal mortality or morbidities, and no data on long-term growth or neurological outcomes. Despite that lack of evidence of benefit from randomised controlled trials, it is likely that taurine will continue to be added to formula milks and parenteral nutrition solutions used for feeding preterm and low birth weight infants given the putative association of taurine deficiency with various adverse outcomes. Further randomised controlled trials of taurine supplementation versus no supplementation in preterm or low birth weight infants are unlikely to be viewed as a research priority, but there may be issues related to dose or duration of supplementation in specific subgroups of infants that merit further research.

This review sought evidence that supplementing the diet of preterm and low birth weight infants with taurine improves their growth and development. Nine small trials were found, but these did not provide any evidence that providing extra taurine improved outcomes. However, further trials of taurine supplementation are not likely to take place since taurine is naturally present in breast milk and current standard practice is to add taurine to formula milk and to intravenous nutrition solutions for feeding preterm and low birth weight infants.

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Seven randomised controlled trials involving 1943 patients with follicular lymphoma, mantle cell lymphoma, or other indolent lymphomas were included in the meta-analysis. Five studies were published as full-text articles, and two were in abstract form. Patients treated with R-chemo had better overall survival (hazard ratio [HR] for mortality 0.65; 95% confidence interval (CI) 0.54 to 0.78), overall response (relative risk of tumour response 1.21; 95% CI 1.16 to 1.27), and disease control (HR of disease event 0.62; 95% CI 0.55 to 0.71) than patients treated with chemotherapy alone. R-chemo improved overall survival in patients with follicular lymphoma (HR for mortality 0.63; 95% CI 0.51 to 0.79) and in patients with mantle cell lymphoma (HR for mortality 0.60; 95% CI 0.37 to 0.98). However, in the latter case, there was heterogeneity among the trials (P 0.07), making the survival benefit less reliable. The systematic review demonstrated improved OS for patients with indolent lymphoma, particularly in the subgroups of follicular and in mantle cell lymphoma when treated with R-chemo compared to chemotherapy alone.

Limitations: Heterogeneity among the analysed mantle cell lymphoma trials precluded reliable assessment of efficacy of R-chemo with respect to overall survival. Variability in treatment regimens among trials precluded determination of which chemotherapy regimen is the best to combine with rituximab or about the optimal number of cycles needed to treat patients with indolent lymphoma. Future directions: From our view future studies should focus on the following points: 1. Which standard chemotherapy should be used in combination with Rituximab 2. Influence of clinical and biologic prognostic markers after R-chemotherapy. What is similar and what is different 3. Understanding rituximab efficacy and resistance 4. Role of rituximab in treatment of progressive disease 5. Mechanism of rituximab in combination with chemotherapy 6. Role of Pharmacokinetic, pharmacogenetics in the treatment with R-chemo 7. Role of subsequent therapy with rituximab after R-chemo

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Fifteen RCTs were included, giving a total of 473 participants with ELP (study sizes ranged between 8-94). All studies involved oral sites only. Six studies included participants with non-erosive lichen planus but only the erosive subgroup was included for intended subgroup analysis. We were unable to pool data from any of the nine studies with only ELP participants or any of the six studies with the ELP subgroup, due to small numbers and the heterogeneity of the interventions, design methods, and outcome variables between studies. One study involving 50 participants found that 0.025% clobetasol propionate administered as liquid microspheres significantly reduced pain compared to ointment (Mean difference (MD) -18.30, 95% confidence interval (CI) -28.57 to -8.03), but outcome data was only available in 45 participants (high risk of performance bias for blinding of participants, low/unclear risk of bias overall). However, in another study, a significant difference in pain was seen in the small subgroup of 11 ELP participants, favouring ciclosporin solution over 0.1% triamcinolone acetonide in orabase (MD -1.40, 95% CI -1.86 to -0.94) (high risk of performance and detection bias due to likely lack of blinding, low/unclear risk of bias overall). Aloe vera gel was 6 times more likely to result in at least a 50% improvement in pain symptoms compared to placebo in a study involving 45 ELP participants (Risk ratio (RR) 6.16, 95% CI 2.35 to 16.13) (low risk of bias overall). No significant difference was seen in Physician Global Assessment in these three studies. In a small single study involving 20 ELP participants, 1% pimecrolimus cream was 7 times more likely to result in a strong improvement as rated by the Physician Global Assessment when compared to vehicle cream (RR 7.00, 95% CI 1.04 to 46.95) (low risk of bias overall). In a study involving a small subgroup of 8 ELP participants, a significant difference was seen for an improvement in the severity of the disease as rated by the Physician Global Assessment, in favour of the ciclosporin group when compared to the vehicle (MD -1.40, 95% CI -1.86 to -0.94) (unclear risk of selection bias for allocation concealment, overall risk of bias low). No statistically significant benefits were shown for topical tacrolimus or fluticasone spray in two separate studies of 29 and 44 participants respectively. There is no overwhelming evidence for the efficacy of a single treatment, including topical steroids, which are the widely accepted first-line therapy for ELP. Several side-effects were reported, but none were serious. With topical corticosteroids, the main side-effects were oral candidiasis and dyspepsia. This review suggests that there is only weak evidence for the effectiveness of any of the treatments for oral ELP, whilst no evidence was found for genital ELP. More RCTs on a larger scale are needed in the oral and genital ELP populations. We suggest that future studies should have standardised outcome variables that are clinically important to affected individuals. We recommend the measurement of a clinical severity score and a participant-rated symptom score using agreed and validated severity scoring tools. We also recommend the development of a validated combined severity scoring tool for both oral and genital populations.

This review looked at the effectiveness of treatments for ELP and included 15 studies, with 473 participants with ELP. All involved oral, but not genital, disease. Many studies were excluded either because they were not randomised controlled trials (where participants are divided into two groups at random) or because they recruited participants with all types of lichen planus, rather than just the erosive subtypes. All of these studies recruited small numbers of participants (12 to 94) and used a variety of different assessment methods and timings; hence, it was not possible to combine or compare results between studies directly. We found only weak evidence for the effectiveness of any of the treatments for oral ELP. None of the studies involved genital or oesophageal disease; hence, no evidence was found for the treatment of these conditions. One small study found that 0.025% clobetasol propionate (a very potent topical steroid) administered as a spray significantly reduced pain when compared to ointment. In another study, a significant difference in pain was seen in the small subgroup of 11 ELP participants, favouring ciclosporin solution over 0.1% triamcinolone acetonide in orabase (a potent topical steroid). In a study involving 45 ELP participants, aloe vera gel was 6 times more likely to result in at least a 50% improvement in pain symptoms compared to placebo. In a study involving a small subgroup of 8 ELP participants, a significant difference was seen for an improvement in the severity of the disease in favour of the ciclosporin group when compared to the vehicle. Several side-effects were reported, but none were serious. With topical corticosteroids, the main side-effects were oral candida (yeast) infection and pain or discomfort in the upper abdomen. Temporary burning was a common side-effect reported with tacrolimus 0.1% ointment and pimecrolimus 0.1% cream. Overall, there was no overwhelming evidence for the effectiveness of any single treatment, including topical steroids, which are the widely accepted first-line therapy for ELP. This was mainly due to the lack of good-quality, well-conducted trials and small participant numbers. Another Cochrane review has already assessed interventions for lichen planus affecting the mouth.

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We included 70 studies in the review; 66 studies with 17,067 participants were included in the quantitative analysis. An additional 18 studies are awaiting classification and 12 are ongoing. Fifteen of the 18 studies awaiting classification mainly correspond to congress summaries published before 2010, in which the available information does not allow the complete evaluation of all their risks of bias and characteristics. Our main outcome was prevention of PDPH, but we also assessed the onset of severe PDPH, headache in general and adverse events. The quality of evidence was moderate for most of the outcomes mainly due to risk of bias issues. For the analysis, we undertook three main comparisons: 1) traumatic needles versus atraumatic needles; 2) larger gauge traumatic needles versus smaller gauge traumatic needles; and 3) larger gauge atraumatic needles versus smaller gauge atraumatic needles. For each main comparison, if data were available, we performed a subgroup analysis evaluating lumbar puncture indication, age and posture. For the first comparison, the use of traumatic needles showed a higher risk of onset of PDPH compared to atraumatic needles (36 studies, 9378 participants, risk ratio (RR) 2.14, 95% confidence interval (CI) 1.72 to 2.67, I2 = 9%). In the second comparison of traumatic needles, studies comparing various sizes of large and small gauges showed no significant difference in effects in terms of risk of PDPH, with the exception of one study comparing 26 and 27 gauge needles (one study, 658 participants, RR 6.47, 95% CI 2.55 to 16.43). In the third comparison of atraumatic needles, studies comparing various sizes of large and small gauges showed no significant difference in effects in terms of risk of PDPH. We observed no significant difference in the risk of paraesthesia, backache, severe PDPH and any headache between traumatic and atraumatic needles. Sensitivity analyses of PDPH results between traumatic and atraumatic needles omitting high risk of bias studies showed similar results regarding the benefit of atraumatic needles in the prevention of PDPH (three studies, RR 2.78, 95% CI 1.26 to 6.15; I2 = 51%). There is moderate-quality evidence that atraumatic needles reduce the risk of post-dural puncture headache (PDPH) without increasing adverse events such as paraesthesia or backache. The studies did not report very clearly on aspects related to randomization, such as random sequence generation and allocation concealment, making it difficult to interpret the risk of bias in the included studies. The moderate quality of the evidence for traumatic versus atraumatic needles suggests that further research is likely to have an important impact on our confidence in the estimate of effect.

We searched the medical literature for studies carried out in any setting comparing needles of different characteristics (i.e. different tip designs and sizes) for the prevention of PDPH. The evidence is current to September 2016. We included 70 studies and were able to include information from 66 of those studies (17,067 participants) in the numerical analysis. An additional 18 studies are awaiting classification and 12 are ongoing. We found that the use of needles with a traumatic tip resulted in a higher risk of PDPH when compared to needles with atraumatic tips. When we compared the different studies comparing various sizes of large and small traumatic gauges, we did not find any difference in effects in terms of the risk of PDPH. Finally, when we compared atraumatic needles with a higher gauge to those with a smaller gauge, we observed no significant differences in terms of the development of PDPH in any of the scenarios analysed. We also found no significant differences in the use of traumatic versus atraumatic needles in the development of adverse effects such as paraesthesia, backache and severe PDPH. The studies did not report clearly on aspects of their design related to randomization. (This is a method that uses the play of chance to assign participants to comparison groups in a trial). This made it difficult for us to interpret the risk of bias in the included studies. We therefore considered the quality of the evidence for most of the outcomes assessed in this review to be moderate.

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We included nine studies in this review. Eight studies involved 485 participants with CD. We assessed six of the studies to be at high risk of bias, and two to be at low risk of bias. We judged one study on RPD with 72 randomised participants to be at high risk of bias. Overall, the quality of the evidence for each comparison and outcome was either low or very low, therefore, results should be interpreted with caution, as future research is likely to change the findings. Complete dentures Two studies compared the same material and different techniques (one study contributed data to a secondary outcome only); two studies compared the same technique and different materials; and four studies compared different materials and techniques. One study (10 participants) evaluated two stage–two step, Biofunctional Prosthetic system (BPS) using additional silicone elastomer compared to conventional methods, and found no evidence of a clear difference for oral health-related quality of life, or quality of the dentures (denture satisfaction). The study reported that BPS required fewer adjustments. We assessed the quality of the evidence as very low. One study (27 participants) compared selective pressure final-impression technique using wax versus polysulfide elastomeric (rubber) material. The study did not measure quality of life or dentures, and found no evidence of a clear difference between interventions in the need for adjustments (RR 0.81, 95% CI 0.38 to 1.70). We assessed the quality of the evidence as very low. One study compared two stage–two step final impression with alginate versus silicone elastomer. Oral health-related quality of life measured by the OHIP-EDENT seemed to be better with silicone (MD 7.20, 95% CI 2.71 to 11.69; 144 participants). The study found no clear differences in participant-reported quality of the denture (comfort) after a two-week 'confirmation' period, but reported that silicone was better for stability and chewing efficiency. We assessed the quality of the evidence as low. Three studies compared single-stage impressions with alginate versus two stage-two step with elastomer (silicone, polysulfide, or polyether) impressions. There was no evidence of a clear difference in the OHIP-EDENT at one month (MD 0.05, 95% CI -2.37 to 2.47; two studies, 98 participants). There was no evidence of a clear difference in participant-rated general satisfaction with dentures at six months (MD 0.00, 95% CI -8.23 to 8.23; one study, 105 participants). We assessed the quality of the evidence as very low. One study compared single-stage alginate versus two stage-two step using zinc-oxide eugenol, and found no evidence of a clear difference in OHIP-EDENT (MD 0.50, 95% CI -2.67 to 3.67; 39 participants), or general satisfaction (RR 3.15, 95% CI 0.14 to 72.88; 39 participants) at six months. We assessed the quality of the evidence as very low. Removable partial dentures One study randomised 72 participants and compared altered-cast technique versus one-piece cast technique. The study did not measure quality of life, but reported that most participants were satisfied with the dentures and there was no evidence of any clear difference between groups for general satisfaction at one-year follow-up (low-quality evidence). There was no evidence of a clear difference in number of intaglio adjustments at one year (RR 1.43, 95% CI 0.61 to 3.34) (very low-quality evidence). We conclude that there is no clear evidence that one technique or material has a substantial advantage over another for making complete dentures and removable partial dentures. Available evidence for the relative benefits of different denture fabrication techniques and final-impression materials is limited and is of low or very low quality. More high-quality RCTs are required.

The evidence in this review is current to 22 November 2017. We found eight studies with a total of 485 participants for complete dentures, and one study with 72 participants for removable partial dentures. The participants ranged from 45 to 75 years old, and had been without their teeth for 10 to 35 years. The studies compared different materials used to make the final impression for dentures (alginate, zinc-oxide eugenol, wax, and addtional silicone, polysulfide or polyether) and different techniques for making the final impression (open-mouth versus closed-mouth, single-stage versus two stage-two step), or both. For most comparisons and outcomes, there was no evidence of a clear difference between the techniques or materials compared. Very low quality-evidence from one study (10 participants) suggested that making dentures with an additional silicone elastomer biofunctional prosthetic required fewer adjustments than conventional methods. Low-quality evidence from another study (144 participants) suggested that complete dentures made with silicone elastomer in a two stage–two step final impression, may be better than those made with alginate, in terms of oral health-related quality of life, stability of the denture, and chewing efficiency. With the limited evidence available, we are unable to draw any conclusions about the best impression techniques and materials for complete and partial removable dentures. There is a need for further research in this area. The quality of the evidence base overall is low to very low. Only one or two studies assessed each intervention and comparison, and most of the studies were at high risk of bias. Many of the studies did not measure our key outcomes. For both complete and partial removable dentures, we conclude that we have no reliable findings.

