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cochrane-simplification-train-800

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We included six RCTs (1539 participants) in this review. Trial sizes ranged from 50 to 703 participants. These six trials made four comparisons, namely: transparent dressings versus gauze; bordered transparent dressings versus a securement device; bordered transparent dressings versus tape; and transparent dressing versus sticking plaster. There is very low quality evidence of fewer catheter dislodgements or accidental removals with transparent dressings compared with gauze (two studies, 278 participants, RR 0.40; 95% CI 0.17 to 0.92, P = 0.03%). The relative effects of transparent dressings and gauze on phlebitis (RR 0.89; 95% CI 0.47 to 1.68) and infiltration (RR 0.80; 95% CI 0.48 to 1.33) are unclear. The relative effects on PVC failure of a bordered transparent dressing and a securement device have been assessed in only one small study and these were unclear. There was very low quality evidence from the same single study of less frequent dislodgement or accidental catheter removal with bordered transparent dressings than securement devices (RR 0.14, 95% CI 0.03 to 0.63) but more phlebitis with bordered dressings (RR 8.11, 95% CI 1.03 to 64.02) (very low quality evidence). A small single study compared bordered transparent dressings with tape and found very low quality evidence of more PVC failure with the bordered dressing (RR 1.84, 95% CI 1.08 to 3.11) but the relative effects on dislodgement were not clear (very low quality evidence). The relative effects of transparent dressings and a sticking plaster have only been compared in one small study and are unclear. More high quality RCTs are required to determine the relative effects of alternative PVC dressings and securement devices. It is not clear if any one dressing or securement device is better than any other in securing peripheral venous catheters. There is a need for further, independent high quality trials to evaluate the many traditional as well as the newer, high use products. Given the large cost differences between some different dressings and securement devices, future trials should include a robust cost-effectiveness analysis.

We searched the medical literature for studies that compared different types of products that are used to keep PVCs in place. We found six studies (involving 1539 participants) that compared four different ways of securing PVCs. These included: 1. a plain transparent film dressing compared with a gauze (woven fabric) dressing; 2. a bordered transparent dressing (clear transparent window with a reinforced fabric edge) compared with a securement device (that has anchor points or clips that hold the PVC in place over a strong adhesive base pad on the skin) that is used in conjunction with a transparent film dressing; 3. a bordered transparent dressing compared with non-sterile medical tape; 4. a plain transparent film dressing compared with sticking plaster. The participants in the studies were both adults and children on medical and surgical wards. There were no studies based in emergency departments. Two studies provided very low quality evidence that PVCs were less likely to fail when a transparent dressing was used rather than gauze. Other positive outcomes favouring one dressing over another were based on the results of very low quality, single studies. Overall there is a lack of high quality evidence and continued uncertainty regarding the best methods of securing a peripheral venous catheter remains. More high quality research is needed in this area. We assessed a number of quality indicators regarding the methods used in each study and graded the overall quality of studies as very low. Each study had a high or unclear risk of bias for some of the quality indicators. For example, it is likely that clinical staff responsible for assessing participants' outcomes knew the treatment group to which each person belonged, as the securement methods for PVCs looked different. There were only a limited number of studies available for consideration in this review, and they did not investigate some securement products that are in common use.

10.1002/14651858.CD011070.pub2

cochrane-simplification-train-801

cochrane-simplification-train-801

All four included studies were in Chinese; two of which were unpublished. Effect sizes were not clinically relevant and there was low quality evidence for all outcomes due to study limitations and sparse data (single studies). Two trials (680 participants) found that Compound Qishe Tablets relieved pain better in the short-term than either placebo or Jingfukang; one trial (60 participants) found than an oral herbal formula of Huangqi ((Radix Astragali)18 g, Dangshen (Radix Codonopsis) 9 g, Sanqi (Radix Notoginseng) 9 g, Chuanxiong (Rhizoma Chuanxiong)12 g, Lujiao (Cornu Cervi Pantotrichum) 12 g, and Zhimu (Rhizoma Anemarrhenae)12 g) relieved pain better than Mobicox or Methycobal and one trial (360 participants) showed that a topical herbal medicine, Compound Extractum Nucis Vomicae, relieved pain better than Diclofenac Diethylamine Emulgel. There is low quality evidence that an oral herbal medication, Compound Qishe Tablet, reduced pain more than placebo or Jingfukang and a topical herbal medicine, Compound Extractum Nucis Vomicae, reduced pain more than Diclofenac Diethylamine Emulgel. Further research is very likely to change both the effect size and our confidence in the results.

Oral herbal medications may reduce neck pain more than placebo and Jingfukang. A topical herbal medicine (Compound Extractum Nucis Vomicae) also relieved neck pain in the short term (four weeks), but the trail had a high risk of bias. All four included studies were in Chinese and two of these studies were unpublished. Half of the trials had a low risk of bias, but they only tested the effects of short term use (up to eight weeks). The size of the studies was small. There is a need for trials with adequate numbers of participants that address the long-term efficacy or effectiveness of Chinese herbal medicine compared to placebo. For chronic neck pain with or without radicular symptoms, there is low quality evidence that Compound Qishe Tablet is more effective than placebo for pain relief, measured at the end of the treatment. However, the size of the studies was small and the effect was measured in the short-term. Further research is very likely to change both the effect size and our confidence in the results. There is a need for trials with adequate numbers of participants that address long-term efficacy or effectiveness of herbal medicine compared to placebo.

10.1002/14651858.CD006556.pub2

cochrane-simplification-train-802

cochrane-simplification-train-802

We identified 14 RCTs (2616 participants); nine studies were multi-centre and two studies involved children. The risk of bias was high in most studies; only three studies demonstrated adequate random sequence generation and only two studies were at low risk of bias for allocation concealment. Blinding of participants and personnel was at low risk of bias in one study. Blinding of outcome assessment was judged at low risk in 13 studies as the outcome measures were reported as laboratory results and therefore unlikely to be influenced by blinding. Attrition bias was at low risk of bias in eight studies while selective reporting was at low risk in six included studies. Four interventions were compared: epoetin alpha or beta at different frequencies using the same total dose (six studies); epoetin alpha at the same frequency and different total doses (two studies); epoetin alpha administered intravenously versus subcutaneous administration (one study); epoetin alpha or beta versus other epoetins or biosimilars (five studies). One study compared both different frequencies of epoetin alpha at the same total dose and at the same frequency using different total doses. Data from only 7/14 studies could be included in our meta-analyses. There were no significant differences in final haemoglobin (Hb) levels when dosing every two weeks was compared with weekly dosing (4 studies, 785 participants: MD -0.20 g/dL, 95% CI -0.33 to -0.07), when four weekly dosing was compared with two weekly dosing (three studies, 671 participants: MD -0.16 g/dL, 95% CI -0.43 to 0.10) or when different total doses were administered at the same frequency (four weekly administration: one study, 144 participants: MD 0.17 g/dL 95% CI -0.19 to 0.53). Five studies evaluated different interventions. One study compared epoetin theta with epoetin alpha and found no significant differences in Hb levels (288 participants: MD -0.02 g/dL, 95% CI -0.25 to 0.21). One study found significantly higher pain scores with subcutaneous epoetin alpha compared with epoetin beta. Two studies (165 participants) compared epoetin delta with epoetin alpha, with no results available since the pharmaceutical company withdrew epoetin delta for commercial reasons. The fifth study comparing the biosimilar HX575 with epoetin alpha was stopped after patients receiving HX575 subcutaneously developed anti-epoetin antibodies and no results were available. Adverse events were poorly reported in all studies and did not differ significantly within comparisons. Mortality was only detailed adequately in four studies and only one study included quality of life data. Epoetin alpha given at higher doses for extended intervals (two or four weekly) is non-inferior to more frequent dosing intervals in maintaining final Hb levels with no significant differences in adverse effects in non-dialysed CKD patients. However the data are of low methodological quality so that differences in efficacy and safety cannot be excluded. Further large, well designed, RCTs with patient-centred outcomes are required to assess the safety and efficacy of large doses of the shorter acting ESAs, including biosimilars of epoetin alpha, administered less frequently compared with more frequent administration of smaller doses in children and adults with CKD not on dialysis.

We examined the evidence from 14 studies with 2616 participants with CKD not receiving dialysis published before 12 September 2016 to determine whether differences in improvement in anaemia and in side effects existed between different short-acting epoetins or between the same epoetins given at different frequencies. We did not find any studies using different frequencies of epoetins in children. We found that the traditionally shorter acting epoetins given less often (two weekly to every four weeks) resulted in similar correction of anaemia compared with administration every week or every two weeks; there were no differences in side effects between the different comparisons. One study comparing subcutaneous administration of a newly manufactured HX575 epoetin alpha compared with epoetin alpha was discontinued after two patients developed anti-erythropoietin antibodies. However more studies are required as most studies were small and poorly designed, which limits their application to the care of patients.

10.1002/14651858.CD011690.pub2

cochrane-simplification-train-803

cochrane-simplification-train-803

Four RCTs (307 participants) were included. Two studies compared clinical homeopathy (homeopathic remedy, asafoetida or asafoetida plus nux vomica) to placebo for IBS with constipation (IBS-C). One study compared individualised homeopathic treatment (consultation plus remedy) to usual care for the treatment of IBS in female patients. One study was a three armed RCT comparing individualised homeopathic treatment to supportive listening or usual care. The risk of bias in three studies (the two studies assessing clinical homeopathy and the study comparing individualised homeopathic treatment to usual care) was unclear on most criteria and high for selective reporting in one of the clinical homeopathy studies. The three armed study comparing individualised homeopathic treatment to usual care and supportive listening was at low risk of bias in four of the domains and high risk of bias in two (performance bias and detection bias). A meta-analysis of the studies assessing clinical homeopathy, (171 participants with IBS-C) was conducted. At short-term follow-up of two weeks, global improvement in symptoms was experienced by 73% (46/63) of asafoetida participants compared to 45% (30/66) of placebo participants (RR 1.61, 95% CI 1.18 to 2.18; 2 studies, very low certainty evidence). In the other clinical homeopathy study at two weeks, 68% (13/19) of those in the asafoetida plus nux vomica arm and 52% (12/23) of those in the placebo arm experienced a global improvement in symptoms (RR 1.31, 95% CI 0.80 to 2.15; very low certainty evidence). In the study comparing individualised homeopathic treatment to usual care (N = 20), the mean global improvement score (feeling unwell) at 12 weeks was 1.44 + 4.55 (n = 9) in the individualised homeopathic treatment arm compared to 1.41 + 1.97 (n=11) in the usual care arm (MD 0.03; 95% CI -3.16 to 3.22; very low certainty evidence). In the study comparing individualised homeopathic treatment to usual care, the mean IBS symptom severity score at 6 months was 210.44 + 112.4 (n = 16) in the individualised homeopathic treatment arm compared to 237.3 + 110.22 (n = 60) in the usual care arm (MD -26.86, 95% CI -88.59 to 34.87; low certainty evidence). The mean quality of life score (EQ-5D) at 6 months in homeopathy participants was 69.07 (SD 17.35) compared to 63.41 (SD 23.31) in usual care participants (MD 5.66, 95% CI -4.69 to 16.01; low certainty evidence). For In the study comparing individualised homeopathic treatment to supportive listening, the mean IBS symptom severity score at 6 months was 210.44 + 112.4 (n = 16) in the individualised homeopathic treatment arm compared to 262 + 120.72 (n = 18) in the supportive listening arm (MD -51.56, 95% CI -129.94 to 26.82; very low certainty evidence). The mean quality of life score at 6 months in homeopathy participants was 69.07 (SD 17.35) compared to 63.09 (SD 24.38) in supportive listening participants (MD 5.98, 95% CI -8.13 to 20.09; very low certainty evidence). None of the included studies reported on abdominal pain, stool frequency, stool consistency, or adverse events. The results for the outcomes assessed in this review are uncertain. Thus no firm conclusions regarding the effectiveness and safety of homeopathy for the treatment of IBS can be drawn. Further high quality, adequately powered RCTs are required to assess the efficacy and safety of clinical and individualised homeopathy for IBS compared to placebo or usual care.

Four randomised controlled trials (RCTs) with 307 participants with IBS were included. Two RCTs (129 participants) compared a homeopathic remedy (asafoetida and asafoetida plus nux vomica) to a placebo remedy for the treatment of people with IBS-C. One study (23 participants) compared individualised homeopathic treatment to usual care in female patients diagnosed with IBS. One study (94 participants) was a three armed study comparing individualised homeopathic treatment plus usual care, supportive listening plus usual care and usual care. The four trials tested the effects of homeopathic treatment on the severity of IBS symptoms. No conclusions can be drawn from the RCT comparing individualised homeopathic treatment to usual care due to the small number of participants and the low quality of reporting in this trial. This study was carried out in 1990 and usual care for IBS may have changed since then making the results difficult to compare to current treatments. No conclusions can be drawn from the three armed study comparing individualised homeopathic treatment plus usual care, supportive listening plus usual care and usual care due to the small number of participants in the homeopathic treatment arm (n=16). The results of two small studies were combined (129 participants) and this suggested that there may be a possible benefit for clinical homeopathy, using the remedy asafoetida, over placebo for patients with IBS-C at a short-term follow-up of two weeks. However both of the studies were carried out in the 1970s when the reporting of trials was not as comprehensive as it is now and we are very uncertain about these results and cannot suggest a possible benefit for clinical homeopathy. The results for the outcomes assessed in this review are uncertain. Thus no firm conclusions regarding the effectiveness and safety of homeopathy for the treatment of IBS can be drawn. Further high quality RCTs enrolling larger numbers of patients are required to assess the effectiveness and safety of clinical and individualised homeopathy for IBS.

10.1002/14651858.CD009710.pub3

cochrane-simplification-train-804

cochrane-simplification-train-804

We included seven randomised clinical trials. None of them had high quality. Plasma vaccine was significantly more effective than placebo in achieving hepatitis B antibodies (RR 23.0, 95% CI 14.39 to 36.76, 3 trials). We found no statistically significant difference between plasma vaccine or placebo regarding hepatitis B virus infections (RR 0.50, 95% CI 0.20 to 1.24). We found no statistically significant differences between recombinant vaccine and plasma vaccine in achieving hepatitis B antibodies (RR 0.65, 95% CI 0.28 to 1.53, 2 trials). Heterogeneity was significant and appeared to be attributable to the dose of vaccine. Two trials examined a reinforced recombinant vaccine strategy, which was not statistically more effective than three inoculations of recombinant vaccine regarding development of hepatitis B antibodies (RR 1.36, 95% CI 0.85 to 2.16). Plasma derived vaccines are more effective than placebo in achieving hepatitis B antibodies, while no statistically significant difference was found between recombinant and plasma vaccines. No statistically significant difference of effectiveness was observed between a reinforced vaccination series versus routine vaccinations of three inoculations of recombinant vaccine.

This review was undertaken to determine the beneficial and harmful effects of vaccination against hepatitis B and of a reinforced recombinant vaccination series. None of the trials had high methodological quality. Plasma vaccine was significantly more effective than placebo in achieving hepatitis B antibodies. Yet no statistically significant difference was found between the use of plasma vaccine or placebo in preventing hepatitis B virus infections. No trials comparing recombinant vaccine with placebo were identified. There was no significant difference between recombinant and plasma vaccines or between a reinforced vaccination series and routine vaccinations of three inoculations using recombinant vaccine regarding achieving hepatitis B antibodies.

10.1002/14651858.CD003775.pub2

cochrane-simplification-train-805

cochrane-simplification-train-805

The review includes 16 studies (eight new studies included in this update) representing data from 556 participants. Studies are diverse in their design and their methods. They cover interventions with generic approaches, as well as interventions developed specifically to target disease-specific symptoms and problems in people with cystic fibrosis. These include cognitive behavioural interventions to improve adherence to nutrition or psychosocial adjustment, cognitive interventions to improve adherence or those associated with decision making in lung transplantation, a community-based support intervention and other interventions, such as self-hypnosis, respiratory muscle biofeedback, music therapy, dance and movement therapy, and a tele-medicine intervention to support patients awaiting transplantation. A substantial proportion of outcomes relate to adherence, changes in physical status or other specific treatment concerns during the chronic phase of the disease. There is some evidence that behavioural interventions targeting nutrition and growth in children (4 to 12 years) with cystic fibrosis are effective in the short term. Evidence was found that providing a structured decision-making tool for patients considering lung transplantation improves patients' knowledge of and expectations about the transplant, and reduces decisional conflict in the short term. One study about training in biofeedback-assisted breathing demonstrated some evidence that it improved some lung function measurements. Currently there is insufficient evidence for interventions aimed at other aspects of the disease process. Currently, insufficient evidence exists on psychological interventions or approaches to support people with cystic fibrosis and their caregivers, although some of the studies were promising. Due to the heterogeneity between studies, more of each type of intervention are needed to support preliminary evidence. Multicentre studies, with consequent funding implications, are needed to increase the sample size of these studies and enhance the statistical power and precision to detect important findings. In addition, multicentre studies could improve the generalisation of results by minimizing centre or therapist effects. Psychological interventions should be targeted to illness-specific symptoms or behaviours to demonstrate efficacy.

We looked for studies of psychological treatments in individuals of all ages with cystic fibrosis and their families which aimed to reduce anxiety and depression, to improve adjustment, quality of life, and even medical outcomes, as well as knowledge, skills, and decisions regarding care. The review includes 16 studies with a total of 556 participants. Even though there many different psychological interventions, only a few have been evaluated for individuals with CF and their families. Due to the lack of high quality studies, it is not possible to currently show which psychological treatments are most helpful to those with cystic fibrosis and their caregivers. Five out of the 16 studies we found evaluated behavioural interventions to improve dietary intake. We found that in children aged 4 to 12 years receiving a nutritional intervention plus behavioural management training, consumed about 276 per day more than children just receiving the nutritional intervention. We also found that a structured decision-making tool for adults considering lung transplantation improved their knowledge, assisted in setting realistic expectations, and reduced indecision. In summary, there is some evidence that behavioural interventions targeting specific illness-related symptoms and behaviours can work. More studies on psychological interventions with more people are urgently needed. There are several ongoing randomised controlled studies aimed at improving adherence to prescribed treatments, but final results are not yet available. We recommend multicentre studies to provide evidence for which interventions are most effective for the key issues faced by people with cystic fibrosis and their caregivers.

10.1002/14651858.CD003148.pub3

cochrane-simplification-train-806

cochrane-simplification-train-806

We included 12 trials involving 478 individuals. A number of trials showed a high risk of bias and others an unclear risk of bias due to poor reporting. The quality of the evidence was 'low' for most of the outcomes and 'moderate' for hand function, according to the GRADE system. In most of the studies, AO was followed by some form of physical activity. Primary outcome: the impact of AO on arm function showed a small significant effect (standardized mean difference (SMD) 0.36, 95% CI 0.13 to 0.60; 8 studies; 314 participants; low-quality evidence); and a large significant effect (mean difference (MD) 2.90, 95% CI 1.13 to 4.66; 3 studies; 132 participants; moderate-quality evidence) on hand function. Secondary outcomes: there was a large significant effect for ADL outcome (SMD 0.86, 95% CI 0.11 to 1.61; 4 studies, 226 participants; low-quality evidence). We were unable to pool other secondary outcomes to extract the evidence. Only two studies reported adverse effects without significant adverse AO events. We found evidence that AO is beneficial in improving upper limb motor function and dependence in activities of daily living (ADL) in people with stroke, when compared with any control group; however, we considered the quality of the evidence to be low. We considered the effect of AO on hand function to be large, but it does not appear to be clinically relevant, although we considered the quality of the evidence as moderate. As such, our confidence in the effect estimate is limited because it will likely change with future research.

We identified 12 studies involving 478 individuals after stroke. Most used video sequences and AO followed by some form of physical activity, using a range of activities, with task complexity increased over the course of training or when it was easy for the participant to carry out. The evidence is current to October 2017. Studies tested whether the use of AO compared with an alternative intervention or no intervention resulted in participants' improved ability to use their arms and hands, and found that AO therapy resulted in better arm (eight trials) and hand function (three trials). We classified the quality of the evidence as moderate for hand function, low for arm function and dependence on activities of daily living, and very low for motor performance and quality of life. Participants could engage in AO safely, since adverse events were not significant in scale or magnitude. The quality of the evidence for each outcome was limited due to the small number of study participants, low study quality, and poor reporting of study details.

10.1002/14651858.CD011887.pub2

cochrane-simplification-train-807

cochrane-simplification-train-807

72 RCTs met our inclusion criteria. The methodological quality of included studies varied. An organized system of regular review allied to vigorous antihypertensive drug therapy was shown to reduce systolic blood pressure (weighted mean difference (WMD) -8.0 mmHg, 95% CI: -8.8 to -7.2 mmHg) and diastolic blood pressure (WMD -4.3 mmHg, 95% CI: -4.7 to -3.9 mmHg) for three strata of entry blood pressure, and all-cause mortality at five years follow-up (6.4% versus 7.8%, difference 1.4%) in a single large RCT- the Hypertension Detection and Follow-Up study. Other interventions had variable effects. Self-monitoring was associated with moderate net reduction in systolic blood pressure (WMD -2.5 mmHg, 95% CI: -3.7 to -1.3 mmHg) and diastolic blood pressure (WMD -1.8 mmHg, 95% CI: -2.4 to -1.2 mmHg). RCTs of educational interventions directed at patients or health professionals were heterogeneous but appeared unlikely to be associated with large net reductions in blood pressure by themselves. Nurse or pharmacist led care may be a promising way forward, with the majority of RCTs being associated with improved blood pressure control and mean SBP and DBP but these interventions require further evaluation. Appointment reminder systems also require further evaluation due to heterogeneity and small trial numbers, but the majority of trials increased the proportion of individuals who attended for follow-up (odds ratio 0.41, 95% CI 0.32 to 0.51) and in two small trials also led to improved blood pressure control, odds ratio favouring intervention 0.54 (95% CI 0.41 to 0.73). Family practices and community-based clinics need to have an organized system of regular follow-up and review of their hypertensive patients. Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target blood pressure levels. Self-monitoring and appointment reminders may be useful adjuncts to the above strategies to improve blood pressure control but require further evaluation.

Seventy two randomised controlled trials met our inclusion criteria. The range of interventions used included (1) self-monitoring, (2) educational interventions directed to the patient, (3) educational interventions directed to the health professional, (4) health professional (nurse or pharmacist) led care, (5) organizational interventions that aimed to improve the delivery of care, (6) appointment reminder systems. The trials showed a wide variety of methodological quality, part of which may be attributed to poor reporting. An organized system of regular review allied to vigorous antihypertensive drug therapy was shown to reduce blood pressure and all-cause mortality in a single large RCT- the Hypertension Detection and Follow-Up study. Other interventions had variable effects. Weighted data analysis showed that self-monitoring was associated with moderate net reductions in systolic blood pressure (weighted mean difference -2.5 mmHg, 95% CI: -3.7 to -1.3 mmHg) and diastolic blood pressure (weighted mean difference -1.8 mmHg, 95% CI: -2.4 to -1.2 mmHg). Trials of educational interventions directed at patients or health professionals were heterogeneous but appeared unlikely to be associated with large net reductions in blood pressure by themselves. Nurse or pharmacist led care may be a promising way of improving control in patients with hypertension, with the majority of RCTs being associated with improved blood pressure control, improved systolic blood pressure and more modestly improved diastolic blood pressure, but these interventions require further evaluation. Appointment reminder systems increased the proportion of individuals who attended for follow-up (absolute difference 16%, but this pooled result should be treated with caution because of the heterogeneous results from individual RCTs) and in two small trials also led to improved blood pressure control, odds ratio favouring intervention 0.54 (95% CI 0.41 to 0.73). We conclude that an organized system of registration, recall and regular review allied to a vigorous stepped care approach to antihypertensive drug treatment appears the most likely way to improve the control of high blood pressure. Health professional (nurse or pharmacist) led care and appointment reminder systems requires further evaluation. Education alone, either to health professionals or patients, does not appear to be associated with large net reductions in blood pressure.

10.1002/14651858.CD005182.pub4

cochrane-simplification-train-808

cochrane-simplification-train-808

We included 28 trials with 8487 participants on five SGAs: amisulpride, aripiprazole, olanzapine, quetiapine and risperidone. Three studies (1092 participants) provided data on aripiprazole augmentation in MDD. All efficacy data (response n = 1092, three RCTs, OR 0.48; 95% CI 0.37 to 0.63), (MADRS n = 1077, three RCTs, MD -3.04; 95% CI -4.09 to -2) indicated a benefit for aripiprazole but  more side effects (weight gain, EPS) . Seven trials (1754 participants) reported data on olanzapine. Compared to placebo fewer people discontinued treatment due to inefficacy; compared to antidepressants there were no efficacy differences, olanzapine augmentation showed symptom reduction (MADRS n = 808, five RCTs, MD -2.84; 95% CI -5.48 to -0.20), but also more weight or prolactin increase. Quetiapine data are based on seven trials (3414 participants). Compared to placebo, quetiapine monotherapy (response n = 1342, three RCTs, OR 0.52; 95% CI 0.41 to 0.66) and quetiapine augmentation (response n = 937, two RCTs, OR 0.68; 95% CI 0.52 to 0.90) showed symptom reduction, but quetiapine induced more sedation. Four trials (637 participants) presented data on risperidone augmentation, response data were better for risperidone (n = 371, two RCTs, OR 0.57; 95% CI 0.36 to 0.89) but augmentation showed more prolactin increase and weight gain. Five studies (1313 participants) presented data on amisulpride treatment for dysthymia. There were some beneficial effects compared to placebo or antidepressants but tolerability was worse. Quetiapine was more effective than placebo treatment. Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo. Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people. Most SGAs showed worse tolerability.

This review found 28 studies on five second-generation antipsychotic drugs (amisulpride, aripiprazole, olanzapine, quetiapine and risperidone) comparing the effects of the drugs alone or adding them or placebo to antidepressants for major depressive disorder and dysthymia. There is evidence that amisulpride might lead to symptom reduction in dysthymia, while no important differences were seen for major depression. There is limited evidence that aripiprazole leads to symptom reduction when added to antidepressants. Olanzapine had no beneficial effects for treatment of depression when compared to antidepressants or compared to placebo but there was limited evidence for the benefits of olanzapine as additional treatment. Data on quetiapine indicated beneficial effects for quetiapine alone or as additional treatment when compared to placebo; data on quetiapine versus duloxetine did not show beneficial effects in terms of symptom reduction for either group, but quetiapine treatment was less well tolerated. The data, however, are very limited. Slight benefits of risperidone as additional treatment, in terms of symptom reduction, are also based on a rather small number of randomised participants. Generally, treatment with second-generation antipsychotic drugs was associated with worse tolerability, mainly due to sedation, weight gain or laboratory values such as prolactin increase.

10.1002/14651858.CD008121.pub2

cochrane-simplification-train-809

cochrane-simplification-train-809

We included 15 studies, of which two were at low risk of bias, seven were at high risk of bias and six were unclear. Fixed appliances with mid-palatal expansion Nine studies tested fixed appliances with mid-palatal expansion against each other. No study reported a difference between any type of appliance. Fixed versus removable appliances Fixed quad-helix appliances may be 20% more likely to correct crossbites than removable expansion plates (RR 1.20; 95% CI 1.04 to 1.37; two studies; 96 participants; low-quality evidence). Quad-helix appliances may achieve 1.15 mm more molar expansion than expansion plates (MD 1.15 mm; 95% CI 0.40 to 1.90; two studies; 96 participants; moderate-quality evidence). There was insufficient evidence of a difference in canine expansion or the stability of crossbite correction. Very limited evidence showed that both fixed quad-helix appliances and removable expansion plates were superior to composite onlays in terms of crossbite correction, molar and canine expansion. Other comparisons Very limited evidence showed that treatments were superior to no treatment, but there was insufficient evidence of a difference between any active treatments. There is a very small body of low- to moderate-quality evidence to suggest that the quad-helix appliance may be more successful than removable expansion plates at correcting posterior crossbites and expanding the inter-molar width for children in the early mixed dentition (aged eight to 10 years). The remaining evidence we found was of very low quality and was insufficient to allow the conclusion that any one intervention is better than another for any of the outcomes in this review.

Authors from the Cochrane Oral Health Group carried out this review update of existing studies and the evidence is current up to 21 January 2014. It includes 15 studies published from 1984 to 2013. Nine of these studies compared fixed (always in the mouth) appliances either against different fixed appliances, or against the same fixed appliance but comparing different rates of expansion. Two studies compared a fixed appliance with a removable appliance. The remaining four studies evaluated other comparisons that were more difficult to classify. There is some evidence to suggest that the quad-helix (fixed) appliance may be more successful than removable expansion plates at correcting posterior crossbites and expanding the top back teeth for children with a mixture of baby and adult teeth (aged eight to 10 years). The remaining evidence we found did not allow the conclusion that any one treatment is better than another. The evidence presented is mostly of low to very low quality due to the small amount of available studies and issues with the way in which they were conducted.

10.1002/14651858.CD000979.pub2

cochrane-simplification-train-810

cochrane-simplification-train-810

Three trials (of poor methodological quality) met the inclusion criteria. Complete remission of haemorrhoidal symptom was better with excisional haemorrhoidectomy (EH) (three studies, 202 patients, RR 1.68, 95% CI 1.00 to 2.83). There was significant heterogeneity between the studies (I2 = 90.5%; P = 0.0001). Similar analysis based on the grading of haemorrhoids revealed the superiority of EH over RBL for grade III haemorrhoids (prolapse that needs manual reduction) (two trials, 116 patients, RR 1.23, CI 1.04 to 1.45; P = 0.01). However, no significant difference was noticed in grade II haemorrhoids (prolapse that reduces spontaneously on cessation of straining) (one trial, 32 patients, RR 1.07, CI 0.94 to 1.21; P = 0.32) Fewer patients required re-treatment after EH (three trials, RR 0.20 CI 0.09 to 0.40; P < 0.00001). Patients undergoing EH were at significantly higher risk of postoperative pain (three trials, fixed effect; 212 patients, RR 1.94, 95% CI 1.62 to 2.33, P < 0.00001). The overall delayed complication rate showed significant difference (P = 0.03) (three trials, 204 patients, RR 6.32, CI 1.15 to 34.89) between the two interventions. The present systematic review confirms the long-term efficacy of EH, at least for grade III haemorrhoids, compared to the less invasive technique of RBL but at the expense of increased pain, higher complications and more time off work. However, despite these disadvantages of EH, patient satisfaction and patient's acceptance of the treatment modalities seems to be similar following both the techniques implying patient's preference for complete long-term cure of symptoms and possibly less concern for minor complications. So, RBL can be adopted as the choice of treatment for grade II haemorrhoids with similar results but with out the side effects of EH while reserving EH for grade III haemorrhoids or recurrence after RBL. More robust study is required to make definitive conclusions. One additional study was identified from the updated search (Ali 2005). However, after careful review and discussion among the authors, it was decided that this study did not meet the necessary criteria for including in the analysis. Hence, the results and conclusion remains the same.