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We include 70 studies involving a total of 4761 participants in the review. The first primary outcome for this review was reduction in the severity of PTSD symptoms, using a standardised measure rated by a clinician. For this outcome, individual TFCBT and EMDR were more effective than waitlist/usual care (standardised mean difference (SMD) -1.62; 95% CI -2.03 to -1.21; 28 studies; n = 1256 and SMD -1.17; 95% CI -2.04 to -0.30; 6 studies; n = 183 respectively). There was no statistically significant difference between individual TFCBT, EMDR and Stress Management (SM) immediately post-treatment although there was some evidence that individual TFCBT and EMDR were superior to non-TFCBT at follow-up, and that individual TFCBT, EMDR and non-TFCBT were more effective than other therapies. Non-TFCBT was more effective than waitlist/usual care and other therapies. Other therapies were superior to waitlist/usual care control as was group TFCBT. There was some evidence of greater drop-out (the second primary outcome for this review) in active treatment groups. Many of the studies were rated as being at 'high' or 'unclear' risk of bias in multiple domains, and there was considerable unexplained heterogeneity; in addition, we assessed the quality of the evidence for each comparison as very low. As such, the findings of this review should be interpreted with caution. The evidence for each of the comparisons made in this review was assessed as very low quality. This evidence showed that individual TFCBT and EMDR did better than waitlist/usual care in reducing clinician-assessed PTSD symptoms. There was evidence that individual TFCBT, EMDR and non-TFCBT are equally effective immediately post-treatment in the treatment of PTSD. There was some evidence that TFCBT and EMDR are superior to non-TFCBT between one to four months following treatment, and also that individual TFCBT, EMDR and non-TFCBT are more effective than other therapies. There was evidence of greater drop-out in active treatment groups. Although a substantial number of studies were included in the review, the conclusions are compromised by methodological issues evident in some. Sample sizes were small, and it is apparent that many of the studies were underpowered. There were limited follow-up data, which compromises conclusions regarding the long-term effects of psychological treatment.

This review draws together up-to-date evidence from 70 studies including a total of 4761 people. There is continued support for the efficacy of individual TFCBT, EMDR, non-TFCBT and group TFCBT in the treatment of chronic PTSD in adults. Other non-trauma-focused psychological therapies did not reduce PTSD symptoms as significantly. There was evidence that individual TFCBT, EMDR and non-TFCBT are equally effective immediately post-treatment in the treatment of PTSD. There was some evidence that TFCBT and EMDR are superior to non-TFCBT between one to four months following treatment, and also that individual TFCBT, EMDR and non-TFCBT are more effective than other therapies. No specific conflicts of interest were identified. Although we included a substantial number of studies in this review, each only included small numbers of people and some were poorly designed. We assessed the overall quality of the studies as very low and so the findings of this review should be interpreted with caution. There is insufficient evidence to show whether or not psychological therapy is harmful.

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We identified three RCTs including a total of 466 participants with a diagnosis of onchocerciasis. All trials compared doxycycline plus ivermectin versus ivermectin alone. One study investigated improvement in visual impairment at six-month follow-up; the other two studies measured microfilarial loads in skin snips to assess sustained effects of treatment at follow-up of 21 months or longer. The studies were conducted at various centers across three countries (Cameroon, Ghana, and Liberia). We judged all studies to be at overall high risk of bias because of inadequate randomization and lack of masking (one study), missing data (two studies), and selective outcome reporting (three studies). Only one study measured visual outcomes. This study reported uncertainty about the difference in the proportion of participants with improvement in visual impairment at six-month follow-up for doxycycline plus ivermectin compared with ivermectin alone (risk ratio (RR) 1.06, 95% confidence interval (95% CI) 0.80 to 1.39; 240 participants; very low-quality evidence). No participant in either group showed improvement in optic atrophy, chorioretinitis, or sclerosing keratitis at six-month follow-up. More participants in the doxycycline plus ivermectin group than in the ivermectin alone group showed improvement in iridocyclitis (RR 1.24, 95% CI 0.69 to 2.22) and punctate keratitis (RR 1.43, 95% CI 1.02 to 2.00) at six-month follow-up; however, we graded these results as very low quality. Two studies reported that a six-week course of doxycycline may result in Wolbachia depletion and macrofilaricidal and sterilizing activities in female Onchocerca worms; however, no analysis was possible because data were missing and incomplete (graded evidence as very low quality). Adverse events were reported in 16 of 135 (12%) participants in one of these studies and included itching, headaches, body pains, and vertigo; no difference between treatment groups was reported for any adverse event. The second study reported that one (1.3%) participant in the doxycycline plus ivermectin group had bloody diarrhea after treatment was initiated. Available evidence on the effectiveness of doxycycline plus ivermectin compared with ivermectin alone in preventing and treating onchocerciasis is unclear. Limited evidence of very low quality from two studies indicates that a six-week course of doxycycline followed by ivermectin may result in more frequent macrofilaricidal and microfilaricidal activity and sterilization of female adult Onchocerca compared with ivermectin alone; however, effects on vision-related outcomes are uncertain. Future studies should consider the effectiveness of treatments in preventing visual acuity and visual field loss and their effects on anterior and posterior segment lesions, particularly chorioretinitis. These studies should report outcomes in a uniform and consistent manner at follow-up of three years or longer to allow detection of meaningful changes in vision-related outcomes.

As of 15 July 2015, we identified three randomized controlled trials. A total of 466 people with RB participated in the three trials. The trials were conducted in Cameroon, Ghana, and Liberia. In the Cameroon and Ghana trials, people with RB took doxycycline or placebo (sugar pills) for four weeks or six weeks. One dose of ivermectin was then given four or six months later. People were then followed for two to three years. In the trial from Liberia, people with RB were divided into two groups. One group was given doxycycline for 6 weeks followed by a single dose of ivermectin. The other group was given ivermectin alone. Both Liberian groups were followed up for six months. Evidence of the effect of adding doxycycline to the usual treatment of ivermectin for people with river blindness is unclear. Only one of the three trials looked at the vision of participants. This trial reported insufficient evidence to show a difference between treatment groups in the proportion of participants with visual improvement six months after the start of the study. Two trials showed reduced bacteria (Wolbachia) and fewer adult worms with combined doxycycline and ivermectin treatment than with ivermectin alone after about two years. However, new worms with the bacteria were found after treatment in one trial. Two trials reported adverse treatment effects in some participants; both reported no differences between treatment groups. One study reported that adverse treatment effects, including itching, fever, headache, body pain, and vertigo, occurred in 12% of study participants. The other study reported that one (1.3%) person had bloody diarrhea after starting treatment with doxycycline plus ivermectin, which stopped when treatment was withdrawn. We judged the overall quality of the evidence as very low because of methodological issues noted in the trials.

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Twenty-three studies (2344 participants) were included in this update, including nine new studies. A broad variety of conservative interventions were evaluated. Two studies included patients with chronic symptoms (longer than three months), two included subacute (four to six weeks) symptoms, two had undefined duration of symptoms, and 17 studied patients with acute (less than three weeks) symptoms. Only eight studies (33.3%) satisfied one of our criteria of high quality, indicating overall, a poor methodological quality. Interventions were divided into passive (such as rest, immobilisation, ultrasound, etc) and active interventions (such as exercises, act as usual approach, etc.) and were compared with no treatment, a placebo or each other. Clinical and statistical heterogeneity and lack of data precluded pooling. Individual studies demonstrated effectiveness of one treatment over another, but the comparisons were varied and results inconsistent. Therefore, the evidence neither supports nor refutes the effectiveness of either passive or active treatments to relieve the symptoms of WAD, Grades 1 or 2. The current literature is of poor methodological quality and is insufficiently homogeneous to allow the pooling of results. Therefore, clearly effective treatments are not supported at this time for the treatment of acute, subacute or chronic symptoms of whiplash-associated disorders.

We included 23 studies (2344 participants with WAD Grades 1 or 2), nine of which were new for this update. Overall, the methodological quality was poor and the studies included populations and interventions that were too different to pool. Two studies examined treatments for patients with chronic pain (longer than three months), two looked at subacute pain (four to six weeks), two were unclear (but one was probably chronic), and the rest looked at patients with acute symptoms of less than three weeks. In 11 studies, an active treatment approach (treatment strategy including exercises or advice to 'act as usual') was compared to a passive strategy, no treatment or was an additional treatment. Eight studies compared an active intervention with a passive one (the patient received a treatment such as advice to rest and wear a neck collar, an educational video, electrotherapy, manipulation, hot and cold packs, traction, or acupuncture). Eight studies compared an intervention with a placebo or no treatment. In seven studies, two active treatments were compared against each other and in one, a passive intervention was compared to injections. Since we were unable to pool any of the studies, we remain unable to either support or refute the effects of conservative treatments for acute, subacute or chronic whiplash-associated disorders with the current evidence.

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Thirteen studies were eligible for inclusion, but only 12 studies contributed data, with a total of 3446 CVCs assessed. The total number of participants enrolled was unclear as some studies did not provide such information. The participants were mainly adults admitted to intensive care units, haematology oncology units or general wards. Most studies assessed skin antisepsis prior to insertion and regularly thereafter during the in-dwelling period of the CVC, ranging from every 24 h to every 72 h. The methodological quality of the included studies was mixed due to wide variation in their risk of bias. Most trials did not adequately blind the participants or personnel, and four of the 12 studies had a high risk of bias for incomplete outcome data. Three studies compared different antisepsis regimens with no antisepsis. There was no clear evidence of a difference in all outcomes examined, including catheter-related BSI, septicaemia, catheter colonisation and number of patients who required systemic antibiotics for any of the three comparisons involving three different antisepsis regimens (aqueous povidone-iodine, aqueous chlorhexidine and alcohol compared with no skin antisepsis). However, there were great uncertainties in all estimates due to underpowered analyses and the overall very low quality of evidence presented.There were multiple head-to-head comparisons between different skin antiseptic agents, with different combinations of active substance and base solutions. The most frequent comparison was chlorhexidine solution versus povidone-iodine solution (any base). There was very low quality evidence (downgraded for risk of bias and imprecision) that chlorhexidine may reduce catheter-related BSI compared with povidone-iodine (RR of 0.64, 95% CI 0.41 to 0.99; ARR 2.30%, 95% CI 0.06 to 3.70%). This evidence came from four studies involving 1436 catheters. None of the individual subgroup comparisons of aqueous chlorhexidine versus aqueous povidone-iodine, alcoholic chlorhexidine versus aqueous povidone-iodine and alcoholic chlorhexidine versus alcoholic povidone-iodine showed clear differences for catheter-related BSI or mortality (and were generally underpowered). Mortality was only reported in a single study. There was very low quality evidence that skin antisepsis with chlorhexidine may also reduce catheter colonisation relative to povidone-iodine (RR of 0.68, 95% CI 0.56 to 0.84; ARR 8%, 95% CI 3% to 12%; ; five studies, 1533 catheters, downgraded for risk of bias, indirectness and inconsistency). Evaluations of other skin antiseptic agents were generally in single, small studies, many of which did not report the primary outcome of catheter-related BSI. Trials also poorly reported other outcomes, such as skin infections and adverse events. It is not clear whether cleaning the skin around CVC insertion sites with antiseptic reduces catheter related blood stream infection compared with no skin cleansing. Skin cleansing with chlorhexidine solution may reduce rates of CRBSI and catheter colonisation compared with cleaning with povidone iodine. These results are based on very low quality evidence, which means the true effects may be very different. Moreover these results may be influenced by the nature of the antiseptic solution (i.e. aqueous or alcohol-based). Further RCTs are needed to assess the effectiveness and safety of different skin antisepsis regimens in CVC care; these should measure and report critical clinical outcomes such as sepsis, catheter-related BSI and mortality.

In May 2016 we searched medical databases to find randomised controlled trials looking at the use of skin antiseptics in people with CVCs. We included 13 studies in this review, although only 12 studies contributed data for a total of 3446 CVCs. The study participants were mainly adults in intensive care units or other specialist hospital units. We reported our findings in terms of the number of catheters, as some studies did not provide the number of patients assessed, and some patients had more than one CVC.One study was funded by a national research body, five studies were funded in whole or in part by at least a pharmaceutical company, and in the remaining seven studies funding sources were not stated. Three studies examined the effect of cleansing versus no cleansing, and found no clear evidence of differences in blood infections, infections in the catheter and need for antibiotics between patients who received cleansing compared to those who did not. Chlorhexidine solution may reduce blood infections associated with the catheter compared with povidone-iodine solution (reducing the infection rate from 64 cases per 1000 patients with a CVC with povidone iodine to 41 cases of infection per 1000 with chlorhexidine). This translates into the need to treat 44 people to avoid one additional bloodstream infection. Chlorhexidine solution may (compared with povidone iodine solution) also reduce the presence of infectious organisms within the catheter (reduced from 240 infected catheters per 1000 people to 189 infected catheters per 1000 people). It is unclear whether antiseptic skin cleansing influences mortality rates as only one study reported this and although similar death rates were observed with povidone iodine and chlorhexidine, small numbers mean a difference cannot be ruled out. The overall quality of evidence was poor due to flaws in the way the studies were designed, small study sizes, inconsistency of the results between the included studies and the nature of the outcomes reported. These flaws have reduced our confidence in the results of the studies. This means we cannot be certain whether cleaning the skin around CVC insertion sites with antiseptic reduces catheter-related blood stream infection and other harmful effects, such as overall blood infections and mortality compared with no skin cleansing. Cleansing with chlorhexidine solution may be more effective than povidone iodine but the quality of the evidence was very low.