This review is based upon three randomised controlled trials comparing RBL with EH, with a total of 216 patients. The trials showed that with EH, haemorrhoids did not come back as often as with RBL. EH was better for advanced haemorrhoids, known as grade III haemorrhoids. For less severe grade II haemorrhoids, RBL and EH were equally effective. EH caused more pain after the procedure, more minor complications, and required more time off work. Patient satisfaction was similar for both treatments. This review has been up dated as of October 2010 and the search was carried out with previously used search strategy to identify any possible new randomised controlled study to include in the statistics. Only one additional paper was identified with a potential possibility to include in the study (Ali 2005). However, after a combined common decision from all the authors, it was decided to exclude the paper for the statistics because of the poor data presentation and randomisation method. After up to date search, the conclusion has not changed and the review authors conclude that RBL should be the primary treatment used for grade II haemorrhoids, and EH reserved for patients who failed after repeated RBL or grade III haemorrhoids. They recommend more research be done comparing these techniques with the many newer ones, especially stapled haemorrhoidopexy, to determine which treatment is best.

10.1002/14651858.CD005034.pub2

cochrane-simplification-train-811

cochrane-simplification-train-811

Six studies met the inclusion criteria. One trial compared vas occlusion with clips versus a conventional vasectomy technique. No difference was found in failure to reach azoospermia (no sperm detected). Three trials examined vasectomy with vas irrigation. Two studies looked at irrigation with water versus no irrigation, while one examined irrigation with water versus the spermicide euflavine. None found a difference between the groups for time to azoospermia. However, one trial reported that the median number of ejaculations to azoospermia was lower in the euflavine group compared to the water irrigation group. One high-quality trial compared vasectomy with fascial interposition versus vasectomy without fascial interposition. The fascial interposition group was less likely to have vasectomy failure. Fascial interposition had more surgical difficulties, but the groups were similar in side effects. Lastly, one trial found that an intra-vas was less likely to produce azoospermia than was no-scalpel vasectomy. More men were satisfied with the intra-vas device, however. For vas occlusion with clips or vasectomy with vas irrigation, no conclusions can be made as those studies were of low quality and underpowered. Fascial interposition reduced vasectomy failure. An intra-vas device was less effective in reducing sperm count than was no-scalpel vasectomy. RCTs examining other vasectomy techniques were not available. More and better quality research is needed to examine vasectomy techniques.

In February 2014, we updated the computer searches for studies of vasectomy methods. For the initial review, we also looked at reference lists of articles and book chapters. We included randomized controlled trials in any language. We found six studies. One trial compared closing the vas with clips versus the usual cutting of the vas. The groups did not differ in reaching a low sperm count or in side effects. Three trials looked at flushing fluids through the vas: two compared vasectomy with water flushing versus vasectomy alone, and one compared using water versus euflavine (which kills sperm). None found a difference between the groups in time to low sperm count. However, one trial found that the usual number of ejaculations before low sperm count was lower with euflavine than with water. One trial that compared vasectomy with and without fascial interposition was a high-quality large study. The fascial interposition group was less likely to have vasectomy failure. However, the surgery was more difficult. Side effects were about the same in the two groups. Lastly, one trial looked at a device placed into the vas versus vasectomy without a scalpel. The intra-vas device did not work as well for reaching a low sperm count but more men liked the method. Most of the studies that looked at vasectomy methods were small, not done well, or had poor reports. Therefore, we cannot say if the methods work well, are safe or are liked by men. Vasectomy with fascial interposition worked better than simply cutting and tying the vas, but the surgery was more difficult. More and better research is needed on vasectomy methods.

10.1002/14651858.CD003991.pub4

cochrane-simplification-train-812

cochrane-simplification-train-812

This review included two trials, involving 103 participants, one comparing titanium with resorbable plates and screws and the other titanium with resorbable screws. Both studies were at high risk of bias and provided very limited data for the primary outcomes of this review. All participants in one trial suffered mild to moderate postoperative discomfort with no statistically significant difference between the two plating groups at different follow-up times. Mean scores of patient satisfaction were 7.43 to 8.63 (range 0 to 10) with no statistically significant difference between the two groups throughout follow-up. Adverse effects reported in one study were two plate exposures in each group occurring between the third and ninth months. Plate exposures occurred mainly in the posterior maxillary region, except for one titanium plate exposure in the mandibular premolar region. Known causes of infection were associated with loosened screws and wound dehiscence with no statistically significant difference in the infection rate between titanium (3/196), and resorbable (3/165) plates. We do not have sufficient evidence to determine if titanium plates or resorbable plates are superior for fixation of bones after orthognathic surgery. This review provides insufficient evidence to show any difference in postoperative pain and discomfort, level of patient satisfaction, plate exposure or infection for plate and screw fixation using either titanium or resorbable materials.

We included two studies that analysed a total of 103 participants. The evidence in this review is up to date as of 20 January 2017. Study participants were adults older than 16 years of age. One study compared titanium with resorbable plates and screws and the other titanium with resorbable screws. One study was conducted in China, the other in Germany. Both studies were at high risk of bias and provided very limited data. We do not have sufficient evidence to determine if titanium plates or resorbable plates are superior for the fixation of bones after corrective jaw surgery. This review provides insufficient evidence to show any difference in postoperative pain and discomfort, level of patient satisfaction, plate exposure or infection for plate and screw fixation using either titanium or resorbable materials. Both included studies were assessed as being at high risk of bias and the very limited and weak evidence was of very low quality.

10.1002/14651858.CD006204.pub3

cochrane-simplification-train-813

cochrane-simplification-train-813

Ninety two trials evaluated the dose-related trough BP lowering efficacy of 14 different ACE inhibitors in 12 954 participants with a baseline BP of 157/101 mm Hg. The data do not suggest that any one ACE inhibitor is better or worse at lowering BP. A dose of 1/8 or 1/4 of the manufacturer's maximum recommended daily dose (Max) achieved a BP lowering effect that was 60 to 70% of the BP lowering effect of Max. A dose of 1/2 Max achieved a BP lowering effect that was 90% of Max. ACE inhibitor doses above Max did not significantly lower BP more than Max. Combining the effects of 1/2 Max and higher doses gives an estimate of the average trough BP lowering efficacy for ACE inhibitors as a class of drugs of -8 mm Hg for SBP and -5 mm Hg for DBP. ACE inhibitors reduced BP measured 1 to 12 hours after the dose by about 11/6 mm Hg. There are no clinically meaningful BP lowering differences between different ACE inhibitors. The BP lowering effect of ACE inhibitors is modest; the magnitude of trough BP lowering at one-half the manufacturers' maximum recommended dose and above is -8/-5 mm Hg. Furthermore, 60 to 70% of this trough BP lowering effect occurs with recommended starting doses. The review did not provide a good estimate of the incidence of harms associated with ACE inhibitors because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.

We found 92 trials that randomly assigned participants to take either an ACE inhibitor or an inert substance (placebo). These trials evaluated the blood pressure lowering ability of 14 different ACE inhibitors in 12 954 participants. The trials followed participants for approximately 6 weeks (though people are typically expected to take anti-hypertension drugs for the rest of their lives). The blood pressure lowering effect was modest.  There was an 8-point reduction in the upper number that signifies the systolic pressure and a 5-point reduction in the lower number that signifies the diastolic pressure.  Most of the blood pressure lowering effect (about 70%) can be achieved with the lowest recommended dose of the drugs.  No ACE inhibitor drug appears to be any better or worse than others in terms of blood pressure lowering ability. Most of the trials in this review were funded by companies that make ACE inhibitors and serious adverse effects were not reported by the authors of many of these trials.  This could mean that the drug companies are withholding unfavorable findings related to their drugs.  Due to incomplete reporting of  the number of participants who dropped out of the trials due to adverse drug reactions, as well as the short duration of these trials, this review could not provide a good estimate of the harms associated with this class of drugs.  Prescribing the least expensive ACE inhibitor in lower doses will lead to substantial cost savings, and possibly a reduction in dose-related adverse events.

10.1002/14651858.CD003823.pub2

cochrane-simplification-train-814

cochrane-simplification-train-814

No new trials were included in this 2014 update. We included six studies: two prophylaxis trials (327 young to middle-aged adults in Russia) and four treatment trials (1196 teenagers and adults in France and Germany). The overall standard of trial reporting was poor and hence many important methodological aspects of the trials had unclear risk of bias. There was no statistically significant difference between the effects of Oscillococcinum® and placebo in the prevention of influenza-like illness: risk ratio (RR) 0.48, 95% confidence interval (CI) 0.17 to 1.34, P value = 0.16. Two treatment trials (judged as 'low quality') reported sufficient information to allow full data extraction: 48 hours after commencing treatment, there was an absolute risk reduction of 7.7% in the frequency of symptom relief with Oscillococcinum® compared with that of placebo (risk difference (RD) 0.077, 95% CI 0.03 to 0.12); the RR was 1.86 (95% CI 1.27 to 2.73; P value = 0.001). A significant but lesser effect was observed at three days (RR 1.27, 95% CI 1.03 to 1.56; P value = 0.03), and no significant difference between the groups was noted at four days (RR 1.11, 95% CI 0.98 to 1.27; P value = 0.10) or at five days (RR 1.06, 95% CI 0.96 to 1.16; P value = 0.25). One of the six studies reported one patient who suffered an adverse effect (headache) from taking Oscillococcinum®. There is insufficient good evidence to enable robust conclusions to be made about Oscillococcinum® in the prevention or treatment of influenza and influenza-like illness. Our findings do not rule out the possibility that Oscillococcinum® could have a clinically useful treatment effect but, given the low quality of the eligible studies, the evidence is not compelling. There was no evidence of clinically important harms due to Oscillococcinum®.

We included six studies, which comprised two prevention trials (a total of 327 young to middle-aged adults in Russia) and four treatment trials (a total of 1196 teenagers and adults in France and Germany). The findings from the two prevention trials did not show that Oscillococcinum®can prevent the onset of flu. Although the results from the four other clinical trials suggested that Oscillococcinum®relieved flu symptoms at 48 hours, this might be due to bias in the trial methods. One patient reported headache after taking Oscillococcinum®. The evidence is current to September 2014. The overall standard of research reporting was poor, and thus many aspects of the trials' methods and results were at unclear risk of bias. We therefore judged the evidence overall as low quality, preventing clear conclusions from being made about Oscillococcinum®in the prevention or treatment of flu and flu-like illness.

10.1002/14651858.CD001957.pub6

cochrane-simplification-train-815

cochrane-simplification-train-815

Thirty-six articles reporting a total of eighteen trials following 1467 participants were included. Dietary approaches assessed in this review were low-fat/high-carbohydrate diets, high-fat/low-carbohydrate diets, low-calorie (1000 kcal per day) and very-low-calorie (500 kcal per day) diets and modified fat diets. Two trials compared the American Diabetes Association exchange diet with a standard reduced fat diet and five studies assessed low-fat diets versus moderate fat or low-carbohydrate diets. Two studies assessed the effect of a very-low-calorie diet versus a low-calorie diet. Six studies compared dietary advice with dietary advice plus exercise and three other studies assessed dietary advice versus dietary advice plus behavioural approaches. The studies all measured weight and measures of glycaemic control although not all studies reported these in the articles published. Other outcomes which were measured in these studies included mortality, blood pressure, serum cholesterol (including LDL and HDL cholesterol), serum triglycerides, maximal exercise capacity and compliance. The results suggest that adoption of regular exercise is a good way to promote better glycaemic control in type 2 diabetic patients, however all of these studies were at high risk of bias. There are no high quality data on the efficacy of the dietary treatment of type 2 diabetes, however the data available indicate that the adoption of exercise appears to improve glycated haemoglobin at six and twelve months in people with type 2 diabetes. There is an urgent need for well-designed studies which examine a range of interventions, at various points during follow-up, although there is a promising study currently underway.

This systematic review assesses the effects of studies that examined dietary advice with or without the addition of exercise or behavioural approaches. Eighteen studies were included. No data were found on micro- or macrovascular diabetic complications, mortality or quality of life. It is difficult to draw reliable conclusions from the limited data that are presented in this review, however, the addition of exercise to dietary advice showed improvement of metabolic control after six- and twelve-month follow-up.

10.1002/14651858.CD004097.pub4

cochrane-simplification-train-816

cochrane-simplification-train-816

We included 67 studies with 10,509 participants overall. Of these, 15 studies with 5787 participants used a placebo. Stone clearance: Based on the overall analysis, treatment with an alpha-blocker may result in a large increase in stone clearance (risk ratio (RR) 1.45, 95% confidence interval (CI) 1.36 to 1.55; low-quality evidence). A subset of higher-quality, placebo-controlled trials suggest that the likely effect is probably smaller (RR 1.16, 95% CI 1.07 to 1.25; moderate-quality evidence), corresponding to 116 more (95% CI 51 more to 182 more) stone clearances per 1000 participants. Major adverse events: Based on the overall analysis, treatment with an alpha-blocker may have little effect on major adverse events (RR 1.25, 95% CI 0.80 to 1.96; low-quality evidence). A subset of higher-quality, placebo-controlled trials suggest that alpha-blockers likely increase the risk of major adverse events slightly (RR 2.09, 95% CI 1.13 to 3.86), corresponding to 29 more (95% CI 3 more to 75 more) major adverse events per 1000 participants. Patients treated with alpha-blockers may experience shorter stone expulsion times (mean difference (MD) -3.40 days, 95% CI -4.17 to -2.63; low-quality evidence), may use less diclofenac (MD -82.41, 95% CI -122.51 to -42.31; low-quality evidence), and likely require fewer hospitalisations (RR 0.51, 95% CI 0.34 to 0.77; moderate-quality evidence), corresponding to 69 fewer hospitalisations (95% CI 93 fewer to 32 fewer) per 1000 participants. Meanwhile, the need for surgical intervention appears similar (RR 0.74, 95% CI 0.53 to 1.02; low-quality evidence), corresponding to 28 fewer surgical interventions (95% CI 51 fewer to 2 more) per 1000 participants. A predefined subgroup analysis (test for subgroup differences; P = 0.002) suggests that effects of alpha-blockers may vary with stone size, with RR of 1.06 (95% CI 0.98 to 1.15; P = 0.16; I² = 62%) for stones 5 mm or smaller versus 1.45 (95% CI 1.22 to 1.72; P < 0.0001; I² = 59%) for stones larger than 5 mm. We found no evidence suggesting possible subgroup effects based on stone location or alpha-blocker type. For patients with ureteral stones, alpha-blockers likely increase stone clearance but probably also slightly increase the risk of major adverse events. Subgroup analyses suggest that alpha-blockers may be less effective for smaller (5 mm or smaller) than for larger stones (greater than 5 mm).