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We identified one trial, with 36 participants​ diagnosed ​with syphilis and HIV. The participants were mainly men, with a median age of 34 years. This trial, ​funded by a pharmaceutical company, compared ceftriaxone in 18 participants (2 g daily for 10 days), with penicillin G, also in 18 participants (4 million/Units (MU)/intravenous (IV) every 4 hours for 10 days). The trial reported incomplete and inconclusive results. Three of 18 (16%) participants receiving ceftriaxone versus 2 of 18 (11%) receiving penicillin G achieved serological cure (RR 1.50; 95% CI: 0.28 to 7.93; 1 trial, 36 participants very low-quality evidence); and 8 of 18 (44%) participants receiving ceftriaxone versus 2 of 18 (18%) participants receiving penicillin G achieved clinical cure (RR 4.00; 95% CI: 0.98 to 16.30; 1 trial, 36 participants very low-quality evidence). Although more participants who received ceftriaxone achieved serological and clinical cure compared to those who received penicillin G, the evidence from this trial was insufficient to determine whether there was a difference between treatment with ceftriaxone or penicillin G. In this trial, the authors reported what would usually be adverse events as symptoms and signs in the follow-up of participants. Furthermore, this trial did not evaluate recurrence of neurosyphilis, time to recovery nor quality of life. We judged risk of bias in this clinical trial to be unclear for random sequence generation, allocation, ​and blinding of participants, and high for incomplete outcome data, potential conflicts of interest (funding bias), and other bias, due to the lack of a sample size calculation. We rated the quality of evidence as very low. Due to low quality and insufficient evidence, it was not possible to determine whether there was a difference between treatment with ceftriaxone or Penicillin G. Also, the benefits to people without HIV and neurosyphilis are unknown, as is the ceftriaxone safety profile.Therefore, these results should be interpreted with caution. This conclusion does not mean that antibiotics should not be used for treating this clinical entity. This Cochrane Review has identified the need of adequately powered trials, which should be planned according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) recommendations, conducted and reported as recommended by the CONSORT statement. Furthermore, the outcomes should be based on patients' perspectives taking into account Patient-Centered Outcomes Research Institute (PCORI) recommendations.

We searched the medical literature up to April 2019 for trials that evaluated the effectiveness and safety of drugs proposed for the management of neurosyphilis in adults. We found only one randomised clinical trial that met our criteria (patients are randomly put into groups to receive different treatments). This trial involved 36 adults with both syphilis and HIV, who were mainly men, with a median age of 34 years. The trial compared two drugs: ceftriaxone (2 g once daily), and penicillin G (4 million units every 4 hours for 10 days). It was funded by a pharmaceutical company. The trial reported serological cure, which is a decrease in the levels of the infection shown by laboratory analysis of fluids in the brain and spinal cord (known as cerebrospinal fluids), and clinical cure, which is the absence of signs or symptoms of neurosyphilis. Only three of 18 participants receiving ceftriaxone and two of 18 participants receiving penicillin G achieved serological cure; and eight of 18 participants receiving ceftriaxone and two of 18 participants receiving penicillin G achieved clinical cure. There was not enough evidence to allow us to state if there is a difference between treatment with ceftriaxone or Penicillin G for neurosyphilis in adults. The outcomes evaluated could change when trials with a better design become available. Additionally, we did not identify any evidence related to the effectiveness and safety of other drugs proposed to manage this condition. The quality of the evidence was very low for the outcomes serological cure and clinical cure due to problems with the trial's design and methods, and because there was only a small number of participants.

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We included three studies (total n=289; 2 RCTs zotepine vs clozapine; 1 RCT zotepine vs clozapine vs risperidone (at 4 mg, 8 mg doses) vs remoxipride. All studies were of limited methodological quality. When zotepine was compared with clozapine, it was clozapine that was found to be more effective in terms of global state (n=59, 1 RCT, RR No clinically significant response 8.23 CI 1.14 to 59.17). Mental state scores also favoured clozapine (n=59, 1 RCT, MD average score (BPRS total, high = poor) 6.00 CI 2.17 to 9.83) and there was less use of antiparkinson medication in the clozapine group (n=116, 2 RCTs, RR 20.96 CI 2.89 to 151.90). In the comparison of zotepine and risperidone, mental state scoring found no significant difference between the groups (vs 4 mg: n=40, 1 RCT, MD average endpoint score (BPRS total, high=poor) 1.40 CI -9.82 to 12.62; vs 8 mg: n=40, 1 RCT, MD -1.30 CI -12.95 to 10.35) and use of antiparkinson medication was equivocal (vs 4 mg: n=40, 1 RCT, MD 1.80 CI -0.64 to 4.24; vs 8 mg: n=40, 1 RCT, MD 2.50 CI -0.05 to 5.05). Finally, when zotepine was compared with remoxipride, again no effect was found for mental state (n=58, 1 RCT, MD average endpoint score (BPRS total, high=poor) 5.70 CI -4.13 to 15.53) and there was no significant difference between the two groups in terms of use of antiparkinson medication (n=49, 1 RCT, RR 0.97 CI 0.41 to 2.29). Data on important other outcomes such as other adverse events, service use or satisfaction with care, quality of life were not available. The evidence base around zotepine is insufficient to provide firm conclusions on its absolute or relative effects. This is despite it being in use in Austria, France, Germany, Japan and the UK.

This review compares the effects of zotepine to other second generation antipsychotic drugs. Three trials suggest that the efficacy of zotepine may be comparable to risperidone and remoxipride. The evidence base is insufficient to provide firm conclusions as to whether zotepine is as effective or less effective than clozapine. The movement disorders and the cognitive changes appear to be similar to clozapine, risperidone and remoxipride. The need for antiparkinson medication is similar to risperidone and remoxipride, but may be associated with increased need than necessary with clozapine.

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We included 35 placebo controlled and three active controlled RCTs (N = 7365). The mean reduction on the IRLS was −5.7 points lower in dopamine agonist treatment compared to placebo (95% confidence interval (CI) −6.7 to −4.7). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) were −22.4/h lower than in placebo (95% CI −27.8 to −16.9). Self rated quality of sleep and disease specific quality of life were improved by a standardised mean difference (SMD) of 0.40 (95% CI 0.33 to 0.47) and 0.34 (95% CI 0.23 to 0.44), respectively. Patients were more likely to drop out (odds ratio (OR) 1.82, 95% CI 1.35 to 2.45) and experienced more adverse events under dopamine agonist treatment than with placebo (OR 1.82, 95% CI 1.59 to 2.08). Visual inspection of forest plots showed the highest efficacy in three studies investigating cabergoline and pergolide (N = 3). Active controlled trials investigated effects of cabergoline, pergolide, and pramipexole in a number of outcomes. The IRLS score was lower with cabergoline and pramipexole compared to levodopa (MD −5.3, 95% CI −8.4 to −2.1). Only four studies investigated treatment efficacy up to seven months. The most severe side effect, augmentation, was not assessed reliably. The meta-analyses show the superiority of dopamine agonists over placebo in RCTs up to seven months. Cabergoline and pramipexole showed larger efficacy compared to levodopa in some but not all outcomes.

We could include 38 trials in the meta-analyses which investigated the efficacy and safety of dopamine agonist treatment compared to placebo or to other treatments for RLS. The studies were performed mostly in European and Northern American countries. Treatment durations varied from one week to seven months, but most treatments had durations of one to 12 weeks. Patients suffered from moderate to severe RLS and were treated with the dopamine agonists cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine, and sumanirole. Dopamine agonists lead to a larger improvement on the International RLS Severity Rating Scale (IRLS) compared to placebo. Clinicians rated RLS symptoms as more improved with dopamine agonists compared to placebo (CGI-I). Also periodic limb movements in sleep were significantly reduced by dopamine agonists compared to placebo. Sleep efficiency was also slightly improved. Patients rated their quality of sleep and quality of life as markedly improved. Patients were, however, more likely to discontinue dopamine agonist treatment and experienced more adverse events when treated with dopamine agonists compared to placebo. All dopamine agonists were superior to placebo except sumanirole. Indirect descriptive comparisons revealed the highest efficacy for the ergoline dopamine agonists cabergoline and pergolide, which has to be weighed against potentially serious side effects such as cardiac valve fibrosis. The non-ergoline dopamine agonists lisuride, pramipexole, rotigotine, and ropinirole showed adequate efficacy. Augmentation, a serious adverse event in dopaminergic treatment, has not been sufficiently assessed. Future studies need to investigate long-term efficacy of dopamine agonists against placebo or other active treatment and the frequency and the impact of augmentation on treatment outcome during dopaminergic treatment.

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We found one RCT and one retrospective study that met our inclusion criteria. The data from these studies were too sparse to adequately assess the effectiveness and safety of adjuvant chemotherapy in the treatment of malignant germ cell ovarian cancer. All comparisons were restricted to single study analyses and this review was only based on 32 women, so it was not adequately powered to detect differences in survival. Adverse effects of treatment and recurrence-free survival were incompletely documented and QoL was not reported in any of the studies. We did not find any studies that reported specifically on adults so there were problems in separating data on adults and children in many of the potentially relevant studies. We found only low quality evidence on the use of chemotherapy in malignant germ cell tumours of the ovaries. Therefore we are unable to reach definite conclusions about the relative benefits and harms of chemotherapy use in this disease regardless of disease stage. Due to the benefit of chemotherapy in germ cell cancer of the testis, a trial of chemotherapy versus best supportive care is unlikely to be feasible. Despite this, good quality randomised studies are warranted in this disease to define the role of chemotherapy (type of chemotherapy, duration of treatment, benefit, short and long term toxicities). Given the rarity of this disease, we feel a trans-global approach would be essential in order to perform such trials.

Due to its rarity, this review is based on only one very small RCT and one small retrospective study. The data from these studies were too sparse to adequately assess the effectiveness and safety of chemotherapy after surgery (adjuvant chemotherapy) in the treatment of malignant germ cell ovarian cancer. All comparisons were restricted to single study analyses and this review was only based on 32 women, so it was not adequately powered to detect differences in survival. Adverse effects of treatment and recurrence-free survival were incompletely documented and QoL was not reported in any of the studies. We did not find any studies that reported specifically on adults as this disease usually afflicts younger people as opposed to the older population, so there were problems in separating data on adults and children in many of the studies. Many of the treatments used were taken from experiences of treating patients with testicular cancer, as they look similar under the microscope and behave similar clinically. Due to the small number of patients with malignant germ cell cancer in the two studies, our review shows that there were no good quality studies assessing the role of chemotherapy in this disease, be it in early or late stages. There was insufficient evidence to conclude that any form of chemotherapy or best supportive care is superior over the other. This review highlights the need for future good quality, well designed studies.

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We included six trials with 560 patients. One trial involving 129 patients did not state the number of patients randomised to the two groups. In the remaining five trials 431 patients were randomised, 212 to the robot assistant group and 219 to the human assistant group. All the trials were at high risk of bias. Mortality and morbidity were reported in only one trial with 40 patients. There was no mortality or morbidity in either group. Mortality and morbidity were not reported in the remaining trials. Quality of life or the proportion of patients who were discharged as day-patient laparoscopic cholecystectomy patients were not reported in any trial. There was no significant difference in the proportion of patients who required conversion to open cholecystectomy (2 trials; 4/63 (weighted proportion 6.4%) in the robot assistant group versus 5/70 (7.1%) in the human assistant group; RR 0.90; 95% CI 0.25 to 3.20). There was no significant difference in the operating time between the two groups (4 trials; 324 patients; MD 5.00 minutes; 95% CI -0.55 to 10.54). In one trial, about one sixth of the laparoscopic cholecystectomies in which a robot assistant was used required temporary use of a human assistant. In another trial, there was no requirement for human assistants. One trial did not report this information. It appears that there was little or no requirement for human assistants in the other three trials. There were no randomised trials comparing one type of robot versus another type of robot. Robot assisted laparoscopic cholecystectomy does not seem to offer any significant advantages over human assisted laparoscopic cholecystectomy. However, all trials had a high risk of systematic errors or bias (that is, risk of overestimation of benefit and underestimation of harm). All trials were small, with few or no outcomes. Hence, the risk of random errors (that is, play of chance) is high. Further randomised trials with low risk of bias or random errors are needed.

A detailed and systematic review of the literature revealed that there were six randomised clinical trials including 560 patients. One trial involving 129 patients did not state the number of patients randomised to the two groups. Of the remaining 431 patients in the remaining five trials, 212 patients underwent laparoscopic cholecystectomy with the help of robot assistant and 219 patients underwent the same procedure with the help of a human assistant. All the trials were at high risk of bias (that is, they were prone to systematic underestimation of harms or overestimation of the benefits of the robotic assistant group or the human assistant group because of the beliefs of the people conducting the trial) and errors due to play of chance. Mortality and surgical complications were reported in only one trial with 40 patients. There were no mortality or surgical complications in either group in this trial. Mortality and morbidity were not reported in the remaining trials. Quality of life or the proportion of patients who were discharged as day-patient laparoscopic cholecystectomy patients were not reported in any trial. There was no significant difference in the proportion of patients who underwent conversion to open cholecystectomy or in the operating time between the two groups. In one trial, about one sixth of the laparoscopic cholecystectomies in which a robot assistant was used required temporary use of a human assistant. In another trial, there was no requirement for human assistants. One trial did not report this information. It appears that there was little or no requirement for human assistants in the other three trials. Robot-assisted laparoscopic cholecystectomy does not seem to offer any significant advantages over human-assisted laparoscopic cholecystectomy. However, our present evidence base is limited by trials that all have high risk of systematic errors (potential to underestimate harms or overestimate benefits of the robot assistant group or the human assistant group) and random errors (that is, play of chance). Therefore, further well-designed randomised trials with low risk of systematic errors and low risk of random errors are needed.

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We included 12 trials of varying sample sizes (N = 9 to 135), mainly from high-income countries, including a total of 578 participants. Ten trials recruited children (N = 448 participants). Two trials recruited adolescents and adults (N = 130 participants). We considered only three trials to be of high methodological quality (one trial each of diphenhydramine, pertussis immunoglobulin and montelukast). Included studies did not show a statistically significant benefit for any of the interventions. Only six trials, including a total of 196 participants, reported data in sufficient detail for analysis. Diphenhydramine did not change coughing episodes; the mean difference (MD) of coughing spells per 24 hours was 1.9; 95% confidence interval (CI) -4.7 to 8.5 (N = 49 participants from one trial). One trial on pertussis immunoglobulin reported a possible mean reduction of -3.1 whoops per 24 hours (95% CI -6.2 to 0.02, N = 47 participants) but no change in hospital stay (MD -0.7 days; 95% CI -3.8 to 2.4, N = 46 participants). Dexamethasone did not show a clear decrease in length of hospital stay (MD -3.5 days; 95% CI -15.3 to 8.4, N = 11 participants from one trial) and salbutamol showed no change in coughing paroxysms per day (MD -0.2; 95% CI -4.1 to 3.7, N = 42 participants from two trials). Only one trial comparing pertussis immunoglobulin versus placebo (N = 47 participants) reported data on adverse events: 4.3% in the treatment group (rash) versus 5.3% in the placebo group (loose stools, pain and swelling at injection site). There is insufficient evidence to draw conclusions about the effectiveness of interventions for the cough in whooping cough. More high-quality trials are needed to assess the effectiveness of potential antitussive treatments in patients with whooping cough.

The evidence in this review is current up to January 2014. We included 12 studies, which included a total of 578 participants. Ten studies involved a total of 448 children and two involved a total of 130 adolescents and adults. Five studies did laboratory tests to confirm the presence of whooping cough in all participants who took part. Nine studies compared the medicine to a placebo (i.e. a 'dummy' medicine which did not contain the active ingredient being studied) and three studies compared the medicine to no treatment. Seven studies involved hospital inpatients. Three studies reported their start and finish dates; one study recruited participants over 14 months, another over 18 months and another over 31 months. Six studies including 196 participants reported their results in enough detail for us to assess them. Based on these results, antihistamines (one study, 49 participants), pertussis immunoglobulin (one study, 24 participants) and salbutamol (two studies, 42 participants) did not reduce the number of coughing bouts in patients with whooping cough. Neither pertussis immunoglobulin (one study, 46 participants) nor steroids (one study, 11 participants) decreased the length of time participants spent in hospital. One study reported similar rates of side effects in participants treated with pertussis immunoglobulin (4%; rash) or placebo (5%; loose stools, pain and swelling of the skin around where the injection was given). Studies of antihistamines, salbutamol and steroids did not report any results on side effects. None of these six studies reported any results on vomiting, cyanosis, serious complications, death or admission to hospital. Overall, the quality of evidence was low and many of the studies were conducted some years ago. Only three trials reported adequate details of how the type of treatment given was properly concealed from both participants and healthcare professionals. Methods of recording numbers of coughing bouts and whoops also differed between studies. Estimates of the effects of the different treatments were imprecise due to the small numbers of participants from whom results were available. Additionally, these results may not be generalisable to adults or community settings, since most studies involved children and were done in hospital inpatient settings.

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Of the 27,865 records identified, 39 clinical trials and 14 observational studies, including a total of 945,240 participants, were eligible for inclusion. Five studies are awaiting classification. Overall, we found 114 adverse events in 33 studies (30 RCTs and three observational studies), and mortality was reported in 41 studies (32 RCTs and nine observational studies). Most studies were at low to moderate risk of bias for harms outcomes. However, overall harm assessment and reporting were of moderate to low quality in the RCTs, and of low quality in the observational studies. We downgraded the GRADE quality of evidence for venous thromboembolism and mortality to very low and low, respectively, because of risk of bias, high inconsistency, imprecision and limitations of study design. It is unclear whether there is an increase in the risk of any adverse events (Bayesian risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.21; 3099 participants; 9 studies; low-quality evidence) or venous thromboembolism (Bayesian RR 1.04, 95% CI 0.70 to 1.41; 18,917 participants; 18 studies; very low-quality evidence). There was a decreased risk of mortality with off-label use of ESAs in critically-ill people (Bayesian RR 0.76, 95% CI 0.61 to 0.92; 930,470 participants; 34 studies; low-quality evidence). Low quality of evidence suggests that off-label use of ESAs may reduce mortality in a critical care setting. There was a lack of high-quality evidence about the harm of ESAs in critically-ill people. The information for biosimilar ESAs is less conclusive. Most studies neither evaluated ESAs' harm as a primary outcome nor predefined adverse events. Any further studies of ESA should address the quality of evaluating, recording and reporting of adverse events.

We searched 10 databases for studies where ESAs were used to treat critically-ill people. The evidence is current to February 2017. We found 53 studies, involving 945,240 participants treated with epoetin-alfa, epoetin-beta, and darbepoetin-alfa or placebo. Five studies are awaiting classification. Based on mainly low-quality evidence, we were unable to exclude relevant harms in terms of adverse effects of ESAs. 'Adverse effects' included any adverse events and problems from blood clotting in the veins. However, we found low-quality evidence for protective effects on the overall risk of dying in critically-ill people.

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We included 14 studies (909 participants) in this review. Surgical interventions, including laser therapy and cryotherapy, have never been studied by means of an RCT that included a no treatment or placebo arm. The included trials tested a range of medical and complementary treatments, in particular, vitamin A and retinoids (four studies); beta carotene or carotenoids (three studies); non-steroidal anti-inflammatory drugs (NSAIDs), specifically ketorolac and celecoxib (two studies); herbal extracts (four studies), including tea components, a Chinese herbal mixture and freeze-dried black raspberry gel; bleomycin (one study); and Bowman-Birk inhibitor (one study). We judged one study to be at low risk of bias, seven at unclear risk and six at high risk. In general, we judged the overall quality of the evidence to be low or very low, so findings are uncertain and further research is needed. Five studies recorded cancer incidence, only three of which provided useable data. None of the studies provided evidence that active treatment reduced the risk of oral cancer more than placebo: systemic vitamin A (RR 0.11, 95% CI 0.01 to 2.05; 85 participants, one study); systemic beta carotene (RR 0.71, 95% CI 0.24 to 2.09; 132 participants, two studies); and topical bleomycin (RR 3.00, 95% CI 0.32 to 27.83; 20 participants, one study). Follow-up ranged between two and seven years. Some individual studies suggested effectiveness of some proposed treatments, namely, systemic vitamin A, beta carotene and lycopene, for achieving clinical resolution of lesions more often than placebo. Similarly, single studies found that systemic retinoic acid and lycopene may provide some benefit in terms of improvement in histological features. Some studies also reported a high rate of relapse. Side effects of varying severity were often described; however, it seems likely that interventions were well accepted by participants because drop-out rates were similar between treatment and control groups. Surgical treatment for oral leukoplakia has not been assessed in an RCT that included a no treatment or placebo comparison. Nor has cessation of risk factors such as smoking been assessed. The available evidence on medical and complementary interventions for treating people with leukoplakia is very limited. We do not currently have evidence of a treatment that is effective for preventing the development of oral cancer. Treatments such as vitamin A and beta carotene may be effective in healing oral lesions, but relapses and adverse effects are common. Larger trials of longer duration are required to properly evaluate the effects of leukoplakia treatments on the risk of developing oral cancer. High-quality research is particularly needed to assess surgical treatment and to assess the effects of risk factor cessation in people with leukoplakia.

The evidence on which this review is based is up-to-date as of May 2016. We found 14 randomised controlled trials (RCTs) of medical and complementary treatments, which involved 909 participants in total. Treatments included herbal extracts, anti-inflammatory drugs, vitamin A, beta carotene supplements and others. Surgical treatment has not been compared with placebo or no treatment in an RCT. Cancer development was measured in studies of three treatments: systemic vitamin A, systemic beta carotene and topical bleomycin. None of these treatments showed effectiveness in preventing cancer development, as measured up to two years for vitamin A and beta carotene, and seven years for bleomycin. Some individual studies of vitamin A and beta carotene suggested that these treatments may be effective for improving or healing oral lesions. However, some studies observed a high rate of relapse in participants whose lesions were initially resolved by treatment. Most treatments caused side effects of differing severity in a high proportion of participants. It seems likely that interventions were well accepted by participants because drop-out rates were similar between treatment and control groups. The available evidence is very limited. Most interventions were assessed by only one small study. Most studies had problems in the way they were conducted, making their results unreliable. We judged the quality of evidence for the outcome of cancer development to be very low. Larger, better studies of longer duration are required. As well as further studies of drug treatment and alternative treatments like vitamins, studies are needed to evaluate the effectiveness and safety of surgery, and of stopping risk factor habits such as smoking.

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Six RCTs, with a total of 372 participants, evaluated preoperative iron therapy to correct anaemia before planned surgery. Four studies compared iron therapy (either oral (one study) or intravenous (three studies)) with no treatment, placebo or usual care, and two studies compared intravenous iron therapy with oral iron therapy. Iron therapy was delivered over a range of periods that varied from 48 hours to three weeks prior to surgery. The 372 participants in our analysis fall far short of the 819 required - as calculated by our information size calculation - to detect a 30% reduction in blood transfusions. Five trials, involving 310 people, reported the proportion of participants who received allogeneic blood transfusions. Meta-analysis of iron therapy versus placebo or standard care showed no difference in the proportion of participants who received a blood transfusion (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.87 to 1.70; 4 studies, 200 participants; moderate-quality evidence). Only one study that compared oral versus intravenous iron therapy measured this outcome, and reported no difference in risk of transfusion between groups. There was no difference between the iron therapy and placebo/standard care groups for haemoglobin level preoperatively at the end of the intervention (mean difference (MD) 0.63 g/dL, 95% CI -0.07 to 1.34; 2 studies, 83 participants; low-quality evidence). However, intravenous iron therapy produced an increase in preoperative postintervention haemoglobin levels compared with oral iron (MD 1.23 g/dL, 95% CI 0.80 to 1.65; 2 studies, 172 participants; low-quality evidence). Ferritin levels were increased by intravenous iron, both when compared to standard care ((MD 149.00, 95% CI 25.84 to 272.16; 1 study, 63 participants; low-quality evidence) or to oral iron (MD 395.03 ng/mL, 95% CI 227.72 to 562.35; 2 studies, 151 participants; low-quality evidence). Not all studies measured quality of life, short-term mortality or postoperative morbidity. Some measured the outcomes, but did not report the data, and the studies which did report the data were underpowered. Therefore, uncertainty remains regarding these outcomes. The inclusion of new research in the future is very likely to change these results. The use of iron therapy for preoperative anaemia does not show a clinically significant reduction in the proportion of trial participants who received an allogeneic blood transfusion compared to no iron therapy. Results for intravenous iron are consistent with a greater increase in haemoglobin and ferritin when compared to oral iron, but do not provide reliable evidence. These conclusions are drawn from six studies, three of which included very small numbers of participants. Further, well-designed, adequately powered, RCTs are required to determine the true effectiveness of iron therapy for preoperative anaemia. Two studies are currently in progress, and will include 1500 randomised participants.

we looked at adults with anaemia who were due to have an operation, who received iron treatment or usual care, or a 'pretend' iron treatment (placebo) prior to their surgery. We also compared different forms of iron therapy with each other. We included six studies and a total of 372 participants. iron treatment did not reduce the risk of blood transfusion. There is currently insufficient evidence to say whether iron therapy given before surgery prevents transfusions. To date, too few studies involving too small a number of people have been undertaken, and it is not yet possible to obtain a reliable result for the effects of this treatment. the major limitation in study design for all trials was the small size of the sample groups. More research in larger, well-designed trials is needed before a definitive answer can be given about whether iron therapy before surgery is helpful. The Cochrane Review authors judged that five of the six studies included in this review were at a low risk of bias (and so their results are likely to be reliable). This was despite a lack of blinding of participants in five of the trials (which would usually decrease the reliability of the evidence), as the measurement used to assess how well the therapy had worked (blood haemoglobin level) was unlikely to be influenced by the participant or investigator knowing which treatment had been received. The results of one study are at a high risk of bias because participants who did not take 80% of their assigned treatment were not included in the analysis. Overall the quality of evidence is low (according to the GRADE criteria). When additional research becomes available in the future, it is likely to change the results obtained in this review.

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We included eight studies involving 646 participants, most of which were of poor methodological quality. The urinary biomarkers were evaluated either in a specific phase of menstrual cycle or irrespective of the cycle phase. Five studies evaluated the diagnostic performance of four urinary biomarkers for endometriosis, including three biomarkers distinguishing women with and without endometriosis (enolase 1 (NNE); vitamin D binding protein (VDBP); and urinary peptide profiling); and one biomarker (cytokeratin 19 (CK 19)) showing no significant difference between the two groups. All of these biomarkers were assessed in small individual studies and could not be statistically evaluated in a meaningful way. None of the biomarkers met the criteria for a replacement test or a triage test. Three studies evaluated three biomarkers that did not differentiate women with endometriosis from disease-free controls. There was insufficient evidence to recommend any urinary biomarker for use as a replacement or triage test in clinical practice for the diagnosis of endometriosis. Several urinary biomarkers may have diagnostic potential, but require further evaluation before being introduced into routine clinical practice. Laparoscopy remains the gold standard for the diagnosis of endometriosis, and diagnosis of endometriosis using urinary biomarkers should only be undertaken in a research setting.

The evidence included in this review is current to July 2015. We included eight studies involving 646 participants. All studies evaluated reproductive-aged women who were undertaking diagnostic surgery to investigate symptoms of endometriosis or for other indications. Five studies evaluated the diagnostic accuracy of four urinary biomarkers, including four biomarkers that were expressed differently in women with and without endometriosis and one showing no difference between the two groups. Three other studies just identified three biomarkers that did not distinguish the two groups. None of the assessed biomarkers, including cytokeratin 19 (CK 19), enolase 1 (NNE), vitamin D binding protein (VDBP) and urinary peptide profiling have been evaluated by enough studies to provide a meaningful assessment of test accuracy. None of the tests were accurate enough to replace diagnostic surgery. Several studies identified biomarkers that might be of value in diagnosing endometriosis, but there are too few reports to be sure of their diagnostic benefit. There is not enough evidence to recommend any urinary biomarker for use in clinical practice for the diagnosis of endometriosis. Generally, the reports were of low methodological quality and urine tests were only assessed in small individual studies. More high quality research trials are needed to accurately assess the diagnostic potential of urinary biomarkers identified in small numbers of studies as having value in detecting endometriosis.

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29 RCTs, with eight weeks to five years follow-up, met our inclusion criteria; four were excluded from the primary meta-analysis because of inadequate outcome data. The remaining 25 trials assessed 1,198 participants, but adequate randomisation was confirmed in only seven trials and concealment of allocation in only one. Only one trial reported deaths, heart attacks and strokes (one of each). Meta-analysis indicated that relaxation resulted in small, statistically significant reductions in SBP (mean difference: -5.5 mmHg, 95% CI: -8.2 to -2.8, I2 =72%) and DBP (mean difference: -3.5 mmHg, 95% CI: -5.3 to -1.6, I2 =75%) compared to control. The substantial heterogeneity between trials was not explained by duration of follow-up, type of control, type of relaxation therapy or baseline blood pressure. The nine trials that reported blinding of outcome assessors found a non-significant net reduction in blood pressure (SBP mean difference: -3.2 mmHg, 95% CI: -7.7 to 1.4, I2 =69%) associated with relaxation. The 15 trials comparing relaxation with sham therapy likewise found a non-significant reduction in blood pressure (SBP mean difference: -3.5 mmHg, 95% CI: -7.1 to 0.2, I2 =63%). In view of the poor quality of included trials and unexplained variation between trials, the evidence in favour of causal association between relaxation and blood pressure reduction is weak. Some of the apparent benefit of relaxation was probably due to aspects of treatment unrelated to relaxation.