Based on our latest search of the literature from November 2017, we included 64 studies with 10,509 participants. Of these, 15 studies compared alpha-blockers with placebo with 5787 participants. A placebo is a pill that looks and tastes exactly like the real medication, so participants did not know what they were getting. These were the higher-quality studies, which we trusted more. Based on the subset of higher-quality studies that used a placebo, alpha-blockers likely resulted in more people passing their stones. However, these patients are likely to experience slightly more serious unwanted effects of this medication. People taking alpha-blockers may pass their stones in a shorter time, may use less diclofenac (which is a type of pain medication), and are likely to be admitted to the hospital less often. Meanwhile, the need for surgery for their stones was similar. Upon completing additional analyses, we found that effects of alpha-blockers may be different in people with small (5 mm or smaller) versus larger (larger than 5 mm) stones. It appears that this medication works better in people with larger stones. We could find no difference in how well alpha-blockers work, no matter where in the ureter the stone is stuck or what type of alpha-blocker is used. For patients with stones stuck in the ureter, alpha-blockers likely make passing the stone easier but cause slightly more unwanted effects. It appears that alpha-blockers work better in people with larger (greater than 5 mm) rather than smaller (5 mm or smaller) stones. The quality of the evidence for most outcomes was moderate or low, meaning that we have moderate or low confidence in most of the reported results.

10.1002/14651858.CD008509.pub3

cochrane-simplification-train-817

cochrane-simplification-train-817

We included two randomized controlled trials assessing very early, early, non-early (or a combination of these) discharge in children with cancer and febrile neutropenia. We graded the evidence as low quality; we downgraded for risk of bias and imprecision. One study, Santolaya 2004, consisted of 149 randomized low-risk episodes and compared early discharge (mean/median of less than five days) to non-early discharge (mean/median of five days or more). This study found no clear evidence of difference in treatment failure (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.24 to 3.50, P value = 0.89 for rehospitalization or adjustment of antimicrobial treatment, or both; Fischer's exact P value = 0.477 for death) or duration of treatment (mean difference -0.3 days, 95% CI -1.22 to 0.62, P value = 0.52 for any antimicrobial treatment; mean difference -0.5 days, 95% CI -1.36 to 0.36, P value = 0.25 for intravenous antimicrobial treatment; mean difference 0.2 days, 95% CI -0.51 to 0.91, P value = 0.58 for oral antimicrobial treatment). Costs were lower in the early discharge group (mean difference USD -265, 95% CI USD -403.14 to USD -126.86, P value = 0.0002). The second included study, Brack 2012, consisted of 62 randomized low-risk episodes and compared very early discharge (mean/median of less than 24 hours) to early discharge (mean/median of less than five days). This study also found no clear evidence of difference in treatment failure (RR 0.54, 95% CI 0.15 to 1.89, P value = 0.34 for rehospitalization or adjustment of antimicrobial treatment (or both); Fischer's exact P value = 0.557 for death). Regarding duration of treatment, median duration of intravenous antimicrobial treatment was shorter in the very early discharge group (Wilcoxon's P value ≤ 0.001, stated in the study) and median duration of oral antimicrobial treatment was shorter in the early discharge group (Wilcoxon's P ≤ 0.001, stated in the study) as compared to one another. However, there was no clear evidence of difference in median duration of any antimicrobial treatment (Wilcoxon's P value = 0.34, stated in the study). Costs were not assessed in this study. Neither of the included studies assessed quality of life. Meta-analysis was not possible as the included studies assessed different discharge moments and used different risk stratification models. Very limited data were available regarding the safety of early discharge compared to non-early discharge from in-hospital treatment in children with cancer and febrile neutropenia and a low risk for invasive infection. The absence of clear evidence of differences in both studies could be due to lack of power. Evidently, there are still profound gaps regarding very early and early discharge in children with cancer and febrile neutropenia. Future studies that assess this subject should have a large sample size and aim to establish uniform and objective criteria regarding the identification of a low-risk febrile neutropenic episode.

The evidence is current to December 2015. The current review identified one study,Santolaya 2004, in which early discharge was compared to non-early discharge in this group of children, and one study,Brack 2012, in which very early discharge was compared to early discharge. Early discharge did not appear to be less safe than non-early discharge in children with cancer and fever during neutropenia with a low risk for bacterial infections; there was no clear evidence of difference in treatment failure between the two groups. Moreover, the treatment costs in the early discharge group were lower than in the non-early discharge group. Regarding very early discharge, this did not appear to be less safe than early discharge; there was no clear evidence of difference in treatment failure between the two groups. Duration of treatment differed between very early discharge and early discharge; duration of intravenous antibiotic treatment was shorter in the very early discharge group, and duration of oral antibiotic treatment was shorter in the early discharge group, as compared to one another. However, there was no clear evidence of difference in total treatment duration of any antibiotic treatment between these groups. For both reported comparisons, the quality of the evidence was low. The included studies were relatively small with a low number of participants, thus it was possible that the absence of clear evidence of differences in the included studies could be due to, for example, the lack of power. Unfortunately, it was not possible to pool data in the two studies. In conclusion, regarding both rehospitalization or adjustment of antibiotics (or both) and death, evidence was fairly limited; however, there was no evidence that early discharge was less safe than non-early discharge or very early discharge was less safe than early discharge of children with cancer and fever during neutropenia and a low risk for invasive bacterial infection. Future larger trials are needed to confirm or contradict these results.

10.1002/14651858.CD008382.pub2

cochrane-simplification-train-818

cochrane-simplification-train-818

Four trials were included with a total of 220 participants (118 treated with atherectomy, 102 treated with balloon angioplasty) and 259 treated vessels (129 treated with atherectomy, 130 treated with balloon angioplasty). All studies compared atherectomy with angioplasty. No study was properly powered or assessors blinded to the procedures and there was a high risk of selection, attrition, detection and reporting biases. The estimated risk of success was similar between the treatment modalities although the confidence interval (CI) was compatible with small benefits of either treatment for the initial procedural success rate (Mantel-Haenszel risk ratio (RR) 0.92, 95% CI 0.44 to 1.91, P = 0.82), patency at six months (Mantel-Haenszel RR 0.92, 95% CI 0.51 to 1.66, P = 0.79) and patency at 12 months (Mantel-Haenszel RR 1.17, 95% CI 0.72 to 1.90, P = 0.53) following the procedure. The reduction in all-cause mortality with atherectomy was most likely due to an unexpectedly high mortality in the balloon angioplasty group in one of the two trials that reported mortality (Mantel-Haenszel RR 0.24, 95% CI 0.06 to 0.91, P = 0.04). Cardiovascular events were not reported in any study. There was a reduction in the rate of bailout stenting following atherectomy (Mantel-Haenszel RR 0.45, 95% CI 0.24 to 0.84, P = 0.01), and balloon inflation pressures were lower following atherectomy (mean difference -2.73 mmHg, 95% CI -3.48 to -1.98, P < 0.00001). Complications such as embolisation and vessel dissection were reported in two trials indicating more embolisations in the atherectomy group and more vessel dissections in the angioplasty group, but the data could not be pooled. From the limited data available, there was no clear evidence of different rates of adverse events between the atherectomy and balloon angioplasty groups for target vessel revascularisation and above-knee amputation. Quality of life and clinical and symptomatic outcomes such as walking distance or symptom relief were not reported in the studies. This review has identified poor quality evidence to support atherectomy as an alternative to balloon angioplasty in maintaining primary patency at any time interval. There was no evidence for superiority of atherectomy over angioplasty on any outcome, and distal embolisation was not reported in all trials of atherectomy. Properly powered trials are recommended.

In this review, we compared atherectomy to the more established treatments such as balloon angioplasty and bypass surgery. We identified four studies with a total of 220 participants. All studies compared atherectomy with balloon angioplasty. The studies were of low quality as there was no blinding of the procedures, the studies were not properly powered to show an effect, not all study outcomes were reported and a large number of the initial study populations did not complete the studies. Although the results of the meta-analyses were imprecise, the average effect of the two treatments was similar in terms of initial success and unobstructed arteries (patency) at six months or 12 months following the procedure. There was a lower risk of death with atherectomy, most likely due to an unexpectedly high number of deaths in the balloon angioplasty group in one of the two trials reporting deaths. Cardiovascular events were not reported in any of the included studies. There was a reduction in the rate of emergency stenting procedures following atherectomy, and balloon inflation pressures were lower following atherectomy. Complications such as formation of clots (embolisation) and tears along the vessels (vessel dissection) were reported in two trials indicating more embolisations in the atherectomy group and more vessel dissections in the angioplasty group but the data could not be combined. The limited data available indicated that there was no clear evidence of a difference between the atherectomy and balloon angioplasty groups for adverse events such as the need for re-intervention due to obstruction of the treated vessel and above-knee amputation. Quality of life and clinical and symptomatic outcomes such as walking distance or symptom relief were not reported in the studies. We showed that the limited evidence available does not support a significant advantage of atherectomy over conventional balloon angioplasty.

10.1002/14651858.CD006680.pub2

cochrane-simplification-train-819

cochrane-simplification-train-819

Four RCTs (n = 607) of user-held records versus treatment as usual met the inclusion criteria. When the effect of user-held records on psychiatric hospital admissions was compared with treatment as usual in four studies, the pooled treatment effect showed no significant impact of the intervention and was of very low magnitude (n = 597, 4 RCTs, RR 0.99 CI 0.71 to 1.38, moderate quality evidence). Similarly, there was no significant effect of the intervention in three studies which investigated compulsory psychiatric hospital admissions (n = 507, 4 RCTs, RR 0.64 CI 0.37 to 1.10, moderate quality evidence). Other outcomes including satisfaction and mental state were investigated but pooled estimates were not obtainable due to skewed or poorly reported data, or only being investigated by one study. Two outcomes (violence and death) were not investigated by the included studies. Two important randomised studies are ongoing. The evidence gap remains regarding user-held, personalised, accessible clinical information for people with psychotic illnesses for many of the outcomes of interest. However, based on moderate quality evidence, this review suggests that there is no effect of the intervention on hospital or outpatient appointment use for individuals with psychotic disorders. The number of studies is low, however, and further evidence is required to ascertain whether these results are mediated by the type of intervention, such as involvement of a clinical team or the type of information included.

Based on a search in 2011, this review includes four trials with a total of 607 people and evaluates the effects of user-held information for people with severe mental illness. In the main, the number of relevant studies is low, with poor reporting of some outcomes. Based on moderate quality evidence, the review found that user-held information did not decrease hospital admissions, and did not decrease compulsory admissions or encourage people with severe mental illness to attend appointments (when compared to treatment as usual). Other important outcomes, such as satisfaction with care, costs and effect on mental health, were not available due to the limited quality of the four studies. There is therefore a gap in knowledge and evidence regarding user-held information for people with severe mental health problems. Further evidence is also required on the different types of user-held information (for example, if it involves the mental health team and what type of information is included in the record). Large-scale, well-conducted and well-reported studies are required to assess the effects of user-held information for people with mental illness. Two important randomised studies are currently taking place. For the present, despite a gap in evidence, user-held information is low cost and acceptable to patients, so its use is likely to grow. However, it cannot be assumed that user-held information is of benefit to people and is cost-effective without further large-scale, well-conducted and well-reported trials. This plain language summary has been written by a consumer, Benjamin Gray: Rethink Mental Illness. E-mail: [email protected]

10.1002/14651858.CD001711.pub2

cochrane-simplification-train-820

cochrane-simplification-train-820

We included four randomised controlled trials in this review. A total of 868 participants with a clinical or radiological diagnosis of RAAA were randomised to receive either eEVAR or open surgical repair. Overall risk of bias was low, but we considered one study that performed randomisation in blocks by week and performed no allocation concealment and no blinding to be at high risk of selection bias. Another study did not adequately report random sequence generation, putting it at risk of selection bias, and two studies were underpowered. There was no clear evidence to support a difference between the two interventions for 30-day (or in-hospital) mortality (OR 0.88, 95% CI 0.66 to 1.16; moderate-quality evidence). There were a total of 44 endoleak events in 128 participants from three studies (low-quality evidence). Thirty-day complication outcomes (myocardial infarction, stroke, composite cardiac complications, renal complications, severe bowel ischaemia, spinal cord ischaemia, reoperation, amputation, and respiratory failure) were reported in between one and three studies, therefore we were unable to draw a robust conclusion. We downgraded the quality of the evidence for myocardial infarction, renal complications, and respiratory failure due to imprecision, inconsistency, and risk of bias. Odds ratios for complications outcomes were OR 2.38 (95% CI 0.34 to 16.53; 139 participants; 2 studies; low-quality evidence) for myocardial infarction; OR 1.07 (95% CI 0.21 to 5.42; 255 participants; 3 studies; low-quality evidence) for renal complications; and OR 3.62 (95% CI 0.14 to 95.78; 32 participants; 1 study; low-quality evidence) for respiratory failure. There was low-quality evidence of a reduction in bowel ischaemia in the eEVAR treatment group, but very few events were reported (OR 0.37, 95% CI 0.14 to 0.94), and we downgraded the evidence due to imprecision and risk of bias. Six-month and one-year outcomes were evaluated in three studies, but only results from a single study could be used for each outcome, which showed no clear evidence of a difference between the interventions. We rated six-month mortality evidence as of moderate quality due to imprecision (OR 0.89, 95% CI 0.40 to 1.98; 116 participants). The conclusions of this review are currently limited by the paucity of data. We found from the data available moderate-quality evidence suggesting there is no difference in 30-day mortality between eEVAR and open repair. Not enough information was provided for complications for us to make a well-informed conclusion, although it is possible that eEVAR is associated with a reduction in bowel ischaemia. Long-term data were lacking for both survival and late complications. More high-quality randomised controlled trials comparing eEVAR and open repair for the treatment of RAAA are needed to better understand if one method is superior to the other, or if there is no difference between the methods on relevant outcomes.

The present review looked at the available evidence for endovascular repair effectiveness compared with open surgery for ruptured aneurysms. We included four studies with a total of 868 participants. Risk of bias was generally low, but one study was at high risk of selection bias due to their use of the block method of randomisation; one study did not adequately report randomisation methods; and two studies may not have included a sufficient number of participants to adequately answer the questions posed by the studies. We found that from the data currently available there appears to be no difference in death within 30 days of the procedure between endovascular repair and open repair. Endoleaks were reported in 44 participants from three studies. The data on complications (myocardial infarction, stroke, combined cardiac complications, renal complications, spinal cord ischaemia, reoperation, amputation, and respiratory failure) are not robust enough at this point to make any strong conclusions on superiority of either repair technique, but emergency endovascular aneurysm repair (eEVAR) may be associated with a lower risk of bowel ischaemia. No robust conclusion can be made on outcomes at six months or one year. More studies are needed to better understand whether or not one of the aneurysm repair techniques, endovascular or open surgical, is superior based on patient outcomes. We found from the data available moderate-quality evidence suggesting there is no difference in 30-day mortality between eEVAR and open repair. Not enough information was provided for complications for us to make a well-informed conclusion, although it is possible that eEVAR is associated with a reduction in bowel ischaemia. We downgraded the quality of the evidence as some studies contained too few participants, not all studies reported on all complication outcomes, and the number of complications occurring between studies varied substantially.

10.1002/14651858.CD005261.pub4

cochrane-simplification-train-821

cochrane-simplification-train-821

We found one randomised controlled trial with a low risk of bias which was carried out in a tertiary neonatal care centre in Australia. The study involved 36 women (18 received intravaginal prostaglandin E 2 gel and 18 received placebo). There was one case of neonatal respiratory distress in the control group, which the trialist reported as transient tachypnoea of the newborn (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.01 to 7.68, one study, n = 36). None of the neonates required mechanical ventilation and the trial authors reported median Apgar scores at one and five minutes as being similar in both groups. There were no treatment-related side effects in either group. Noradrenaline concentrations (median values (range)) were reported as being significantly higher in the cord blood samples of the intervention group compared to the control group. Although the trial authors reported a significant increase in catecholamine levels in the intervention group, there was no significant difference in the respiratory outcomes between intervention and control groups. The quality of evidence was graded as low because the sample size was small and there were few events. No definite conclusions can thus be drawn on the effects of prostaglandins on neonatal respiratory outcomes from this review.

We found one small randomised trial (involving 36 women) that compared prostaglandin E2 intravaginal gel administered before caesarean section compared with a placebo gel. The information obtained from this study did not permit us to be certain that prostaglandins improve neonatal breathing following planned caesarean section at term. Only one baby in the placebo group had respiratory distress assessed as rapid breathing. Further studies have to be carried out in order to find out the impact of prostaglandins on the newborn lungs after caesarean section.

10.1002/14651858.CD010087.pub2

cochrane-simplification-train-822

cochrane-simplification-train-822

We identified 26 new trials in this update, of which 9 await classification due to insufficient data for eligibility assessment, and 17 trials (N = 3105) met the inclusion criteria. We included a total of 28 trials involving 4195 infants with acute bronchiolitis, of whom 2222 infants received hypertonic saline. Hospitalised infants treated with nebulised hypertonic saline had a statistically significant shorter mean length of hospital stay compared to those treated with nebulised 0.9% saline (MD -0.41 days, 95% CI -0.75 to -0.07; P = 0.02, I² = 79%; 17 trials; 1867 infants) (GRADE quality of evidence: low). Infants who received hypertonic saline also had statistically significant lower post-inhalation clinical scores than infants who received 0.9% saline in the first three days of treatment (day 1: MD -0.77, 95% CI -1.18 to -0.36, P < 0.001; day 2: MD -1.28, 95% CI -1.91 to -0.65, P < 0.001; day 3: MD -1.43, 95% CI -1.82 to -1.04, P < 0.001) (GRADE quality of evidence: low). Nebulised hypertonic saline reduced the risk of hospitalisation by 14% compared with nebulised 0.9% saline among infants who were outpatients and those treated in the emergency department (RR 0.86, 95% CI 0.76 to 0.98; P = 0.02, I² = 7%; 8 trials; 1723 infants) (GRADE quality of evidence: moderate). Twenty-four trials presented safety data: 13 trials (1363 infants, 703 treated with hypertonic saline) did not report any adverse events, and 11 trials (2360 infants, 1265 treated with hypertonic saline) reported at least one adverse event, most of which were mild and resolved spontaneously. Nebulised hypertonic saline may modestly reduce length of stay among infants hospitalised with acute bronchiolitis and improve clinical severity score. Treatment with nebulised hypertonic saline may also reduce the risk of hospitalisation among outpatients and emergency department patients. However, we assessed the quality of the evidence as low to moderate.

We identified 26 new studies in this update, of which 9 await assessment and 17 trials (N = 3105) were added. We included a total of 28 trials involving 4195 infants with acute bronchiolitis. Nebulised hypertonic saline may reduce hospital stay by 10 hours in comparison to normal saline for infants admitted with acute bronchiolitis. We found that 'clinical severity scores', which are used by doctors to assess patient health, for children treated as outpatients or in hospital improved when administered nebulised hypertonic saline compared to normal saline. Nebulised hypertonic saline may also reduce the risk of hospitalisation by 14% among children treated as outpatients or in the emergency department. We found only minor and spontaneously resolved adverse effects from the use of nebulised hypertonic saline when given with treatment to relax airways (bronchodilators). Reductions in hospital stay were smaller than previously thought. However, an average reduction of 10 hours in the length of hospital stay for infants is significant because bronchiolitis usually has a short duration. Nebulised hypertonic saline appears to be safe and widely available at low cost. The quality of the evidence was low to moderate: there were inconsistencies in results among trials and risk of bias in some trials. Future large trials are therefore needed to confirm the benefits of nebulised hypertonic saline for children with bronchiolitis treated as outpatients and in hospital.

10.1002/14651858.CD006458.pub4

cochrane-simplification-train-823

cochrane-simplification-train-823

One quasi-randomised and 19 randomised controlled studies (924 children and adults) were included; 16 studies (n = 639) analysed oral antioxidant supplementation and four analysed inhaled supplements (n = 285). Only one of the 20 included studies was judged to be free of bias. Oral supplements versus control The change from baseline in forced expiratory volume in one second (FEV1) % predicted at three months and six months was only reported for the comparison of NAC to control. Four studies (125 participants) reported at three months; we are uncertain whether NAC improved FEV1 % predicted as the quality of the evidence was very low, mean difference (MD) 2.83% (95% confidence interval (CI) -2.16 to 7.83). However, at six months two studies (109 participants) showed that NAC probably increased FEV1 % predicted from baseline (moderate-quality evidence), MD 4.38% (95% CI 0.89 to 7.87). A study of a combined vitamin and selenium supplement (46 participants) reported a greater change from baseline in FEV1 % predicted in the control group at two months, MD -4.30% (95% CI -5.64 to -2.96). One study (61 participants) found that NAC probably makes little or no difference in the change from baseline in quality of life (QoL) at six months (moderate-quality evidence), standardised mean difference (SMD) -0.03 (95% CI -0.53 to 0.47), but the two-month combined vitamin and selenium study reported a small difference in QoL in favour of the control group, SMD -0.66 (95% CI -1.26 to -0.07). The NAC study reported on the change from baseline in body mass index (BMI) (62 participants) and similarly found that NAC probably made no difference between groups (moderate-quality evidence). One study (69 participants) found that a mixed vitamin and mineral supplement may lead to a slightly lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) provided information on adverse events, but did not find any clear and consistent evidence of differences between treatment or control groups with the quality of the evidence ranging from low to moderate. Studies of β-carotene and vitamin E consistently reported greater plasma levels of the respective antioxidants. Inhaled supplements versus control Two studies (258 participants) showed inhaled glutathione probably improves FEV1 % predicted at three months, MD 3.50% (95% CI 1.38 to 5.62), but not at six months compared to placebo, MD 2.30% (95% CI -0.12 to 4.71) (moderate-quality evidence). The same studies additionally reported an improvement in FEV1 L in the treated group compared to placebo at both three and six months. One study (153 participants) reported inhaled glutathione probably made little or no difference to the change in QoL from baseline, MD 0.80 (95% CI -1.63 to 3.23) (moderate-quality evidence). No study reported on the change from baseline in BMI at six months, but one study (16 participants) reported at two months and a further study (105 participants) at 12 months; neither study found any difference at either time point. One study (153 participants) reported no difference in the time to the first pulmonary exacerbation at six months. Two studies (223 participants) reported treatment may make little or no difference in adverse events (low-quality evidence), a further study (153 participants) reported that the number of serious adverse events were similar across groups. With regards to micronutrients, there does not appear to be a positive treatment effect of antioxidant micronutrients on clinical end-points; however, oral supplementation with glutathione showed some benefit to lung function and nutritional status. Based on the available evidence, inhaled and oral glutathione appear to improve lung function, while oral administration decreases oxidative stress; however, due to the very intensive antibiotic treatment and other concurrent treatments that people with CF take, the beneficial effect of antioxidants remains difficult to assess in those with chronic infection without a very large population sample and a long-term study period. Further studies, especially in very young children, using outcome measures such as lung clearance index and the bronchiectasis scores derived from chest scans, with improved focus on study design variables (such as dose levels and timing), and elucidating clear biological pathways by which oxidative stress is involved in CF, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn. The benefit of antioxidants in people with CF who receive CFTR modulators therapies should also be assessed in the future.

We included 20 studies (924 people with CF, almost equal gender split, aged six months to 59 years); 16 studies compared oral supplements to placebo ('dummy' treatment) and four compared inhaled supplements to placebo. Oral supplements We are uncertain whether NAC changes lung function (forced expiratory volume in one second (FEV1) % predicted) at three months (four studies, 125 participants, very low-quality evidence), but at six months two studies (109 participants) reported NAC probably improved FEV1 % predicted (moderate-quality evidence). One study (46 participants) reported a greater change in FEV1 % predicted with placebo than with a combined vitamin and selenium supplement after two months. One study (61 participants) reported little or no difference in quality of life (QoL) scores between NAC and control after six months (moderate-quality evidence), but the two-month combined vitamin and selenium study reported slightly better QoL scores in the control group. NAC probably made no difference to body mass index (BMI) (one study, 62 participants, moderate-quality evidence). One study (69 participants) reported that a mixed vitamin and mineral supplement may lead to a lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) did not find any clear and consistent differences in side effects between groups (evidence ranged from low to moderate quality). Vitamin E and β-carotene studies consistently reported greater levels of these antioxidants in blood samples. Inhaled supplements In two studies (258 participants), inhaled glutathione probably improved FEV1 % predicted compared to placebo at three months but not at six months (moderate-quality evidence); these studies also reported a greater improvement in FEV1 litres with glutathione compared to placebo at both time points. Two studies (258 participants) found little or no difference in the change in QoL scores (moderate-quality evidence). One two-month study (16 participants) and a 12-month study (105 participants) reported no difference between groups in the change in BMI. There was no difference in the time to the first pulmonary exacerbation in one six-month study. Two studies (223 participants) reported no difference between groups in side effects (low-quality evidence) and another study (153 participants) reported that the number of serious side effects were similar across groups. Vitamin and mineral supplements do not seem to improve clinical outcomes. Inhaled glutathione appears to improve lung function, while oral administration lowers oxidative stress, with benefits to lung function and nutritional measures. Intensive antibiotic and other concurrent treatments for people with CF and chronic infection mean it is difficult to assess the effect of antioxidants without a very large and long study. Future research should look at how antioxidants affect people with CF taking CFTR modulator therapies. Evidence ranged from very low to moderate quality. All but one study had some bias; mostly because data were not fully reported (likely to affect our results). We were also largely unsure if participants knew which treatment they received, both in advance and once the studies started (unsure how this might affect our results).

10.1002/14651858.CD007020.pub4

cochrane-simplification-train-824

cochrane-simplification-train-824

Eight RCTs with a total of 660 participants met review inclusion criteria. Duration of the included trials varied from 12 weeks to 18 months. Only one trial used an inactive control. Most studies were at unclear or high risk of bias in several domains. Overall, our ability to draw conclusions was hampered by very low-quality evidence. Almost all results were very imprecise; there were also problems related to risk of bias, inconsistency between trials, and indirectness of the evidence. No trial provided data on incident dementia. For comparisons of CCT with both active and inactive controls, the quality of evidence on our other primary outcome of global cognitive function immediately after the intervention period was very low. Therefore, we were unable to draw any conclusions about this outcome. Due to very low quality of evidence, we were also unable to determine whether there was any effect of CCT compared to active control on our secondary outcomes of episodic memory, working memory, executive function, depression, functional performance, and mortality. We found low-quality evidence suggesting that there is probably no effect on speed of processing (SMD 0.20, 95% confidence interval (CI) -0.16 to 0.56; 2 studies; 119 participants), verbal fluency (SMD -0.16, 95% CI -0.76 to 0.44; 3 studies; 150 participants), or quality of life (mean difference (MD) 0.40, 95% CI -1.85 to 2.65; 1 study; 19 participants). When CCT was compared with inactive control, we obtained data on five secondary outcomes, including episodic memory, executive function, verbal fluency, depression, and functional performance. We found very low-quality evidence; therefore, we were unable to draw any conclusions about these outcomes. Currently available evidence does not allow us to determine whether or not computerised cognitive training will prevent clinical dementia or improve or maintain cognitive function in those who already have evidence of cognitive impairment. Small numbers of trials, small samples, risk of bias, inconsistency between trials, and highly imprecise results mean that it is not possible to derive any implications for clinical practice, despite some observed large effect sizes from individual studies. Direct adverse events are unlikely to occur, although the time and sometimes the money involved in computerised cognitive training programmes may represent significant burdens. Further research is necessary and should concentrate on improving methodological rigour, selecting suitable outcomes measures, and assessing generalisability and persistence of any effects. Trials with long-term follow-up are needed to determine the potential of this intervention to reduce the risk of dementia.

We found eight trials with 660 participants to include in the review. Seven of the trials (623 participants) compared CCT to an alternative activity. None of the included trials examined development of dementia, so this review presents no evidence on whether taking part in computerised cognitive training will help to prevent dementia. Our main finding in relation to all of the other outcomes in which we were interested was that the overall quality of the evidence was very low. This very low quality was mainly due to small sample sizes, problems with study methods, and differences between trials. Therefore, although we found some evidence for a few benefits of CCT for cognition, we were highly uncertain about study results and consider it likely that future research might lead to different results. Unfortunately, it is not yet possible to answer our review question with any certainty. We think it remains an important area for further study. We would like to see larger studies, which would be more able to detect effects of CCT, and longer studies, which are needed to show whether there are any benefits, whether benefits are long-lasting, and whether there is a chance of preventing or delaying the development of dementia.

10.1002/14651858.CD012279.pub2

cochrane-simplification-train-825

cochrane-simplification-train-825

This systematic review attempted to summarise evidence from randomised clinical trials on the treatment of spontaneous bacterial peritonitis. Thirteen studies were included; each one of them compared different antibiotics in their experimental and control groups. No meta-analyses could be performed, though data on the main outcomes were collected and analysed separately for each included trial. Currently, the evidence showing that lower dosage or short-term treatment with third generation cephalosporins is as effective as higher dosage or long-term treatment is weak. Oral quinolones could be considered an option for those with less severe manifestations of the disease. This review provides no clear evidence for the treatment of cirrhotic patients with spontaneous bacterial peritonitis. In practice, third generation cephalosporins have already been established as the standard treatment of spontaneous bacterial peritonitis, and it is clear, that empirical antibiotic therapy should be provided in any case. However, until large, well-conducted trials provide more information, practice will remain based on impression, not evidence.

This review aimed to evaluate the beneficial and harmful effects of different types and modes of antibiotic therapy in the treatment of spontaneous bacterial peritonitis in cirrhotic patients. Thirteen trials were included; each one of them compared different antibiotics in their experimental and control groups. No meta-analyses could be performed, though data on the main outcomes were collected and analysed separately for each included trial. Based on the identified evidence, we cannot suggest the most appropriate management to treat spontaneous bacterial peritonitis in regard to the type, dosage, duration, or administration route of the antibiotic therapy. The clinical trials found dealt with different types of antibiotics, and, therefore, could not be combined. This review found no evidence that the effect or safety of one antibiotic is more beneficial than another. Further randomised clinical trials with an adequate design, including a large number of participants and sufficient duration should be carefully planned to provide a more precise estimate of the beneficial and harmful effects of antibiotic treatment for spontaneous bacterial peritonitis.

10.1002/14651858.CD002232.pub2

cochrane-simplification-train-826

cochrane-simplification-train-826

Of 35 studies considered potentially relevant, 14 studies enrolling 1025 subjects met the entry criteria. Scopolamine was administered via transdermal patches, tablets or capsules, oral solutions or intravenously. Scopolamine was compared against placebo, calcium channel antagonists, antihistamine, methscopolamine or a combination of scopolamine and ephedrine. Studies were generally small in size and of varying quality. Scopolamine was more effective than placebo in the prevention of symptoms. Comparisons between scopolamine and other agents were few and suggested that scopolamine was superior (versus methscopolamine) or equivalent (versus antihistamines) as a preventative agent. Evidence comparing scopolamine to cinnarizine or combinations of scopolamine and ephedrine is equivocal or minimal. Although sample sizes were small, scopolamine was no more likely to induce drowsiness, blurring of vision or dizziness compared to other agents. Dry mouth was more likely with scopolamine than with methscopolamine or cinnarizine. No studies were available relating to the therapeutic effectiveness of scopolamine in the management of established symptoms of motion sickness. The use of scopolamine versus placebo in preventing motion sickness has been shown to be effective. No conclusions can be made on the comparative effectiveness of scopolamine and other agents such as antihistamines and calcium channel antagonists. In addition, we identified no randomised controlled trials that examined the effectiveness of scopolamine in the treatment of established symptoms of motion sickness.