Our review pooled findings from 1,198 people with blood pressure over 140/85 mmHg who were enrolled in 25 randomised controlled trials. These trials compared the effect of relaxation either with no treatment or with a dummy treatment which wasn't expected to reduce blood pressure. Overall, relaxation reduced blood pressure by a small amount: the average reduction was 5/3 mmHg, but might be anywhere between 8/5 mmHg and 3/2 mmHg. Different trials gave different − sometimes inconsistent − results. Many of the trials were not well designed or conducted. In the good quality trials, relaxation resulted in smaller average reductions in blood pressure and the results could even be consistent with an average increase in blood pressure. Even when all the trials were put together, the combined group of all the people in all the trials wasn't large enough and the trials didn't run for long enough to tell us whether relaxation could reduce the risk of death, heart attack or stroke. Few people reported side-effects of relaxation and, on average, people were just as likely to report side-effects of the comparison treatment. Different types of relaxation were taught in different trials. It was difficult to disentangle their effects, especially as many trials used a combination of methods. Overall, we found no evidence that autogenic training was effective. Progressive muscle relaxation, cognitive/behavioural therapies and biofeedback seemed to be more likely to reduce blood pressure. However, some of the reduction in blood pressure was almost certainly due to aspects of treatment that were not related to relaxation, such as frequent contact with professionals who were trying to help.

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The 2010 search strategy identified 1664 abstracts (and 827 duplicates) of which we obtained 23 studies in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria. The updated searches carried out in November 2013 identified 304 abstracts (261 excluding duplicates) of which we obtained 18 references in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria, therefore there were no included studies in this review. We found no registered trials of droperidol for the management of nausea or vomiting in palliative care. Since first publication of this review, no new studies were found. There is insufficient evidence to advise on the use of droperidol for the management of nausea and vomiting in palliative care. Studies of antiemetics in palliative care settings are needed to identify which agents are most effective, with minimum side effects.

In our search updated in November 2013 we found no randomised studies of droperidol for the treatment of nausea or vomiting for people receiving palliative care or suffering from an incurable progressive medical condition. Several studies reported on the use of droperidol for the prevention of nausea and vomiting associated with chemotherapy. Further studies are needed to find out which medications are most suitable to treat nausea and vomiting in palliative care.

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Six randomized controlled clinical trials met selection criteria and were included in this review. In these studies of infants with signs and symptoms of RDS, intubation and early surfactant therapy followed by extubation to nasal CPAP (NCPAP) compared with later selective surfactant administration was associated with a lower incidence of mechanical ventilation [typical RR 0.67, 95% CI 0.57, 0.79], air leak syndromes [typical RR 0.52, 95% CI 0.28, 0.96] and BPD [typical RR 0.51, 95% CI 0.26, 0.99]. A larger proportion of infants in the early surfactant group received surfactant than in the selective surfactant group [typical RR 1.62, 95% CI 1.41, 1.86]. The number of surfactant doses per patient was significantly greater among patients randomized to the early surfactant group [WMD 0.57 doses per patient, 95% CI 0.44, 0.69]. In stratified analysis by FIO2 at study entry, a lower threshold for treatment (FIO2< 0.45) resulted in lower incidence of airleak [typical RR 0.46 and 95% CI 0.23, 0.93] and BPD [typical RR 0.43, 95% CI 0.20, 0.92]. A higher treatment threshold (FIO2 > 0.45) at study entry was associated with a higher incidence of patent ductus arteriosus requiring treatment [typical RR 2.15, 95% CI 1.09, 4.13]. Early surfactant replacement therapy with extubation to NCPAP compared with later selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator support is associated with less need mechanical ventilation, lower incidence of BPD and fewer air leak syndromes. A lower treatment threshold (FIO2< 0.45) confers greater advantage in reducing the incidences of airleak syndromes and BPD; moreover a higher treatment threshold (FIO2 at study > 0.45) was associated with increased risk of PDA. These data suggest that treatment with surfactant by transient intubation using a low treatment threshold (FIO2< 0.45) is preferable to later, selective surfactant therapy by transient intubation using a higher threshold for study entry (FIO2 > 0.45) or at the time of respiratory failure and initiation of mechanical ventilation.

An early surfactant therapy strategy results in a greater number of infants receiving surfactant and so more infants being exposed to the potential risks of intubation and surfactant administration. Although no complications of surfactant administration were reported in the studies reviewed, infants treated with an early surfactant therapy strategy tended to have a higher prevalence of patent ductus arteriosus (PDA). Two trials were terminated prior to achieving the targeted enrollment when the need for mechanical ventilation was found to be significantly different between groups at a scheduled interim analysis. Two other trials experienced slow enrollment leading to reduced numbers.

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This review included three RCTs with a total of 228 eyes. The range of myopia of included patients was -6.0 D to -20.0 D of myopia with up to 4.0 D of myopic astigmatism. The percentage of eyes with uncorrected visual acuity (UCVA) of 20/20 or better at 12 months postoperative was not significantly different between the two groups. Phakic IOL surgery was safer than excimer laser surgical correction for moderate to high myopia as it results in significantly less loss of best spectacle corrected visual acuity (BSCVA) at 12 months postoperatively. However there is a low risk of developing early cataract with phakic IOLs. Phakic IOL surgery appears to result in better contrast sensitivity than excimer laser correction for moderate to high myopia. Phakic IOL surgery also scored more highly on patient satisfaction/preference questionnaires. The results of this review suggest that, at one year post surgery, phakic IOLs are safer than excimer laser surgical correction for moderate to high myopia in the range of -6.0 to -20.0 D and phakic IOLs are preferred by patients. While phakic IOLs might be accepted clinical practice for higher levels of myopia (greater than or equal to 7.0 D of myopic spherical equivalent with or without astigmatism), it may be worth considering phakic IOL treatment over excimer laser correction for more moderate levels of myopia (less than or equal to 7.0 D of myopic spherical equivalent with or without astigmatism). Further RCTs adequately powered for subgroup analysis are necessary to further elucidate the ideal range of myopia for phakic IOLs. This data should be considered alongside comparative data addressing long-term safety as it emerges.

This review included three randomised controlled trials with a total of 228 eyes. The range of myopia of included patients was -6.0 D to -20.0 D with up to 4.0 D of myopic astigmatism. The results of this review showed that the chance of the uncorrected visual acuity being 20/20 or better was not different between the two groups. Phakic IOL surgery was safer than excimer laser surgical correction for moderate to high myopia as it results in significantly less loss of best spectacle corrected visual acuity (BSCVA) at 12 months postoperatively. Phakic IOL surgery appears to result in better contrast sensitivity than excimer laser correction for moderate to high myopia. Phakic IOL surgery also scored more highly on patient satisfaction/preference questionnaires. Neither technique resulted in any complication that caused a loss of final BSCVA. Only studies that fulfilled the proper requirements were selected for inclusion in the analysis. The limitations of the studies that we included were the relatively short follow up period of one year as well as the fact that many of the interventions studied have now been superseded by more technologically advanced alternatives. In the present day the technology available for both excimer laser and phakic IOL surgical correction of high myopia is better than during the period of the included studies. This review showed that phakic IOLs for the treatment of high myopia were safer and preferred by patients when compared with excimer laser. Studies looking at more up to date technology with longer follow to determine long term safety issues are needed.

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We found and included three unblinded randomised trials in 8221 older adults (mean age 74.8 years), in which higher BP targets of less than 150/90 mmHg (two trials) and less than 160/90 mmHg (one trial) were compared to a lower target of less than 140/90 mmHg. Treatment to the two different BP targets over two to four years failed to produce a difference in any of our primary outcomes, including all-cause mortality (RR 1.24 95% CI 0.99 to 1.54), stroke (RR 1.25 95% CI 0.94 to 1.67) and total cardiovascular serious adverse events (RR 1.19 95% CI 0.98 to 1.45). However, the 95% confidence intervals of these outcomes suggest the lower BP target is probably not worse, and might offer a clinically important benefit. We judged all comparisons to be based on low-quality evidence. Data on adverse effects were not available from all trials and not different, including total serious adverse events, total minor adverse events, and withdrawals due to adverse effects. At the present time there is insufficient evidence to know whether a higher BP target (less than150 to 160/95 to 105 mmHg) or a lower BP target (less than 140/90 mmHg) is better for older adults with high BP. Additional good-quality trials assessing BP targets in this population are needed.

We systematically retrieved all randomised trials that compared the effect of a higher BP target (upper BP number less than 150 to 160 mmHg) with a conventional lower BP target (upper BP number less than140 mmHg) in people over the age of 65 years. The evidence is current to February 2017. We found three randomised trials (the 'gold standard' of medical evidence) that investigated this question in a total of 8221 older adults (average age 75 years, 59% female). We did not find a difference between the higher BP target and the conventional lower BP target, however an important difference favoring the lower BP target could not be ruled out. We judged the pooled evidence to be of low-quality and not able to adequately answer the question as to which target BP was better. More good-quality trials addressing this question are needed.

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Eight RCTs were included, with 305 patients in the intervention groups and 288 in the control groups. They evaluated heat-inactivated varicella zoster virus (VZV) vaccine (two trials), influenza vaccines (five trials) and inactivated poliovirus vaccine (IPV) (one trial). Seven trials had high and one trial had moderate risk of bias. VZV vaccine might reduce herpes zoster compared to no vaccine (RR 0.54, 95% CI 0.3 to 1.0, P=0.05), but not statistically significant. Vaccination also demonstrated efficacy in immune response but frequently caused local adverse effects. One trial reported severity score of zoster, which favored vaccination (MD 2.6, 95% CI 0.94 to 4.26, P=0.002). Two RCTs compared inactivated influenza vaccine with no vaccine and reported lower risk of lower respiratory infections (RR 0.39, 95% CI 0.19 to 0.78, P=0.008) and hospitalization (RR 0.17, 95% CI 0.09 to 0.31, P<0.00001) in vaccine recipients. However, vaccine recipients more frequently experienced irritability and local adverse effects. There was no significant difference in seroconversion between one and two doses of influenza vaccine (one trial), or between recombinant and standard influenza vaccine (one trial), or influenza vaccine given with or without re-induction chemotherapy (one trial). The IPV trial comparing vaccination starting at 6 versus 18 months after stem cell transplant (SCT) found no significant difference in seroconversion. Inactivated VZV vaccine might reduce zoster severity in adult SCT recipients. Inactivated influenza vaccine might reduce respiratory infections and hospitalization in adults with multiple myeloma or children with leukemia or lymphoma. However, the quality of evidence is low. Local adverse effects occur frequently. Further high-quality RCTs are needed.

In the current systematic review of randomized controlled trials (RCTs) we aimed to evaluate the efficacy and safety of viral vaccines in these patients. The pre-defined primary outcome was incidence of the infection concerned. Secondary outcomes were mortality due to the viral infection, all-cause mortality, incidence of complications, incidence of severe viral infection, hospitalization rate, in vitro immune response and frequency of adverse effects. Eight RCTs were included. They evaluated heat-inactivated varicella zoster virus (VZV) vaccine (two trials), influenza vaccines (five trials) and inactivated poliovirus vaccine (one trial). There were no RCTs on other viral vaccines (hepatitis A, hepatitis B, measles, mumps, rubella). Only the two trials on VZV vaccine reported our pre-defined primary outcome. All trials reported some of the pre-defined secondary outcomes. We found that inactivated VZV vaccine might reduce the severity of herpes zoster when given before and after stem cell transplant in adults with lymphoma or leukemia. Inactivated influenza vaccine might reduce upper and lower respiratory infections and hospitalization in adults with multiple myeloma who are undergoing chemotherapy, or children with leukemia or lymphoma within two years post-chemotherapy. However, the quality of evidence is not high. Local adverse effects occur frequently with the vaccines, although serious adverse effects appear uncommon. Further high-quality RCTs are needed to clarify the benefits and optimal regimens of viral vaccines for patients with blood cancers.

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The five eligible trials reported on a total of 359 infants with RDS. Overall the risk of any reported mortality was less frequent in the MV group (summary RR 0.86, 95% CI 0.74, 1.00; RD -0.10, 95% CI -0.20, -0.01; NNT 10, 95% CI 5, 100). In infants with a birth weight of 1 to 2 kg, no significant difference in mortality was found (summary RR 0.86, 95% CI 0.70, 1.07). In infants with a birth weight of more than 2 kg there was a significant reduction in mortality with MV (summary RR 0.67, 95%CI 0.52, 0.87). Any IVH at autopsy was not significantly different between the groups in any study or overall in four studies reporting on 202 infants who had an autopsy. Pneumothorax was reported in two studies of 275 infants and there is a non-significant trend towards an increase in the mechanical ventilation group (summary RR 2.75, 95% CI 0.72, 10.45). When MV was introduced in the 1960s to treat infants with severe respiratory failure due to pulmonary disease, trials showed an overall reduction in mortality which was most marked in infants born with a birthweight of more than 2 kg. This review does not provide information to evaluate the relative benefits or harms of MV in the setting of modern perinatal care.

It was compared with standard treatment in five trials for infants with very severe lung disease and resulted in a reduction in mortality. This effect was observed principally in infants with birth weights over two kilograms. Mechanical ventilation has become standard therapy for severe respiratory failure. There have been no trials in modern neonatal intensive care units so the magnitude of the benefits and harms in current practice are not known.

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For efficacy we included three randomised trials of between five and eight weeks duration with a total of 204 participants. For adverse effects we included two randomised trials and three observational (non-randomised) studies of five to eight weeks duration with a total of 225 participants. Overall, the randomised trials had low-to-moderate risk of bias, and the observational studies had a high risk of bias (due to small size and high attrition). The participants in the studies all met DSM (Diagnostic and Statistics Manual of Mental Disorders) criteria for SAD. The average age was approximately 40 years and 70% of the participants were female. Results from one trial with 68 participants showed that fluoxetine was not significantly more effective than placebo in achieving clinical response (risk ratio (RR) 1.62, 95% confidence interval (CI) 0.92 to 2.83). The number of adverse effects were similar between the two groups. We located two trials that contained a total of 136 participants for the comparison fluoxetine versus light therapy. Our meta-analysis of the results of the two trials showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24), RR of remission 0.81 (95% CI 0.39 to 1.71). The number of adverse effects was similar in both groups. Two of the three randomised trials and three non-randomised studies contained adverse effect data on 225 participants who received fluoxetine, escitalopram, duloxetine, reboxetine, light therapy or placebo. We were only able to obtain crude rates of adverse effects, so any interpretation of this needs to be undertaken with caution. Between 22% and 100% of participants who received a SGA suffered an adverse effect and between 15% and 27% of participants withdrew from the studies because of adverse effects. Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo, which shows a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy, which suggest equivalence between the two interventions. The lack of available evidence precludes the ability to draw any overall conclusions on the use of SGAs for SAD. Further larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs. Data on adverse events were sparse, and a comparative analysis was not possible. Therefore the data we obtained on adverse effects is not robust and our confidence in the data is limited. Overall, up to 27% of participants treated with SGAs for SAD withdrew from the studies early due to adverse effects. The overall quality of evidence in this review is very low.

We found three trials with a total of 204 participants that looked at one SGA (fluoxetine) compared with placebo or light therapy. We did not find any trials on other SGAs. One trial (68 participants) compared fluoxetine with placebo. Fluoxetine appears to work better than placebo for winter depression, but we cannot say this with certainty due to the small numbers involved in the trial. Approximately the same number of participants in both groups experienced a side effect. We found two trials (with 136 participants in total) that compared fluoxetine with light therapy. When we combined the results of these two trials we found that there was no difference between the two groups: approximately 66 people out of 100 improved in both the fluoxetine and light therapy groups. We are unsure whether this summary result is correct because the trials are small and have some problems with their design as well as a high drop-out rate (many participants did not finish the trials). About the same number of participants had side effects in the fluoxetine and light therapy groups. We found three additional studies that gave us information on the side effects of other SGAs (fluoxetine, escitalopram, duloxetine, and reboxetine), but we cannot compare the drugs directly. We can say that about 15% to 27% of people had to leave the studies early because of side effects and that the most common side effects were nausea, diarrhoea, disturbed sleep, decreased sex drive, dry mouth and agitation. We could not compare the rates of side effects in people taking SGAs compared with placebo drugs which means that our confidence in the information on side effects is limited.

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We included nine trials with 645 participants. Six trials assessed TACE versus control and three trials assessed TAE versus control. Seven trials had low risk of selection bias based on adequate generation of allocation sequence and concealment - but all these trials had other risks of bias. Three trials were stopped early due to interim inspections and one due to slow accrual. For all-cause mortality, statistical heterogeneity between trials was low to moderate (I2= 30%). Meta-analysis of trials with low risk of selection bias showed that TACE or TAE versus control does not significantly increase survival (HR 0.88; 95% CI 0.71 to 1.10). Two trials with low risk of selection bias, no early stopping, and no co-intervention did not establish any significant effect of TACE or TAE on overall survival (hazard ratio 1.22, 95% confidence interval 0.82 to 1.83; P = 0.33). Trial sequential analysis confirmed the absence of evidence for a beneficial effect of TACE or TAE on survival indicating the need for future randomisation of up to 383 additional participants. Substantial differences in criteria for assessing tumour response did not allow quantitative analyses. One trial investigated quality of life but did not detect any significant differences between the intervention groups. A range of adverse events including post-embolisation syndrome and serious complications were reported. There is no firm evidence to support or refute TACE or TAE for patients with unresectable HCC. More adequately powered and bias-protected trials are needed.

The review included nine trials with 645 participants. Six trials assessed TACE versus control and three trials assessed TAE versus control. All trials had risks of systematic errors ('bias'). Contrary to current practice in many hospitals, we could not demonstrate any beneficial effect of TACE or TAE on either survival or tumour growth in patients with primary liver cancer not suitable for surgical resection. Furthermore, we calculated that more clinical trials involving a further 383 trial participants may be needed before firm evidence may become available. Importantly, TACE or TAE is associated with a wide range of adverse events, some being potentially serious. Accordingly, we recommend that TACE or TAE should not be used as standard treatment for liver cancer until firmer evidence is available from randomised clinical trials.

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We included 25 trials in this version of the review (13 from the original 2010 review and 12 newly-included studies). Sixteen trials were of adolescents, eight trials of adults (seven of these in young adults aged up to 26 years) and one trial included three age groups: one adolescent, one young adult and one adult. Most investigated family-based therapy or variants. Reporting of trial conduct was generally inadequate, so that in a large number of studies we rated the risk of bias as unclear for many of the domains. Selective reporting bias was particularly problematic, with 68% of studies rated at high risk of bias in this area, followed by incomplete outcome data, with 44% of studies rated at high risk of bias in this area. For the main outcome measure of remission there was some low-quality evidence (from only two studies, 81 participants) suggesting that family therapy approaches might offer some advantage over treatment as usual on rates of remission, post intervention (risk ratio (RR) 3.50, 95% confidence interval (CI) 1.49 to 8.23; I2 = 0%). However, at follow-up, low-quality evidence from only one study suggested this effect was not maintained. There was very low-quality evidence from only one trial, which means it is difficult to determine whether family therapy approaches offer any advantage over educational interventions for remission (RR 9.00, 95% CI 0.53 to 153.79; 1 study, N = 30). Similarly, there was very low-quality evidence from only five trials for remission post-intervention, again meaning that it is difficult to determine whether there is any advantage of family therapy approaches over psychological interventions (RR 1.22, 95% CI 0.89 to 1.67; participants = 252; studies = 5; I2 = 37%) and at long-term follow-up (RR 1.08, 95% CI 0.91 to 1.28; participants = 200; studies = 4 with 1 of these contributing 3 pairwise comparisons for different age groups; I2 = 0%). There was no indication that the age group had any impact on the overall treatment effect; however, it should be noted that there were very few trials undertaken in adults, with the age range of adult studies included in this analysis from 20 to 27. There was some evidence of a small effect favouring family based therapy compared with other psychological interventions in terms of weight gain post-intervention (standardised mean difference (SMD) 0.32, 95% CI 0.01 to 0.63; participants = 210; studies = 4 with 1 of these contributing 3 pairwise comparisons for different age groups; I2 = 11%) . Overall, there was insufficient evidence to determine whether there were any differences between groups across all comparisons for most of the secondary outcomes (weight, eating disorder psychopathology, dropouts, relapse, or family functioning measures), either at post-intervention or at follow-up. There is a limited amount of low-quality evidence to suggest that family therapy approaches may be effective compared to treatment as usual in the short term. This finding is based on two trials that included only a small number of participants, and both had issues about potential bias. There is insufficient evidence to determine whether there is an advantage of family therapy approaches in people of any age compared to educational interventions (one study, very low quality) or other psychological therapies (five studies, very low quality). Most studies contributing to this finding were undertaken in adolescents and youth. There are clear potential impacts on how family therapy approaches might be delivered to different age groups and further work is required to understand what the resulting effects on treatment efficacy might be. There is insufficient evidence to determine whether one type of family therapy approach is more effective than another. The field would benefit from further large, well-conducted trials.

We included 25 trials in the review. Fourteen trials used family-based therapy, one used systems family therapy, one used structural family therapy and seven studies used therapy with family involvement but did not provide specific details about the theory behind the therapy or its procedures, termed other family therapy. Two studies included two family therapy arms each: one included family-based therapy and systems family therapy arms, and one included systems family therapy and other family therapy arms. Four studies compared family therapy approaches to treatment as usual, six compared family therapy approaches to other psychological interventions and two compared family therapy to educational interventions. Twelve studies compared various forms of family therapy approaches to each other. Two studies included both a treatment as usual as well as other psychological intervention arms. Overall there was some low-quality evidence from only two trials to suggest that family therapy approaches may be better than treatment as usual in the short term. The size and very low quality of the evidence base and the consistency of the trial outcomes are insufficient at this time to draw conclusions about whether family therapy approaches offer any clear advantage over educational or psychological interventions. We found very few differences between treatment groups on measures of weight, eating disorder symptoms and family functioning, and these differences were generally not maintained at follow-up. The reporting of death rates was not clear enough to assess whether death is reduced for those treated with family therapy approaches compared to other interventions. There was very little information about the effects of the interventions on general or family functioning. The way the trials were run was not adequately described in many studies and we found potential risks of bias in most of the studies. This limited the meaningful conclusions that we could draw from the studies. Overall, there is a very limited evidence base in this field. There is some low-quality evidence to suggest that family therapy approaches may be effective compared to treatment as usual in the short term. There is insufficient evidence to be able to determine whether family therapy approaches offer any advantage over educational interventions, other types of psychological therapy, or whether one type of family therapy approach is more effective than another. Most of the studies contributing to the findings were undertaken in adolescents and young adults. There are clear implications about how family therapy approaches might be delivered to different age groups, and we need further research to understand what the resulting effects on treatment might be.

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Three small randomised controlled trials, with a total of 109 participants with Orthopaedic Trauma Association/Arbeitsgemeinschaft für Osteosynthesefragen (OTA/AO) type C distal humeral fractures, were included. Overall, the quality of the available evidence is limited. As well as the small sample sizes and detection bias from the lack of blinding of subjective outcomes, the methods and results of all three trials were incompletely reported. One trial, involving 42 participants, compared open reduction-internal fixation (ORIF) with total elbow arthroplasty (TEA) in patients aged over 65 years. Of the 40 participants followed up for two years, five allocated ORIF underwent intraoperative conversion to TEA. These participants were crossed-over to the TEA group in the analyses. The reported Mayo Elbow Performance Score (MEPS) results were consistently better in the TEA group at follow-up after 6, 12, and 24 months, whereas the Disability of the Arm, Shoulder, Hand (DASH) scores showed short term (after 6 months), but not longer term (after 12 and 24 months), superiority in the TEA group. The reoperation rate, complication rate and elbow range of motion results showed no statistically significant differences between the two groups. While an intention-to-treat analysis of treatment failure, where the five cross-over participants are placed in their original allocated group, is in favour of TEA, the result did not reach statistical significance (9/21 versus 3/21; RR 3.00, 95% CI 0.94 to 9.55). The second trial, involving 38 patients but reporting results for 35, compared perpendicular versus parallel double plate fixation strategies. There was a consistent finding of a lack of significant differences between the two treatment groups in terms of MEPS, re-operation for complications (3/17 versus 3/18; RR 1.06, 95% CI 0.25 to 4.54), complications and elbow joint range of motion. The third trial, which included 29 patients with preoperative ulnar nerve compression symptoms, compared anterior subfascial transposition with in situ decompression of the ulnar nerve. Although results for complete recovery of ulnar nerve function (12/15 versus 8/14; RR 1.4, 95% CI 0.83 to 2.35) and grades based on the Bishop rating system tended to favour the transposition group, none of the differences were statistically significant. Overall, this review found there is either no or insufficient evidence from randomised or quasi-randomised controlled trials to determine whether surgery is, and which surgical interventions are, the most appropriate for the management of different types of distal humerus fractures. Well designed and reported large and multi-centre randomised controlled trials testing current interventions, such as pre-contoured and locking plating systems, are needed.

Despite a comprehensive search, we identified only three small randomised controlled trials with a total of 109 participants. Each trial tested different interventions for treating a complete intra-articular fracture in which the joint surface is separated from the shaft of the humerus. One trial compared open reduction and internal fixation versus total elbow replacement in people aged 65 years and older. This found some limited evidence that internal fixation is sometimes not practical for some more complex and difficult fractures and that people treated total elbow replacement may have a better outcome early on (around six months). The second trial compared two ways of placing two plates used for internal fixation. These were either perpendicular (where the plates were at right angles to each other along the bone) or parallel (where the plates were on either side of the bone). The trial did not find any major differences in outcome between the two methods. The third trial did not provide clear evidence of a difference in two surgical approaches of managing pre-operative ulnar nerve dysfunction. In all, none of these three under-sized trials provided adequate evidence to determine which of the surgical interventions under test was the most appropriate. The review found no evidence to inform on the use of more current methods of surgical fixation, specifically the use of locking plates.

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Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of probiotics, or studies at high versus low risk of bias. However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the probiotics group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. Based on this systematic review and meta-analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that probiotics are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that probiotics are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk ≤5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics.

This review includes 39 randomized trials with a total of 9955 participants. Thirty-one studies (8672 participants) assessed the effectiveness of probiotics for preventing CDAD among participants taking antibiotics. Our results suggest that when probiotics are given with antibiotics the risk of developing CDAD is reduced by 60% on average. Among trials enrolling participants at high risk of developing CDAD (> 5%), the potential benefit of probiotics is more pronounced with a 70% risk reduction on average. Side effects were assessed in 32 studies (8305 participants) and our results suggest that taking probiotics does not increase the risk of developing side effects. The most common side effects reported in these studies include abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics.

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The search identified 102 potentially eligible studies. Judged from the information in the title and abstract six of these concerning the percutaneous block, involving 358 participants, fulfilled the inclusion criteria and were included in the review. All were RCTs in which the participants were followed for at least four weeks. We excluded studies published only as abstracts. We identified one RCT comparing EUS-guided or computed tomography (CT) -guided CPB but its aim was to assess efficacy in controlling chronic abdominal pain associated with chronic pancreatitis rather than pancreatic cancer, so it was excluded. For pain (VAS) at four weeks the mean difference was -0.42 in favour of CPB (95% confidence interval (CI) -0.70 to - 0.13, P = 0.004, fixed-effect model). At eight weeks the mean difference was -0.44 (95% CI -0.89 to - 0.01, random-effects model). At eight weeks there was significant heterogeneity (I2 = 89%). Opioid consumption was significantly lower in the CPB group than the control group (P < 0.00001). Although statistical evidence is minimal for the superiority of pain relief over analgesic therapy, the fact that CPB causes fewer adverse effects than opioids is important for patients. Further studies and RCTs are recommended to demonstrate the potential efficacy of a less invasive technique under EUS guidance.

We searched for studies comparing CPB with standard analgesic therapy in patients with inoperable pancreatic cancer. We were interested in the primary outcome of pain, measured on a visual analogue scale (VAS). We also looked at the amount of opioid (morphine-like drugs) patients took (opioid consumption) and adverse effects of the treatment. Six studies (358 participants) comparing CPB with standard therapy (painkillers) met our inclusion criteria. At four weeks pain scores were significantly lower in the CPB group. Opioid consumption was also significantly lower than in the control group. The main adverse effects were diarrhoea or constipation (this symptom was significantly more likely in the control group, where opioid consumption was higher). Endoscopic ultrasonography (EUS)-guided CPB is becoming popular as a minimally invasive technique that has fewer risks, but we were not able to find any RCTs assessing this method (current medical literature on this subject is limited to studies without control groups). Although the data on EUS-guided CPB and pain control are promising, we await rigorously designed RCTs that may validate these findings. We conclude that, although statistical evidence is minimal for the superiority of pain relief over analgesic therapy, the fact that CPB causes fewer adverse effects than opioids is important for patients.