This Cochrane Review summarises evidence from 14 randomised controlled studies evaluating the effectiveness and safety of scopolamine for motion sickness. The results show that scopolamine is more effective than placebo and scopolamine-like derivatives in the prevention of nausea and vomiting associated with motion sickness. However, scopolamine was not shown to be superior to antihistamines and combinations of scopolamine and ephedrine. Scopolamine was less likely to cause drowsiness, blurred vision or dizziness when compared to these other agents.

10.1002/14651858.CD002851.pub4

cochrane-simplification-train-827

cochrane-simplification-train-827

We included four trials with a total of 4663 participants. All four trials reported short PRT courses, with three trials using 25 Gy in five fractions, and one trial using 20 Gy in four fractions. Only one study specifically required TME surgery for inclusion, whereas in another study 90% of participants received TME surgery. Preoperative radiotherapy probably reduces overall mortality at 4 to 12 years' follow-up (4 trials, 4663 participants; Peto OR 0.90, 95% CI 0.83 to 0.98; moderate-quality evidence). For every 1000 people who undergo surgery alone, 454 would die compared with 45 fewer (the true effect may lie between 77 fewer to 9 fewer) in the PRT group. There was some evidence from subgroup analyses that in trials using TME no or little effect of PRT on survival (P = 0.03 for the difference between subgroups). Preoperative radiotherapy may have little or no effect in reducing cause-specific mortality for rectal cancer (2 trials, 2145 participants; Peto OR 0.89, 95% CI 0.77 to 1.03; low-quality evidence). We found moderate-quality evidence that PRT reduces local recurrence (4 trials, 4663 participants; Peto OR 0.48, 95% CI 0.40 to 0.57). In absolute terms, 161 out of 1000 patients receiving surgery alone would experience local recurrence compared with 83 fewer with PRT. The results were consistent in TME and non-TME studies. There may be little or no difference in curative resection (4 trials, 4673 participants; RR 1.00, 95% CI 0.97 to 1.02; low-quality evidence) or in the need for sphincter-sparing surgery (3 trials, 4379 participants; RR 0.99, 95% CI 0.94 to 1.04; I2 = 0%; low-quality evidence) between PRT and surgery alone. Low-quality evidence suggests that PRT may increase the risk of sepsis from 13% to 16% (2 trials, 2698 participants; RR 1.25, 95% CI 1.04 to 1.52) and surgical complications from 25% to 30% (2 trials, 2698 participants; RR 1.20, 95% CI 1.01 to 1.42) compared to surgery alone. Two trials evaluated quality of life using different scales. Both studies concluded that sexual dysfunction occurred more in the PRT group. Mixed results were found for faecal incontinence, and irradiated participants tended to resume work later than non-irradiated participants between 6 and 12 months, but this effect had attenuated after 18 months (low-quality evidence). We found moderate-quality evidence that PRT reduces overall mortality. Subgroup analysis did not confirm this effect in people undergoing TME surgery. We found consistent evidence that PRT reduces local recurrence. Risk of sepsis and postsurgical complications may be higher with PRT. The main limitation of the findings of the present review concerns their applicability. The included trials only assessed short-course radiotherapy and did not use chemotherapy, which is widely used in the contemporary management of rectal cancer disease. The differences between the trials regarding the criteria used to define rectal cancer, staging, radiotherapy delivered, the time between radiotherapy and surgery, and the use of adjuvant or postoperative therapy did not appear to influence the size of effect across the studies. Future trials should focus on identifying participants that are most likely to benefit from PRT especially in terms of improving local control, sphincter preservation, and overall survival while reducing acute and late toxicities (especially rectal and sexual function), as well as determining the effect of radiotherapy when chemotherapy is used and the optimal timing of surgery following radiotherapy.

We searched medical databases on 4 June 2018 for randomised trials (experimental studies where people are randomly allocated to one of two or more treatment groups) to determine whether there is any benefit to radiotherapy before surgical treatment for people with rectal cancer in terms of reducing the risk of dying from any cause, the risk of dying from cancer, and the risk of cancer recurring in the pelvis. We considered high-dose regimen of radiotherapy followed by any type of surgical treatment to remove cancer of the rectum. We found four trials involving 4663 people with operable rectal cancer. Our results suggest that administering short-course radiotherapy before surgery probably reduces mortality. However, when our analysis was limited to a contemporary type of surgery (total mesorectal excision), there was no evidence of a difference between the group receiving radiotherapy before surgery and the group receiving surgery alone. There may be little or no difference between groups in cancer-related death when short-course radiotherapy is used. We found moderate quality evidence that using preoperative radiotherapy compared to surgery alone may provide substantial benefit in terms of reduction of local recurrence of the cancer. There was little or no effect of preoperative radiotherapy on curative resection and sphincter-sparing surgery. We found higher rates of sepsis, surgical complications, and sexual complications in participants treated with radiotherapy compared to those who received only surgery. Overall the studies were well-designed. We judged the quality of the evidence as moderate for cancer recurrence and overall mortality, as there were serious concerns regarding the applicability of the findings to the contemporary management of rectal cancer. We further downgraded the quality of the evidence for the remaining outcomes due to imprecise results and/or variations between the trials regarding the criteria used to define rectal cancer, the stage of participants, preoperative imaging used for assessing stage, the type of surgery performed, the radiation dose and fractioning, the time between radiotherapy and surgery, and the use of adjuvant or postoperative therapy.

10.1002/14651858.CD002102.pub3

cochrane-simplification-train-828

cochrane-simplification-train-828

The review included 12 studies (reported in 22 publications). The included studies assigned 24,846 participants aged one to six months to vitamin A supplementation or control group. There was no effect of vitamin A supplementation for the primary outcome of all-cause mortality based on seven studies that included 21,339 (85%) participants (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.89 to 1.25; I2 = 0%; test for heterogeneity: P = 0.79; quality of evidence: moderate). Also, there was no effect of vitamin A supplementation on mortality or morbidity due to diarrhoea and respiratory tract infection. There was an increased risk of bulging fontanelle within 24 to 72 hours of supplementation in the vitamin A group compared to control (RR 3.10, 95% CI 1.89 to 5.09; I2 = 9%, test for heterogeneity: P = 0.36; quality of evidence: high). There was no reported subsequent increased risk of death, convulsions or irritability in infants who developed bulging fontanelle after vitamin A supplementation, and it resolved in most cases within 72 hours. There was no increased risk of other adverse effects such as vomiting, irritability, diarrhoea, fever and convulsions in the vitamin A supplementation group compared to control. Vitamin A supplementation did not have any statistically significant effect on vitamin A deficiency (RR 0.86, 95% CI 0.70 to 1.06; I2 = 27%; test for heterogeneity: P = 0.25; quality of evidence: moderate). There is no convincing evidence that vitamin A supplementation for infants one to six months of age results in a reduction in infant mortality or morbidity in low- and middle-income countries. There is an increased risk of bulging fontanelle with vitamin A supplementation in this age group; however, there were no reported subsequent complications because of this adverse effect.

The review authors searched the medical literature to identify relevant studies that compared the effect of vitamin A supplementation versus control on death, illnesses, and side effects in randomly selected infants aged one to six months. The literature is current to 5 March 2016. The search identified 12 studies that involved 24,846 infants. Most of the studies were well conducted and included children from Asia, Africa, and Latin America. The results of the studies provided no convincing evidence that vitamin A supplementation reduces death or illness in infants one to six months of age (quality of evidence: moderate). Supplementation had no beneficial effects to reduce death or illness due to diarrhoea or pneumonia. Similarly, vitamin A supplementation did not reduce the proportion of children with vitamin A deficiency based on their blood levels of vitamin A (quality of evidence: moderate). Infants who were given vitamin A had an increased risk of development of bulging of soft spot at the top of the head (called bulging fontanelle) and quality of evidence for this side effect was high. However, this adverse effect did not increase subsequent risk of death or fits. In summary, vitamin A supplementation in infants one to six months of age did not reduce death or illness; however, it increased the risk of bulging fontanelle.

10.1002/14651858.CD007480.pub3

cochrane-simplification-train-829

cochrane-simplification-train-829

We included eight RCTs comprising a total of 662 distinct febrile neutropenia episodes. The studies included adults and children, and had variable design and criteria for discontinuation of antibiotics in both study arms. All included studies but two were performed before the year 2000. All studies included people with cancer with fever of unknown origin and excluded people with microbiological documented infections. We found no significant difference between the short-antibiotic therapy arm and the long-antibiotic therapy arm for all-cause mortality (RR 1.38, 95% CI 0.73 to 2.62; RD 0.02, 95% CI -0.02 to 0.05; low-certainty evidence). We downgraded the certainty of the evidence to low due to imprecision and high risk of selection bias. The number of fever days was significantly lower for people in the short-antibiotic treatment arm compared to the long-antibiotic treatment arm (mean difference -0.64, 95% CI -0.96 to -0.32; I² = 30%). In all studies, total antibiotic days were fewer in the intervention arm by three to seven days compared to the long antibiotic therapy. We found no significant differences in the rates of clinical failure (RR 1.23, 95% CI 0.85 to 1.77; very low-certainty evidence). We downgraded the certainty of the evidence for clinical failure due to variable and inconsistent definitions of clinical failure across studies, possible selection bias, and wide confidence intervals. There was no significant difference in the incidence of bacteraemia occurring after randomisation (RR 1.56, 95% CI 0.91 to 2.66; very low-certainty evidence), while the incidence of any documented infections was significantly higher in the short-antibiotic therapy arm (RR 1.67, 95% CI 1.08 to 2.57). There was no significant difference in the incidence of invasive fungal infections (RR 0.86, 95% CI 0.32 to 2.31) and development of antibiotic resistance (RR 1.49, 95% CI 0.62 to 3.61). The data on hospital stay were too sparse to permit any meaningful conclusions. We could make no strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among people with cancer with febrile neutropenia based on the existing evidence and its low certainty. Results of microbiological outcomes favouring long antibiotic therapy may be misleading due to lower culture positivity rates under antibiotic therapy and not true differences in infection rates. Well-designed, adequately powered RCTs are required that address this issue in the era of rising antibiotic resistance.

We included eight studies involving people with neutropenia and fever and comparing short antibiotic therapy to long antibiotic therapy until normalisation of neutrophils. A total of 662 episodes of fever in people with neutropenia were randomly assigned to a treatment group (314 to short antibiotic treatment and 348 to long antibiotic treatment). All trials excluded people who had bacteria growing in any culture before the time of randomisation. All studies except two excluded people with infection in a specific organ. Three trials did not report funding sources; three were funded by academic sponsors; one had academic sponsorship, but the antibiotics and placebos were provided by pharmaceutical companies; and one was sponsored by government funding. There was no difference in mortality between the short- and long-antibiotic therapy arm. There was no difference in the number of people with severe infections presenting as bacteria in blood. There were more cases of infections with positive cultures in people treated with short antibiotic courses compared to long antibiotic courses, but there was no difference in the rate of unfavourable outcome such as recurrence of fever, need for rehospitalization, and change or restart of antibiotics. We found no differences in the rate of fungal infections and development of antibiotic resistance, with few studies reporting the latter outcome. The number of days with fever was lower for people treated with short antibiotic courses compared to those treated with long antibiotic courses. In all trials the number of antibiotic treatment days was fewer in the short-antibiotic therapy arm by three to seven days compared to the long-antibiotic therapy arm. Data on hospital length of stay were insufficient to permit any meaningful conclusions. The overall certainty of evidence was low or very low, permitting little confidence in the results presented. Most of the included studies were old and not adequately designed. There were also many differences between the studies in terms of design and inclusion criteria. We assessed the certainty of the evidence for the primary outcome of all-cause mortality as low and for the outcomes of clinical failure and bacteraemia occurring after randomisation as very low.

10.1002/14651858.CD012184.pub2

cochrane-simplification-train-830

cochrane-simplification-train-830

Twenty-three trials (total of 912 patients) met the inclusion criteria (22 in RA; one in a mixed population of RA and osteoarthritis); all except one were published before 1990. Most study populations were not taking DMARDs (e.g. methotrexate, sulphasalazine, hydroxychloroquine and leflunomide) and all studies were performed prior to the introduction of biologic therapies (e.g. etanercept, infliximab and adalimumab). All trials were at high risk of bias, heterogeneity precluded meta-analysis, and we were only able to report a general description of results. The majority (18 studies, 78%) found no differences between the combination and monotherapy treatments they studied, while five (22%) reported conflicting results, favouring either the combination or monotherapy arms. From the 12 trials on NSAID + analgesic vs NSAID, nine reported no significant difference between the interventions, while three did: in two, the combination therapy achieved better pain control; and the third trial compared combination therapy with two different dosages of monotherapy (NSAID alone) and reported that a high dose phenylbutazone was superior to combination therapy (paracetamol + aspirin), which was superior to low dose phenylbutazone. From the five studies on the combination of two NSAIDS vs one NSAID, four reported no significant differences between interventions, and one reported significantly better pain control with combination therapy. The single trial comparing a combination of opioid + neuromodulator vs opioid reported better pain control with monotherapy. The remaining trials (NSAID + neuromodulator vs NSAID (3 trials); opioid + NSAID vs NSAID (1 trial); and opioid + analgesic vs analgesic (1 trial)) found no significant difference between combination therapy and monotherapy. Information regarding withdrawals due to inadequate analgesia and safety was incompletely reported, but in general there were no differences between combination therapy and monotherapy. No data were available that addressed the value of combination pain therapy or monotherapy for people with IA who have optimal disease suppression. There were no studies that included patients with AS, PsA or SpA. Based on 23 trials, all at high risk of bias, there is insufficient evidence to establish the value of combination therapy over monotherapy for people with IA. Importantly, there are no studies addressing the value of combination therapy for patients with IA who have persistent pain despite optimal disease suppression. Well designed trials are needed to address this question.

There is insufficient evidence to establish the value of combination therapy over monotherapy for people with IA. We included 23 studies in this review, all at high risk of bias (i.e. high chance of giving invalid results). Twenty-two of the trials were in patients with RA and one in a mixed population (RA and osteoarthritis). There were no studies in patients with AS, PsA or SpA. Included studies were old (all but one were published before 1990) and patients were, in general, not on optimal disease-modifying antirheumatic drugs, as is standard current practice. Therefore, it is not possible to draw conclusions about the value of combination pain therapy over monotherapy for people with IA. Importantly, there are no studies addressing the value of combination therapy for patients with IA who have persistent pain despite optimal disease suppression. Well designed studies are needed to address this question.