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Since 2000, one new trial has been published; the updated review now includes five RCTs involving 4023 women with breast cancer (clinical stage I, II or III). Two trials involving 2563 women compared follow-up based on clinical visits and mammography with a more intensive scheme including radiological and laboratory tests. After pooling the data, no significant differences in overall survival (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.84 to 1.15, two studies, 2563 participants, high-quality evidence), or disease-free survival (HR 0.84, 95% CI 0.71 to 1.00, two studies, 2563 participants, low-quality evidence) emerged. No differences in overall survival and disease-free survival emerged in subgroup analyses according to patient age, tumour size and lymph node status before primary treatment. In 1999, 10-year follow-up data became available for one trial of these trials, and no significant differences in overall survival were found. No difference was noted in quality of life measures (one study, 639 participants, high-quality evidence). The new included trial, together with a previously included trial involving 1264 women compared follow-up performed by a hospital-based specialist versus follow-up performed by general practitioners. No significant differences were noted in overall survival (HR 1.07, 95% CI 0.64 to 1.78, one study, 968 participants, moderate-quality evidence), time to detection of recurrence (HR 1.06, 95% CI 0.76 to 1.47, two studies, 1264 participants, moderate-quality evidence), and quality of life (one study, 356 participants, high-quality evidence). Patient satisfaction was greater among patients treated by general practitioners. One RCT involving 196 women compared regularly scheduled follow-up visits versus less frequent visits restricted to the time of mammography. No significant differences emerged in interim use of telephone and frequency of general practitioners's consultations. This updated review of RCTs conducted almost 20 years ago suggests that follow-up programs based on regular physical examinations and yearly mammography alone are as effective as more intensive approaches based on regular performance of laboratory and instrumental tests in terms of timeliness of recurrence detection, overall survival and quality of life. In two RCTs, follow-up care performed by trained and not trained general practitioners working in an organised practice setting had comparable effectiveness to that delivered by hospital-based specialists in terms of overall survival, recurrence detection, and quality of life.

A literature search up to July 2014 found five trials (involving 4023 women with a median follow-up variable from 16 to 120 months). Since the previous version of this Cochrane review in 2004, one new study has been published. This review of trials found that follow-up programs based on a regular physical examination and a yearly mammogram appear to be as effective as the more intensive approaches and to have similar impact on HRQoL. No significant differences were found between follow-up performed by specialists or family physicians, regularly or on demand. These results should be interpreted with caution bearing in mind that these studies were conducted almost two decades ago; additional trials incorporating new biological knowledge and improved imaging technologies are needed. Allocation concealment was adequate in all but one trial; two trials were judged to be at low risk of selection bias;the blinding of the outcome assessor was not described in two trials. For one trial it was not possible to judge risk of bias because it reported no methodological information.

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We included three RCTs, with 328 participants, that compared six-month regimens with nine-month regimens to treat adults with intestinal and peritoneal TB. All trials were conducted in Asia, and excluded people with HIV, those with co-morbidities and those who had received ATT in the previous five years. Antituberculous regimens were based on isoniazid, rifampicin, pyrazinamide, and ethambutol, and these drugs were administered daily or thrice weekly under a directly observed therapy programme. The median duration of follow-up after completion of treatment was between 12 and 39 months. Relapse was uncommon, with two cases among 140 participants treated for six months, and no events among 129 participants treated for nine months. The small number of participants means we do not know whether or not there is a difference in risk of relapse between the two regimens (very low quality evidence). At the end of therapy, there was probably no difference in the proportion of participants that achieved clinical cure between six-month and nine-month regimens (RR 1.02, 95% CI 0.97 to 1.08; 294 participants, 3 trials, moderate quality evidence). For death, there were 2/150 (1.3%) in the six-month group and 4/144 (2.8%) in the nine-month group. All deaths occurred in the first four months of treatment, so was not linked to the duration of treatment in the included trials. Similarly, the number of participants that defaulted from treatment was small in both groups, and there may be no difference between them (RR 0.50, 95% CI 0.10 to 2.59; 294 participants, 3 trials, low quality evidence). Only one trial reported on adherence to treatment, with only one participant allocated to the nine-month regimen presenting poor adherence to treatment. We do not know whether six-month regimens are associated with fewer people experiencing adverse events that lead to treatment interruption (RR 0.53, 95% CI 0.18 to 1.55; 318 participants, 3 trials, very low quality evidence). We found no evidence to suggest that six-month treatment regimens are inadequate for treating people that have intestinal and peritoneal TB, but numbers are small. We did not find any incremental benefits of nine-month regimens regarding relapse at the end of follow-up, or clinical cure at the end of therapy, but our confidence in the relapse estimate is very low because of size of the trials. Further research is required to make confident conclusions regarding the safety of six-month treatment for people with abdominal TB. Larger studies that include HIV-positive people, with long follow-up for detecting relapse with reliability, would help improve our knowledge around this therapeutic question.

Cochrane researchers examined the available evidence up to the 2 September 2016. We included three trials with 328 participants that compared six-month ATT with nine-month ATT; two were from India and one was from South Korea. The trials were mostly of high quality, although two had concerns of risk of bias for detecting relapse of the disease. All the trials included HIV-negative adults with TB of the gut (gastrointestinal TB), and one also included TB of the peritoneum (peritoneal TB). The results show that relapse was an uncommon event, but we are uncertain whether or not there is a difference between the six-month and nine-month groups as numbers of participants are small (very low quality evidence). Six-month and nine-month regimens are probably similarly effective in terms of the chances of achieving cure (moderate quality evidence). Death was uncommon in both groups, and all deaths occurred during the first four months of ATT, which suggests that duration of treatment did not have an effect on risk of death. Few people had poor treatment compliance, and few participants experienced side effects that led to their treatment being stopped or changed, and it was not possible to detect a difference between the groups. Six-month regimens are probably as good as nine-month regimens in terms of numbers of people cured. We found no evidence to suggest that six-month regimens are less safe for gastrointestinal and peritoneal TB than nine-month regimens, but we still do not know whether there is a difference in risk of relapse between the two regimens. Further studies are needed to increase our confidence as to whether six-month regimens are as good as nine-month regimens for preventing relapse; and to provide information about treating abdominal TB in children and in people with HIV.

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Thirty-nine RCTs met the inclusion criteria contributing a total of 4615 participants. Most trials enrolled a small number of patients and showed moderate to poor (reporting of) methodological quality, in particular regarding allocation concealment and intention-to-treat analysis. Fifteen systemic acting prokinetic drugs were investigated and ten comparisons could be summarized. Six RCTs support the effect of Alvimopan, a novel peripheral mu receptor antagonist. However, the trials do not meet reporting guidelines and the drug is still in an investigational stage. Erythromycin showed homogenous and consistent absence of effect across all included trials and outcomes. The evidence is insufficient to recommend the use of cholecystokinin-like drugs, cisapride, dopamine-antagonists, propranolol or vasopressin. Effects are either inconsistent across outcomes, or trials are too small and often of poor methodological quality. Cisapride has been withdrawn from the market due to adverse cardiac events in many countries. Intravenous lidocaine and neostigmine might show a potential effect, but more evidence on clinically relevant outcomes is needed. Heterogeneity among included trials was seen in 10 comparisons. No major adverse drug effects were evident. Alvimopan may prove to be beneficial but proper judgement needs adherence to reporting standards. Further trials are needed on intravenous lidocaine and neostigmine. The remaining drugs can not be recommended due to lack of evidence or absence of effect.

Many of the 39 studies assessed in this review enrolled only a small number of patients and date back to before 1990. The novel drug alvimopan shortened bowel recovery, but many studies failed to report methodology according to current guidelines. Erythromycin, cholecystokinin, cisapride, dopamine-antagonists, propranolol or vasopressin are not supported due to lack of evidence or absence of effect. Intravenous lidocaine and neostigmine might show to be beneficial, but more evidence is needed.

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Eighteen RCTs out of 64 potentially eligible study reports met the inclusion criteria. They compared undertaking a sinus lift with not doing so, and the use of different sinus lift techniques. There were 650 patients providing data for the outcomes evaluated. Five studies were assessed as low risk of bias, 11 were assessed as high risk of bias, and in two the risk was unclear. Sinus lift versus no sinus lift Four trials of moderate quality (three trials at low and one at high risk of bias) with 102 participants evaluated short implants (5 to 8.5 mm long) as an alternative to sinus lift in bone with residual height between 4 and 9 mm. One year after loading there was insufficient evidence to claim differences between the two procedures for prosthesis failure (OR (Peto) 0.37, 95% confidence interval (CI) 0.05 to 2.68; three trials) or implant failure (OR (Peto) 0.44, 95% CI 0.10 to 1.99; four trials). There was however an increase in complications at treated sites when undertaking the sinus lift (OR (Peto) 4.77, 95% CI 1.79 to 12.71, P value = 0.002; four trials). Different sinus lift techniques Fourteen trials with 548 participants compared different sinus lift techniques. Only three comparisons included more than one trial (two trials for each). These were bone graft versus no bone graft, autogenous bone versus bone substitute, bone graft with or without platelet-rich plasma (PRP). There was insufficient evidence to claim a benefit for any of these techniques for the primary outcomes of prosthesis and implant failure. For the other reported outcomes, in a single study at high risk of bias, only bone gain was greater for the bone graft site than the site without a graft six months after augmentation, however this was not significant at 18 or 30 months. The other comparisons with single studies were rotary versus piezosurgery to open a lateral sinus window, two different bone substitutes, use or not of a membrane to seal the lateral window, one- versus two-stage lateral sinus lift, two-stage granular bone versus one-stage autogenous bone blocks, and crestal versus lateral sinus lift; two trials compared three different crestal sinus lifting techniques: rotatory versus hand malleting (patients preferred rotatory instruments over hand malleting) and hand versus electric malleting. There was no evidence of a benefit for any sinus lift procedure compared to any other for the primary outcomes prosthesis or implant failure. There is moderate quality evidence which is insufficient to determine whether sinus lift procedures in bone with residual height between 4 and 9 mm are more or less successful than placing short implants (5 to 8.5 mm) in reducing prosthesis or implant failure up to one year after loading. However, there are more complications at sites treated with sinus lift procedures. Many trials compared different sinus lift procedures and none of these indicated that one procedure reduced prosthetic or implant failures when compared to the other. Based on low quality evidence, patients may prefer rotary instruments over hand malleting for crestal sinus lift.

The evidence on which this review is based is correct as of 17 January 2014. Eighteen trials with 650 participants were included. Four of the trials, with a total of 102 participants, compared implant-supported prostheses using a sinus lift with prostheses on short implants (5 to 8.5 mm long) without sinus lift. The remaining 14 trials with a total of 548 participants compared different sinus lift techniques. There is not enough evidence to show whether sinus lift techniques are more or less successful in reducing the number of failures of dental prostheses (artificial teeth) or dental implants when compared to simply using short implants, up to one year after loading. However, there is limited evidence that there are fewer complications when short implants are used without surgical lifts. Complications include sinusitis, infection and bleeding, and when bone grafts are taken from the patient complications can also include nerve injury, problems with walking and infection. The quality of the evidence for whether or not to use a sinus lift procedure was moderate. The evidence for the 14 comparisons of different sinus lift procedures was based on a maximum of two comparisons for each comparison and was low.

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We identified six RCTs (707 women), eligible for inclusion in this updated review, however, three RCTs had mixed populations (that is, they included pregnant women with gestational diabetes) and did not report data separately for the relevant subset of women for this review. Therefore we have only included outcome data from three RCTs; data were available for 241 women and their infants. The three RCTs all compared an oral anti-diabetic agent (metformin) with insulin. The women in the RCTs that contributed data had type 2 diabetes diagnosed before or during their pregnancy. Overall, the RCTs were judged to be at varying risk of bias. We assessed the quality of the evidence for selected important outcomes using GRADE; the evidence was low- or very low-quality, due to downgrading because of design limitations (risk of bias) and imprecise effect estimates (for many outcomes only one or two RCTs contributed data). For our primary outcomes there was no clear difference between metformin and insulin groups for pre-eclampsia (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.33 to 1.20; RCTs = 2; participants = 227; very low-quality evidence) although in one RCT women receiving metformin were less likely to have pregnancy-induced hypertension (RR 0.58, 95% CI 0.37 to 0.91; RCTs = 1; participants = 206; low-quality evidence). Women receiving metformin were less likely to have a caesarean section compared with those receiving insulin (RR 0.73, 95% CI 0.61 to 0.88; RCTs = 3; participants = 241; low-quality evidence). In one RCT there was no clear difference between groups for large-for-gestational-age infants (RR 1.12, 95% CI 0.73 to 1.72; RCTs = 1; participants = 206; very low-quality evidence). There were no perinatal deaths in two RCTs (very low-quality evidence). Neonatal mortality or morbidity composite outcome and childhood/adulthood neurosensory disability were not reported. For other secondary outcomes we assessed using GRADE, there were no clear differences between metformin and insulin groups for induction of labour (RR 1.42, 95% CI 0.62 to 3.28; RCTs = 2; participants = 35; very low-quality evidence), though infant hypoglycaemia was reduced in the metformin group (RR 0.34, 95% CI 0.18 to 0.62; RCTs = 3; infants = 241; very low-quality evidence). Perineal trauma, maternal postnatal depression and postnatal weight retention, and childhood/adulthood adiposity and diabetes were not reported. There are insufficient RCT data to evaluate the use of oral anti-diabetic agents in women with established diabetes, impaired glucose tolerance or previous gestational diabetes who are planning a pregnancy, or in pregnant women with pre-existing diabetes. Low to very low-quality evidence suggests possible reductions in pregnancy-induced hypertension, caesarean section birth and neonatal hypoglycaemia with metformin compared with insulin for women with type 2 diabetes diagnosed before or during their pregnancy, and no clear differences in pre-eclampsia, induction of labour and babies that are large-for-gestational age. Further high-quality RCTs that compare any combination of oral anti-diabetic agent, insulin and dietary and lifestyle advice for these women are needed. Future RCTs could be powered to evaluate effects on short- and long-term clinical outcomes; such RCTs could attempt to collect and report on the standard outcomes suggested in this review. We have identified three ongoing studies and four are awaiting classification. We will consider these when this review is updated.

We searched for evidence from randomised controlled trials (RCTs) on 31 October 2016 and included six RCTs (707 women). Three RCTs included women with current gestational diabetes and did not report data separately for the population of women relevant to this review. Therefore we have only included outcome data from three RCTs, involving 241 pregnant women and their infants. The quality of the evidence was assessed as being low or very low and the overall risk of bias of the RCTs was varied. The three RCTs all compared an oral anti-diabetic agent (metformin) with insulin in pregnant women with pre-existing (type 2) diabetes. There was no clear difference in the development of pre-eclampsia (high blood pressure and protein in the urine) for women who received metformin compared with insulin (2 RCTs; 227 women; very low-quality evidence), though women receiving metformin were less likely to have pregnancy-induced high blood pressure in one RCT (206 women; low-quality evidence). Women who received metformin were less likely to have a caesarean section birth (3 RCTs; 241 women; low-quality evidence), though no difference was observed in induction of labour (2 RCTs; 35 women; very low-quality evidence). There was no clear difference between groups of infants born to mothers who received metformin or insulin for being large-for-gestational age (1 RCT; 206 infants; very low-quality evidence), though infants born to mothers who received metformin were less likely to have low blood sugar (hypoglycaemia) (3 RCTs; 241 infants; very low-quality evidence). There were no infant deaths (before birth or shortly afterwards) (2 RCTs; very low-quality evidence). The RCTs did not report on many important short- and long-term outcomes, including perineal trauma and a combined outcome of infant death or morbidity, postnatal depression and weight retention for mothers, and adiposity or disability in childhood or adulthood for infants. There is not enough evidence to guide us on the effects of oral anti-diabetic agents in women with established diabetes, impaired glucose tolerance or previous gestational diabetes who are planning a pregnancy, or pregnant women with pre-existing diabetes. Further large, well-designed, RCTs are required and could assess and report on the outcomes suggested in this review, including both short- and long-term outcomes for mothers and their infants.

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We included 16 trials, with a total of 2144 participants. Two studies included children only. The other 14 studies included predominantly young adults, of whom over 60% were male. Seven studies recruited people with ankle sprains only. Most studies were at low or unclear risk of bias; however, two were at high risk of selection bias, three were at high risk of bias from lack of blinding, one was at high risk of bias due to incomplete outcome data, and four were at high risk of selective outcome reporting bias. The evidence was usually either low quality or very low quality, reflecting study limitations, indirectness such from as suboptimal dosing of single comparators, imprecision, or one or more of these. Thus we are either uncertain or very uncertain of the estimates. Nine studies, involving 991 participants, compared NSAIDs with paracetamol. While tending to favour paracetamol, there was a lack of clinically important differences between the two groups in pain at less than 24 hours (377 participants, 4 studies; moderate-quality evidence), at days 1 to 3 (431 participants, 4 studies; low quality), and at day 7 or over (467 participants, 4 studies; low quality). A similar lack of difference between the two groups applied to swelling at day 3 (86 participants, 1 study; very low quality) and at day 7 or over (77 participants, 1 study; low quality). There was little difference between the two groups in return to function at day 7 or over (316 participants, 3 studies; very low quality): based on an assumed recovery of function of 804 per 1000 participants in the paracetamol group, 8 fewer per 1000 recovered in the NSAID group (95% confidence interval (CI) 80 fewer to 73 more). There was low-quality evidence of a lower risk of gastrointestinal adverse events in the paracetamol group: based on an assumed risk of gastrointestinal adverse events of 16 per 1000 participants in the paracetamol group, 13 more participants per 1000 had a gastrointestinal adverse event in the NSAID group (95% CI 0 to 35 more). Four studies, involving 958 participants, compared NSAIDs with opioids. Since a study of a selective COX-2 inhibitor NSAID (valdecoxib) that was subsequently withdrawn from the market dominates the evidence for this comparison (706 participants included in the analyses for pain, function and gastrointestinal adverse events), the applicability of these results is in doubt and we give only a brief summary. There was low quality evidence for a lack of clinically important differences between the two groups regarding pain at less than 24 hours, at days 4 to 6, and at day 7. Evidence from single studies showed a similar lack of difference between the two groups for swelling at day 3 (68 participants) and day 10 (84 participants). Return to function at day 7 or over favoured the NSAID group (low-quality), and there were fewer gastrointestinal adverse events in the selective COX-2 inhibitor NSAID group (very low quality). Four studies, involving 240 participants, compared NSAIDs with the combination of paracetamol and an opioid. The applicability of findings from these studies is partly in question because the dextropropoxyphene combination analgesic agents used are no longer in general use. While the point estimates favoured NSAID, the very low-quality evidence did not show a difference between the two interventions in the numbers with little or no pain at day 1 (51 participants, 1 study), day 3 (149 participants, 2 studies), or day 7 (138 participants, 2 studies). Very low-quality evidence showed a similar lack of difference between the two groups applied to swelling at day 3 (reported in two studies) and at day 7 (reported in two studies), in return to function at day 7 (89 participants, 1 study), and in gastrointestinal adverse events (141 participants, 3 studies). No studies compared NSAIDs with complementary and alternative medicines, and no study reported re-injury rates. There is generally low- or very low-quality but consistent evidence of no clinically important difference in analgesic efficacy between NSAIDs and other oral analgesics. There is low-quality evidence of more gastrointestinal adverse effects with non-selective NSAID compared with paracetamol. There is low- or very low-quality evidence of better function and fewer adverse events with NSAIDs compared with opioid-containing analgesics; however, one study dominated this evidence using a now unavailable COX-2 selective NSAID and is of uncertain applicability. Further research is required to determine whether there is any difference in return to function or adverse effects between both non-selective and COX-2 selective NSAIDs versus paracetamol.

The evidence available for most outcomes was either low or very low quality. This means that we are unsure of the reliability of these results. We found no evidence for an important difference between NSAIDs and paracetamol for people with strains, sprains and bruises for pain relief, swelling or return to function at seven days or over. However, there was some evidence that people treated with NSAIDs had slightly more side-effects related to the stomach or intestines. Although there was some evidence to suggest a greater return to function at seven days and fewer side-effects for people with sprains, strains and bruises using an NSAID compared with an opioid, we cannot say if this would apply to drugs that are currently available. This is because most of the evidence came from a study that tested an NSAID that is no longer on the market. We found no evidence for an important difference between NSAIDs and a combination of paracetamol and opioid for people with sprains, strains and bruises regarding pain relief, swelling, return to function at seven days or over, or gut-related side-effects. However, the combination painkiller used in the studies is not now in common use. This means that we cannot be sure that these results would currently apply. We found no studies comparing NSAIDs and complementary and alternative medicines. Also, no studies looked at the risk of re-injury after treatment. This review found low or very low-quality but consistent evidence showing no important difference between NSAIDs and paracetamol, opioids or a combination of paracetamol and opioid in pain or swelling after a soft tissue injury. There is low-quality evidence of more gut-related complications with NSAIDs compared with paracetamol. Although there is either low- or very low-quality evidence of better function and fewer adverse events with NSAIDs compared with opioid-containing analgesics, one study dominated this evidence using a now unavailable NSAID and is therefore of uncertain applicability. Further research is required to determine whether there is any difference in return to function or adverse effects between different types of NSAIDs versus paracetamol.

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We included 11 studies randomizing 4014 participants to molecular-targeted therapy plus conventional chemotherapy or chemotherapy alone. Five were at low risk of bias, and we considered the risk of bias in the other six studies to be high, mainly due to their open-label design. All identified studies reported data regarding survival. We found low-quality evidence that molecular-targeted may have a small effect on mortality (HR 0.92, 95% CI 0.80 to 1.05, 10 studies) compared with conventional chemotherapy alone. Similarly, it may have little effect on progression-free survival when compared with conventional chemotherapy alone (HR 0.90, 95% CI 0.78 to 1.04, 11 studies; low-quality evidence). We did not find evidence from subgroup analysis that survival outcomes differed by type of molecular-targeted agent (EGFR- or VEGF-targeting agents) or tumor type, meaning that we were unable to explain the variation in effect across the studies by the presence or absence of prognostic biomarkers or type of molecular-targeted agent. From 11 eligible trials, we were able to use data from 3723 participants with measurable tumors. We found low-quality evidence that molecular-targeted therapy may increase tumor response (OR 1.24, 95% CI 1.00 to 1.55, low-quality evidence). Data from one small trial were too limited to determine the effect of treatment on quality of life (very low-quality evidence). The addition of targeted therapy to chemotherapy probably increases the risk of adverse events (OR 2.23, 95% CI 1.27 to 3.92, 5 trials, 2290 participants, moderate-quality evidence) and severe adverse event (OR 1.19, 95% CI 1.03 to 1.37, 8 trials, 3800 participants), compared with receiving chemotherapy alone. There is uncertainty about the effect of adding targeted therapy to chemotherapy on survival outcomes in people with advanced gastric cancer, with very little information on its impact on quality of life. There is more certain evidence of increased risk of adverse events and serious adverse events. The main limitation of the evidence for survival outcomes was inconsistency of effects across the studies, which we could not explain by prespecified subgroups in terms of the type of therapy or tumor type. Ongoing studies in this area are small and unlikely to improve our understanding of the effects of targeted therapy, and larger studies are needed.

We searched databases until December 2015 for randomized controlled trials (clinical trials where people are randomly allocated to one of two or more treatment groups) in adults (aged 18 years or over), diagnosed with late-stage stomach cancer. We found 11 trials (4014 participants) that met our selection requirements and randomized people to receive targeted treatment plus chemotherapy or chemotherapy alone. Adding molecular-targeted treatment to chemotherapy may have a small effect on survival and on stopping further development of the disease, compared with chemotherapy alone, but the evidence is of low quality. The treatment may increase the likelihood that tumors get smaller (low-quality evidence), but there is insufficient evidence to know how much of a difference it can make to the person's quality of life (very low-quality evidence). It probably increases the risk of adverse events and serious adverse events (moderate-quality evidence). Currently, the evidence is of low quality for survival outcomes, mainly due to the type of study design, and the inconsistencies between the results of individual studies. We therefore suggest that well-designed clinical trials should be performed, to improve the evidence base.

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Twenty-five studies met our inclusion criteria (18 RCTs involving 64,852 participants and seven non-RCTs involving 62,294 participants). Meta-analysis of the RCTs found strong evidence of PPV efficacy against IPD with no statistical heterogeneity (OR 0.26, 95% CI 0.14 to 0.45; random-effects model, I2 statistic = 0%). There was efficacy against all-cause pneumonia in low-income (OR 0.54, 95% CI 0.43 to 0.67, I2 statistic = 19%) but not high-income countries in either the general population (OR 0.71, 95% CI 0.45 to 1.12, I2 statistic = 93%) or in adults with chronic illness (OR 0.93, 95% CI 0.73 to 1.19, I2 statistic = 10%). PPV was not associated with substantial reductions in all-cause mortality (OR 0.90, 95% CI 0.74 to 1.09; random-effects model, I2 statistic = 69%). Vaccine efficacy against primary outcomes appeared poorer in adults with chronic illness. Non-RCTs provided evidence for protection against IPD in populations for whom the vaccine is currently utilised (OR 0.48, 95% CI 0.37 to 0.61; random-effects model, I2 statistic = 31%). This review did not consider adverse events as it was outside the scope of the review. This meta-analysis provides evidence supporting the recommendation for PPV to prevent IPD in adults. The evidence from RCTs is less clear with respect to adults with chronic illness. This might be because of lack of effect or lack of power in the studies. The meta-analysis does not provide evidence to support the routine use of PPV to prevent all-cause pneumonia or mortality.

We found consistently strong evidence that the vaccine is effective in preventing the rarer outcome of invasive pneumococcal disease. Evidence from the included studies indicates vaccination might not afford as much protection in adults with chronic illness as it does for healthy adults. The available evidence does not demonstrate that pneumococcal polysaccharide vaccines prevent pneumonia (of all causes) or mortality in adults. This review did not consider adverse events as it was outside the scope of the study.

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Three RCTs met our inclusion criteria. The trials randomised 153 participants (74 participants to oral vitamin B12 and 79 participants to IM vitamin B12). Treatment duration and follow-up ranged between three and four months. The mean age of participants ranged from 38.6 to 72 years. The treatment frequency and daily dose of vitamin B12 in the oral and IM groups varied among trials. Only one trial had low or unclear risk of bias across all domains and outcome measures. Two trials reported data for serum vitamin B12 levels. The overall quality of evidence for this outcome was low due to serious imprecision (low number of trials and participants). In two trials employing 1000 μg/day oral vitamin B12, there was no clinically relevant difference in vitamin B12 levels when compared with IM vitamin B12. One trial used 2000 μg/day vitamin B12 and demonstrated a mean difference of 680 pg/mL (95% confidence interval 392.7 to 967.3) in favour of oral vitamin B12. Two trials reported data on adverse events (very low-quality evidence due to risk of performance bias, detection bias, and serious imprecision). One trial stated that no treatment-related adverse events were seen in both the oral and IM vitamin B12 groups. One trial reported that 2 of 30 participants (6.7%) in the oral vitamin B12 group left the trial early due to adverse events. Orally taken vitamin B12 showed lower treatment-associated costs than IM vitamin B12 in one trial (low-quality evidence due to serious imprecision). No trial reported on clinical signs and symptoms of vitamin B12 deficiency, health-related quality of life, or acceptability of the treatment scheme. Low quality evidence shows oral and IM vitamin B12 having similar effects in terms of normalising serum vitamin B12 levels, but oral treatment costs less. We found very low-quality evidence that oral vitamin B12 appears as safe as IM vitamin B12. Further trials should conduct better randomisation and blinding procedures, recruit more participants, and provide adequate reporting. Future trials should also measure important outcomes such as the clinical signs and symptoms of vitamin B12 deficiency, health related-quality of life, socioeconomic effects, and report adverse events adequately, preferably in a primary care setting.

We found three randomised controlled studies (clinical studies where people are randomly put into one of two or more treatment groups). The studies randomised 153 participants (74 participants to oral vitamin B12 and 79 participants to intramuscular vitamin B12). Treatment duration and follow-up ranged between three and four months. The mean age of participants ranged from 39 to 72 years. Two studies used 1000 μg/day oral vitamin B12 and showed no relevant difference to intramuscularly applied vitamin B12 with regard to vitamin B12 blood levels. One trial used 2000 μg/day vitamin B12 and showed higher vitamin B12 blood levels in favour of oral vitamin B12. Two studies reported side effects. One study stated that no treatment-related side effects were seen in both the oral and intramuscular vitamin B12 groups. One study reported that 2 of 30 participants in the oral vitamin B12 group left the trial early due to side effects. Orally taken vitamin B12 showed lower treatment-associated costs than intramuscular vitamin B12 in one trial. No study reported on clinical signs and symptoms of vitamin B12 deficiency (e.g. fatigue, depression, neurological complications), health-related quality of life, or acceptability of the treatment scheme. The overall quality of the evidence was low or very low, mainly due to the small number of included studies and the low numbers of participants in these studies.