10.1002/14651858.CD008886.pub2

cochrane-simplification-train-831

cochrane-simplification-train-831

In this update, we found an additional 42 trials and added them to the original 254 studies. The update consists of 296 trials that evaluated dose-related efficacy of atorvastatin in 38,817 participants. Included are 242 before-and-after trials and 54 placebo-controlled RCTs. Log dose-response data from both trial designs revealed linear dose-related effects on blood total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides. The Summary of findings table 1 documents the effect of atorvastatin on LDL-cholesterol over the dose range of 10 to 80 mg/d, which is the range for which this systematic review acquired the greatest quantity of data. Over this range, blood LDL-cholesterol is decreased by 37.1% to 51.7% (Summary of findings table 1). The slope of dose-related effects on cholesterol and LDL-cholesterol was similar for atorvastatin and rosuvastatin, but rosuvastatin is about three-fold more potent. Subgroup analyses suggested that the atorvastatin effect was greater in females than in males and was greater in non-familial than in familial hypercholesterolaemia. Risk of bias for the outcome of withdrawals due to adverse effects (WDAEs) was high, but the mostly unclear risk of bias was judged unlikely to affect lipid measurements. Withdrawals due to adverse effects were not statistically significantly different between atorvastatin and placebo groups in these short-term trials (risk ratio 0.98, 95% confidence interval 0.68 to 1.40). This update resulted in no change to the main conclusions of the review but significantly increases the strength of the evidence. Studies show that atorvastatin decreases blood total cholesterol and LDL-cholesterol in a linear dose-related manner over the commonly prescribed dose range. New findings include that atorvastatin is more than three-fold less potent than rosuvastatin, and that the cholesterol-lowering effects of atorvastatin are greater in females than in males and greater in non-familial than in familial hypercholesterolaemia. This review update does not provide a good estimate of the incidence of harms associated with atorvastatin because included trials were of short duration and adverse effects were not reported in 37% of placebo-controlled trials.

This represents the first update of this review, which was published in 2012 (Adams 2012). Atorvastatin is one of the most widely prescribed drugs and the most widely prescribed statin in the world. It is an HMG-CoA reductase inhibitor that is prescribed to prevent adverse cardiovascular events and to lower blood total cholesterol and LDL-cholesterol. It is therefore important to know the magnitude of the effect that atorvastatin has on cholesterol. We searched for all evidence obtained from three- to 12-week trials reporting the effect of atorvastatin on blood cholesterol. This update found 42 additional trials and reports on 296 trials in 38,817 participants. Atorvastatin showed a consistent effect in lowering blood cholesterol over the dose range of 2.5 to 80 mg daily. The effect was greater with higher doses than with lower doses. Atorvastatin works similarly to rosuvastatin in lowering cholesterol but is about three-fold less potent. Risk of bias for all assessed trials was high. Review authors were unable to assess harms of atorvastatin because the included trials were too short, and because only 34 included trials assessed harms.

10.1002/14651858.CD008226.pub3

cochrane-simplification-train-832

cochrane-simplification-train-832

Five trials, including 1476 participants, were included in the review. Two trials compared interferon with observation alone and three trials compared interferon plus chemotherapy with chemotherapy alone. A meta-analysis of two trials involving 370 participants found no significant difference in both overall survival (HR 1.14, 95% CI 0.84 to 1.55) and progression free survival (HR 0.99, 95% CI 0.79 to 1.24) between the interferon and observation alone groups in post-surgical women who had undergone first-line chemotherapy for advanced EOC. One trial with 293 participants found that while no significant difference was observed in incidence of nausea or vomiting between the two treatment groups, significantly more flu-like symptoms (RR 2.25, 95% CI 1.73 to 2.91) and fatigue (RR 1.54, 95% CI 1.27 to 1.88) were reported in the interferon group. For the second comparison, a meta-analysis of two trials comprising 244 participants found that although there was no significant difference in overall survival between the interferon plus chemotherapy and the chemotherapy alone group (HR 1.14, 95% CI 0.74 to 1.76), women in the interferon plus chemotherapy group had worse progression free survival than those in the chemotherapy alone group (HR 1.43, 95% CI 1.02 to 2.00). Compared to chemotherapy alone, adding interferon to chemotherapy did not alter the incidence of adverse events in post-surgical women with advanced EOC. Implications for practice Based on low quality evidence, the addition of interferon to first-line chemotherapy did not alter the overall survival in post-surgical women with advanced EOC compared with chemotherapy alone. There is low quality evidence to suggest that interferon in combination with chemotherapy worsened the progression free survival in post-surgical women with advanced EOC compared with chemotherapy alone. There is not enough evidence that interferon therapy alone alters overall survival or progression free survival compared to observation alone in post-surgical women who have undergone first-line chemotherapy. Implications for research Three of the five trials included in this review were stopped early and were, therefore, underpowered to detect any true effect of the intervention. The trials did not report the results of important outcomes in a uniform manner, preventing statistical aggregation of the results. Trial methodology was poorly reported resulting in unclear risk of bias. For clear recommendations to be made regarding the effectiveness of interferon in the treatment of advanced EOC, long-term, well conducted and adequately powered RCTs would be needed. However, the available data do not suggest that interferon has an adequately advantageous effect to warrant further investigation.

Five trials, including 1476 participants, were included in the review. Three of the five trials were stopped early. The risk of bias of most of the trials was high or unclear due to incomplete reporting of methods and results. Most of the trials were not large enough to detect any true effect of the intervention. Trials either did not report the results of important outcomes or the results of important outcomes were not uniform between the trials. The evidence from the three trials suggested that the addition of interferon to first-line chemotherapy did not alter the overall survival in post-surgical women with advanced EOC compared with chemotherapy alone. On the contrary, there is evidence that interferon in combination with chemotherapy worsened progression free survival in post-surgical women with advanced EOC compared with chemotherapy alone. Furthermore, there is not enough evidence that interferon therapy alone improves overall survival or progression free survival in post-surgical women who have undergone first-line chemotherapy when compared with observation alone.

10.1002/14651858.CD009620.pub2

cochrane-simplification-train-833

cochrane-simplification-train-833

We included 16 randomized controlled trials of dihydropyridine calcium channel blockers in this systematic review, with 2768 randomized participants. Drugs studied included amlodipine, lercanidipine, mandipine, nifedipine, and felodipine (all administered once daily) and nicardipine (administered twice daily). We analyzed and presented data by hour post dose. The blood pressure-lowering effect was stable over time; there were no clinically important differences in blood pressure-lowering effect of calcium channel blockers between each hour for either systolic blood pressure (estimated mean hourly differences ranged between 9.45 mmHg and 13.2 mmHg) or diastolic blood pressure (estimated mean hourly differences ranged between 5.85 mmHg and 8.5 mmHg). However, there was a moderate risk of bias for this finding. Once-daily dihydropyridine calcium channel blockers appeared to lower blood pressure by a relatively constant amount throughout the 24-hour dosing interval. Six dihydropyridine calcium channel blockers studied in this review lowered blood pressure by a relatively similar amount each hour over the course of 24 hours. The benefits and harms of this pattern of blood pressure lowering are unknown. Further trials are needed with accurate recording of time of drug intake and with reporting of standard deviation of blood pressure at each hour. We did not attempt to assess adverse effects in this review due to the lack of reporting and the short duration of follow-up.

This review explores whether the blood pressure lowering effect of dihydropyridine calcium channel blockers in adults (aged 18 years or over) with high blood pressure (systolic blood pressure (the upper blood pressure reading) of at least 140 mmHg or diastolic blood pressure (the lower blood pressure reading) of at least 90 mmHg, or both of these) is consistent or variable over a 24-hour period. We performed a review of studies that compared the 24-hour blood pressure lowering effects of six of these drugs versus a control treatment for at least three weeks. Blood pressure needed to be measured by an ambulatory blood pressure monitor, which is a device that automatically measures blood pressure at regular intervals. We performed searches for clinical trials up to February 2014. We found 16 trials involving 2768 participants that studied five drugs given once a day (amlodipine, lercanidipine, mandipine, nifedipine, and felodipine) and one drug given twice a day (nicardipine). The amount of blood pressure lowering by dihydropyridine calcium channel blockers stayed relatively the same at every hour throughout a 24-hour day. The average hourly differences in blood pressure were between 9.45 mmHg and 13.2 mmHg for systolic blood pressure and between 5.85 mmHg and 8.5 mmHg for diastolic blood pressure. At the present time, the benefits and harms of this pattern of blood pressure lowering are unknown. We judged the overall quality of the evidence to be moderate. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

10.1002/14651858.CD010052.pub2

cochrane-simplification-train-834

cochrane-simplification-train-834

Four trials involving a total of 300 adults with SMI and PTSD are included. These trials evaluated three active intervention therapies: trauma-focused cognitive behavioural therapy (TF-CBT), eye movement desensitisation and reprocessing (EMDR), and brief psychoeducation for PTSD, all delivered via individual sessions. Our main outcomes of interest were PTSD symptoms, quality of life/well-being, symptoms of co-morbid psychosis, anxiety symptoms, depressive symptoms, adverse events and health economic outcomes. 1. TF-CBT versus usual care/waiting list Three trials provided data for this comparison, however, continuous outcome data available were more often found to be skewed than unskewed, leading to the necessity of conducting analyses separately for the two types of continuous data. Using the unskewed data only, results showed no significant differences between TF-CBT and usual care in reducing clinician-rated PTSD symptoms at short term (1 RCT, n =13, MD 13.15, 95% CI -4.09 to 30.39,low-quality evidence). Limited unskewed data showed equivocal results between groups in terms of general quality of life (1 RCT, n = 39, MD -0.60, 95% CI -4.47 to 3.27, low-quality evidence), symptoms of psychosis (1 RCT, n = 9, MD -6.93, 95% CI -34.17 to 20.31, low-quality evidence), and anxiety (1 RCT, n = 9, MD 12.57, 95% CI -5.54 to 30.68, very low-quality evidence), at medium term. The only available data on depression symptoms were skewed and were equivocal across groups at medium term (2 RCTs, n = 48, MD 3.26, 95% CI -3.66 to 10.18, very low-quality evidence). TF-CBT was not associated with more adverse events (1 RCT, n = 100, RR 0.44, 95% CI 0.09 to 2.31, low-quality evidence) at medium term. No data were available for health economic outcomes. Very limited data for PTSD and other symptoms were available over the long term. 2. EMDR versus waiting list One trial provided data for this comparison. Favourable effects were found for EMDR in terms of PTSD symptom severity at medium term but data were skewed (1 RCT, n = 83, MD -12.31, 95% CI -22.72 to -1.90, very low-quality evidence). EMDR was not associated with more adverse events (1 RCT, n = 102, RR 0.21, 95% CI 0.02 to 1.85, low-quality evidence). No data were available for quality of life, symptoms of co-morbid psychosis, depression, anxiety and health economics. 3. TF-CBT versus EMDR One trial compared TF-CBT with EMDR. PTSD symptom severity, based on skewed data (1 RCT, n = 88, MD -1.69, 95% CI -12.63 to 9.23, very low-quality evidence) was similar between treatment groups. No data were available for the other main outcomes. 4. TF-CBT versus psychoeducation One trial compared TF-CBT with psychoeducation. Results were equivocal for PTSD symptom severity (1 RCT, n = 52, MD 0.23, 95% CI -14.66 to 15.12, low-quality evidence) and general quality of life (1 RCT, n = 49, MD 0.11, 95% CI -0.74 to 0.95, low-quality evidence) by medium term. No data were available for the other outcomes of interest. Very few trials have investigated TFPIs for individuals with SMI and PTSD. Results from trials of TF-CBT are limited and inconclusive regarding its effectiveness on PTSD, or on psychotic symptoms or other symptoms of psychological distress. Only one trial evaluated EMDR and provided limited preliminary evidence favouring EMDR compared to waiting list. Comparing TF-CBT head-to-head with EMDR and brief psychoeducation respectively, showed no clear effect for either therapy. Both TF-CBT and EMDR do not appear to cause more (or less) adverse effects, compared to waiting list or usual care; these findings however, are mostly based on low to very low-quality evidence. Further larger scale trials are now needed to provide high-quality evidence to confirm or refute these preliminary findings, and to establish which intervention modalities and techniques are associated with improved outcomes, especially in the long term.

We searched the Cochrane Schizophrenia Group Trial's Register in January 2015 and March 2016 and found four relevant studies involving 300 adults diagnosed with both SMI and PTSD. The participants received treatments that included trauma-focused cognitive behavioural therapy (TF-CBT), eye movement desensitisation and reprocessing (EMDR), and brief psychoeducation. All of these therapies support individuals to work through and process the memories, emotions and behaviours associated with trauma. Key results When TF-CBT was compared to the care usually received, no effect for reducing PTSD, psychotic, depressive or anxiety symptoms or improving quality of life, was noted. There was some low-quality evidence from two studies that people with SMI and PTSD receiving TF-CBT were more likely to recover from PTSD, that is, having PTSD symptoms which are below diagnostic threshold. TF-CBT was not linked to an increase in side effects. A comparison of people receiving EMDR against those awaiting treatment showed a favourable effect for reducing the symptoms of PTSD (very low-quality evidence). Again, there was no difference in side effects. No data were available for the effect of EMDR on quality of life, psychosis, depression or anxiety. A comparison of TF-CBT with EMDR indicated no difference in reduction of PTSD symptom severity (very low-quality evidence). Finally, when TF-CBT was compared with brief psychoeducation there was no evidence that either therapy was superior in treating a range of PTSD symptoms. Quality of the evidence The review identifies limited, low-quality evidence on TF-CBT and EMDR. The effects of these treatments in reducing the symptoms of PTSD remain unclear although they do not appear to cause any more side effects than waiting for treatment. However, many important outcomes of interest have not been reported on and more research into the benefits of trauma-focused psychological interventions for individuals with SMI and PTSD is required.

10.1002/14651858.CD011464.pub2

cochrane-simplification-train-835

cochrane-simplification-train-835

The 2012 update search identified 19 further relevant studies, most of which were from China. Thus the review currently includes 26 studies with a total of 2184 participants. All trials examined the effectiveness of valproate as an adjunct to antipsychotics. With the exception of two studies, the studies were small, the participants and personnel were not blinded (neither was outcome assessment), and most were short-term and incompletely reported. For this update we prespecified seven main outcomes of interest: clinical response (clinically significant response, aggression/agitation), leaving the study early (acceptability of treatment, overall tolerability), adverse events (sedation, weight gain) and quality of life. Adding valproate to antipsychotic treatment resulted in more clinically significant response than adding placebo to antipsychotic drugs (14 RCTs, n = 1049, RR 1.31, 95% CI 1.16 to 1.47, I2 = 12%, low-quality evidence). However, this effect was removed after excluding open RCTs in a sensitivity analysis. In terms of acceptability of treatment (measured by the number of participants leaving the study early due to any reason) valproate was just as acceptable as placebo (11 RCTs, n = 951, RR 0.76, 95% CI 0.47 to 1.24, I2 = 55%). Also overall tolerability (measured by the number of participants leaving the study early for adverse events) between valproate and placebo was similar (6 RCTs, n = 974, RR 1.33, 95% CI 0.90 to 1.97, I2 = 0). Participants in the valproate group were found to be less aggressive than the control group based on the Modified Overt Aggression Scale (3 RCTs, n = 186, MD -2.55, 95% CI -3.92 to -1.19, I2 = 82%, very low-quality evidence). Participants receiving valproate more frequently experienced sedation (8 RCTs, n = 770, RR 1.38, 95% CI 1.07 to 1.79, I2 = 0, low-quality evidence) but were no more likely to gain weight than those receiving placebo (4 RCTs, n = 427, RR 1.17, 95% CI 0.76 to 1.82, I2 = 0, low-quality evidence). No study reported on the important outcome of quality of life. There is limited evidence, based on a number of trials, that the augmentation of antipsychotics with valproate may be effective for overall clinical response, and also for specific symptoms, especially in terms of excitement and aggression. However, this evidence was entirely based on open RCTs. Moreover, valproate was associated with a number of adverse events among which sedation and dizziness appeared significantly more frequently than in the control groups. Further randomised studies which are blinded are necessary before any clear recommendation can be made. Ideally these would focus on people with schizophrenia and aggression, on those with treatment-resistant forms of the illness and on those with schizoaffective disorders.

The review includes 26 studies, found through electronic searching of relevant databases, with a total of 2184 participants. All trials examined the effectiveness of valproate as an add on to antipsychotics. With the exception of two studies, the studies were small, and most of them were short-term and poorly reported. Data from the included trials showed that participants receiving valproate plus an antipsychotic had better clinical response, compared to those taking an antipsychotic with a placebo. However, this advantage was lost when lower-quality trials were taken out of the analysis. Valproate was also indicated to be effective in controlling excitement and aggression. Acceptability and overall tolerability of the combined treatment was similar between treatment groups and did not cause more weight gain, however, adding valproate did cause greater sedation and dizziness. No trial reported effect on quality of life. Evidence is limited and firm conclusions cannot be made. For the main outcomes of interest, the review authors judged the quality of evidence to be low or very low quality, due to methodological issues in the reviewed studies. Most of them were small, short-term and did not blind the participants or personnel. Large, double-blind and long-term randomised trials should be undertaken to properly determine the clinical effects of adding valproate to antipsychotic treatment for people with schizophrenia. This summary was written by Ben Gray, Senior Peer Researcher, McPin Foundation. mcpin.org/

10.1002/14651858.CD004028.pub4

cochrane-simplification-train-836

cochrane-simplification-train-836

Twenty-one studies met our inclusion criteria (N = 457,202 participants). Nineteen studies provided data for the primary analysis (oxygen saturation threshold < 95% or ≤ 95%; N = 436,758 participants). The overall sensitivity of pulse oximetry for detection of CCHD was 76.3% (95% confidence interval [CI] 69.5 to 82.0) (low certainty of the evidence). Specificity was 99.9% (95% CI 99.7 to 99.9), with a false-positive rate of 0.14% (95% CI 0.07 to 0.22) (high certainty of the evidence). Summary positive and negative likelihood ratios were 535.6 (95% CI 280.3 to 1023.4) and 0.24 (95% CI 0.18 to 0.31), respectively. These results showed that out of 10,000 apparently healthy late preterm or full-term newborn infants, six will have CCHD (median prevalence in our review). Screening by pulse oximetry will detect five of these infants as having CCHD and will miss one case. In addition, screening by pulse oximetry will falsely identify another 14 infants out of the 10,000 as having suspected CCHD when they do not have it. The false-positive rate for detection of CCHD was lower when newborn pulse oximetry was performed longer than 24 hours after birth than when it was performed within 24 hours (0.06%, 95% CI 0.03 to 0.13, vs 0.42%, 95% CI 0.20 to 0.89; P = 0.027). Forest and ROC plots showed greater variability in estimated sensitivity than specificity across studies. We explored heterogeneity by conducting subgroup analyses and meta-regression of inclusion or exclusion of antenatally detected congenital heart defects, timing of testing, and risk of bias for the "flow and timing" domain of QUADAS-2, and we did not find an explanation for the heterogeneity in sensitivity. Pulse oximetry is a highly specific and moderately sensitive test for detection of CCHD with very low false-positive rates. Current evidence supports the introduction of routine screening for CCHD in asymptomatic newborns before discharge from the well-baby nursery.

We searched until March 2017 for evidence on use of pulse oximetry to detect CCHD in newborn infants and found 21 studies. These studies used different thresholds to define a pulse oximetry test as positive. We combined all studies using a threshold around 95% (19 studies with 436,758 newborn infants). This review found that for every 10,000 apparently healthy newborn infants screened, around six of them will have CCHD. The pulse oximetry test will correctly identify five of these newborn infants with CCHD (but will miss one case). Newborn infants who are missed could die or experience major morbidity. For every 10,000 apparently healthy newborn infants screened, 9994 will not have CCHD. The pulse oximetry test will correctly identify 9980 of them (but 14 newborn infants will be investigated for suspected CCHD). Some of these infants may be exposed to unnecessary additional tests and a prolonged hospital stay, but a proportion will have a potentially serious non-cardiac illness. The number of newborn infants incorrectly investigated for CCHD decreases when pulse oximetry is performed longer than 24 hours after birth. We judged the included studies to be mainly at low or unclear risk of bias for several of the certainty domains assessed. Some studies used less robust methods to verify negative results. We considered the overall certainty of the evidence as moderate.

10.1002/14651858.CD011912.pub2

cochrane-simplification-train-837

cochrane-simplification-train-837

The review included one trial involving 200 women and was at moderate to high risk of bias.The trial compared a daily dose of nitrofurantoin and close surveillance (regular clinic visit, urine cultures and antibiotics when a positive culture was found) with close surveillance only. No significant differences were found for the primary outcomes: recurrent pyelonephritis (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.31 to 2.53; one study, 167 women), RUTI before birth (RR 0.30, 95% CI 0.06 to 1.38; one study, 167 women), and preterm birth (before 37 weeks) (RR 1.18, 95% CI 0.42 to 3.35; one study, 147 women). The overall quality of evidence for these outcomes as assessed using GRADE was very low. There were no significant differences between the two comparison groups for any of the following secondary outcomes, birthweight less than 2500 (g) (RR 2.03, 95% CI 0.53 to 7.80; one study, 147 infants), birthweight (mean difference (MD) -113.00, 95% CI -327.20 to 101.20; one study, 147 infants), five-minute Apgar score less than seven (RR 2.03, 95% CI 0.19 to 21.87; one study, 147 infants) and miscarriages (RR 3.11, 95% CI 0.33 to 29.29; one study, 167 women). The evidence for these secondary outcomes was also of very low quality. The incidence of asymptomatic bacteriuria (ASB) (at least 103 colonies per mL) (secondary outcome), only reported in women with a clinic attendance rate of more than 90% (RR 0.55, 95% CI 0.34 to 0.89; one study, 102 women), was significantly reduced in women who received nitrofurantoin and close surveillance. Data on total mortality and small-for-gestational-age babies were not reported. A daily dose of nitrofurantoin and close surveillance has not been shown to prevent RUTI compared with close surveillance alone. A significant reduction of ASB was found in women with a high clinic attendance rate and who received nitrofurantoin and close surveillance. There was limited reporting of both primary and secondary outcomes for both women and infants. No conclusions can be drawn regarding the optimal intervention to prevent RUTI in women who are pregnant. Randomised controlled trials comparing different pharmacological and non-pharmacological interventions are necessary to investigate potentially effective interventions to prevent RUTI in women who are pregnant.

This review identified one study involving 200 pregnant women who received nitrofurantoin (antibiotics) and close surveillance (regular clinic visit, urine cultures and antibiotics when a positive culture was found) or close surveillance alone. Suppressive therapy with daily dose of nitrofurantoin and close surveillance was not shown to prevent RUTI compared with close surveillance alone but the evidence was of very low quality. A significant reduction of asymptomatic bacteriuria (presence of bacteria in the urine without the symptoms of a UTI) was found in women with a high clinic attendance rate who received nitrofurantoin and close surveillance. Due to lack of evidence no conclusions can be drawn. Future randomised controlled trials comparing different pharmacological and non-pharmacological interventions are necessary to assess the optimal intervention to prevent RUTI in women who are pregnant. Such trials should report on a comprehensive range of outcomes for both women and infants.

10.1002/14651858.CD009279.pub3

cochrane-simplification-train-838

cochrane-simplification-train-838

We included one trial of 167 women and their babies. This trial was a pilot study recruiting alongside another study, therefore, a separate sample size was not calculated. The trial compared a twice-weekly surveillance regimen (biophysical profile, nonstress tests, umbilical artery and middle cerebral artery Doppler and uterine artery Doppler) with the same regimen applied fortnightly (both groups had growth assessed fortnightly). There were insufficient data to assess this review's primary infant outcome of composite perinatal mortality and serious morbidity (although there were no perinatal deaths) and no difference was seen in the primary maternal outcome of emergency caesarean section for fetal distress (risk ratio (RR) 0.96; 95% confidence interval (CI) 0.35 to 2.63). In keeping with the more frequent monitoring, mean gestational age at birth was four days less for the twice-weekly surveillance group compared with the fortnightly surveillance group (mean difference (MD) -4.00; 95% CI -7.79 to -0.21). Women in the twice-weekly surveillance group were 25% more likely to have induction of labour than those in the fortnightly surveillance group (RR 1.25; 95% CI 1.04 to 1.50). There is limited evidence from randomised controlled trials to inform best practice for fetal surveillance regimens when caring for women with pregnancies affected by impaired fetal growth. More studies are needed to evaluate the effects of currently used fetal surveillance regimens in impaired fetal growth.

The review authors identified only one controlled trial, from New Zealand. This trial randomised 167 women who were between 24 and 36 weeks' pregnant where ultrasound showed a small-for-gestational-age baby. They received a set combination of tests either twice-weekly or fortnightly. With more frequent testing, women were 25% more likely to have induced labour. Overall their babies were born four days earlier than in the fortnightly surveillance group where spontaneous onset of labour was more likely to occur. The mean gestational age at birth was just under 38 weeks in the twice-weekly group and just over 38 weeks in the fortnightly group, which was unlikely to have an impact on the health of the newborn. The number of caesarean sections, either for fetal distress or because of failure of induction, was no different. No information was available on length of antenatal hospital admission or operative vaginal births and infants were not followed up to determine neurodevelopment and cerebral palsy. This study excluded pregnancies with abnormal Doppler studies and disorders of the amniotic fluid. More studies are needed and the women’s views on the testing are also important.

10.1002/14651858.CD007113.pub3

cochrane-simplification-train-839

cochrane-simplification-train-839

We included 22 studies in this updated analysis, including six new trials with 584 additional participants, resulting in a total of 1428 participants. The risk of bias was low in 11 studies, high in one study and unclear in the remaining studies, due primarily to failure to report methodology for randomisation, and allocation concealment or blinding, or both. Fourteen studies examined intraoperative core temperatures among heated and humidified insufflation cohorts and core temperatures were higher compared to cold gas insufflation (MD 0.31 °C, 95% CI, 0.09 to 0.53, I2 = 88%, P = 0.005) (low-quality evidence). If the analysis was limited to the eight studies at low risk of bias, this result became non-significant but remained heterogeneous (MD 0.18 °C, 95% CI, -0.04 to 0.39, I2= 81%, P = 0.10) (moderate-quality evidence). In comparison to the cold CO2 group, the meta-analysis of the heated, non-humidified group also showed no statistically significant difference between groups. Core temperature was statistically, significantly higher in the heated, humidified CO2 with external warming groups (MD 0.29 °C, 95% CI, 0.05 to 0.52, I2 = 84%, P = 0.02) (moderate-quality evidence). Despite the small difference in temperature of 0.31 °C with heated CO2, this is unlikely to be of clinical significance. For postoperative pain scores, there were no statistically significant differences between heated and cold CO2, either overall, or for any of the subgroups assessed. Interestingly, morphine-equivalent use was homogeneous and higher in heated, non-humidified insufflation compared to cold insufflation for postoperative day one (MD 11.93 mg, 95% CI 0.92 to 22.94, I2 = 0%, P = 0.03) (low-quality evidence) and day two (MD 9.79 mg, 95% CI 1.58 to 18.00, I2 = 0%, P = 0.02) (low-quality evidence). However, morphine use was not significantly different six hours postoperatively or in any humidified insufflation groups. There was no apparent effect on length of hospitalisation, lens fogging or length of operation with heated compared to cold gas insufflation, with or without humidification. Recovery room time was shorter in the heated cohort (MD -26.79 minutes, 95% CI -51.34 to -2.25, I2 = 95%, P = 0.03) (low-quality evidence). When the one and only unclear-risk study was removed from the analysis, the difference in recovery-room time became non-significant and the studies were statistically homogeneous (MD -1.22 minutes, 95% CI, -6.62 to 4.17, I2 = 12%, P = 0.66) (moderate-quality evidence). There were also no differences in the frequency of major adverse events that occurred in the cold or heated cohorts. These results should be interpreted with caution due to some limitations. Heterogeneity of core temperature remained significant despite subgroup analysis, likely due to variations in the study design of the individual trials, as the trials had variations in insufflation gas temperatures (35 ºC to 37 ºC), humidity ranges (88% to 100%), gas volumes and location of the temperature probes. Additionally, some of the trials lacked specific study design information making evaluation difficult. While heated, humidified gas leads to mildly smaller decreases in core body temperatures, clinically this does not account for improved patient outcomes, therefore, there is no clear evidence for the use of heated gas insufflation, with or without humidification, compared to cold gas insufflation in laparoscopic abdominal surgery.

We searched the medical literature for randomised controlled trials (where people are allocated at random to one of two or more treatment groups) that compared heated and cold CO2. We analysed data from the trials for changes in core temperature. We also compared post-operative pain scores and pain medication requirements, length of hospital stay, length of surgery and fogging of the surgical video camera lens. Evidence is current to September 2016. We identified and included 22 trials. There was an increase of 0.31 °C in the heated, humidified CO2 group compared to the cold CO2 group but the data were heterogeneous (highly variable). However, if the analysis was limited to the eight low-risk-of-bias studies that reported core temperatures, no significant difference was found. Also, there was no temperature difference for heated and non-humidified gas compared to cold gas. There was no difference in postoperative pain with heated or cold insufflation. However, pain medication use was higher in only the heated, non-humidified group on postoperative days one and two. Heated gas apparently did not change length of hospitalisation, lens fogging or length of operation. Recovery room stay was shorter with heated gas but the data was heterogeneous (highly variable). When we only included studies at low risk of bias, the data became homogeneous (less variable) and the recovery room time was not significantly different between the heated and cold gas groups. While heated, humidified gas leads to slightly smaller decreases in core body temperatures, this does not account for improvement in any patient outcomes. Therefore, there is no clear evidence for the use of heated gas insufflation, with or without humidification, in laparoscopic abdominal surgery.

10.1002/14651858.CD007821.pub3

cochrane-simplification-train-840

cochrane-simplification-train-840

Five studies treated 177 participants with painful diabetic neuropathy (104) or postherpetic neuralgia (73). The mean or median ages in the studies were 55 to 72 years. Four studies used a cross-over, and one a parallel group design; 145 participants were randomised to receive desipramine 12.5 mg to 250 mg daily, with most taking 100 mg to 150 mg daily following titration. Comparators were placebo in three studies (an 'active placebo' in two studies), fluoxetine, clomipramine (one study each), and amitriptyline (two studies), and treatment was for two to six weeks. All studies had one or more sources of potential major bias. No study provided first or second tier evidence for any outcome. No data were available on the proportion of people with at least 50% or 30% reduction in pain, but data were available from three studies for our other primary outcome of Patient Global Impression of Change, reported as patient evaluation of pain relief that was 'complete' or 'a lot'. No pooling of data was possible, but third tier evidence in individual studies indicated some improvement in pain relief with desipramine compared with placebo, although this was very low quality evidence, derived mainly from group mean data and completer analyses in small, short duration studies where major bias was possible. There were too few participants in comparisons of desipramine with another active treatment to draw any conclusions. All studies reported some information about adverse events, but reporting was inconsistent and fragmented. Participants taking desipramine experienced more adverse events, and a higher rate of withdrawal due to adverse events, than did participants taking placebo (very low quality evidence). This review found little evidence to support the use of desipramine to treat neuropathic pain. There was very low quality evidence of benefit and harm, but this came from studies that were methodologically flawed and potentially subject to major bias. Effective medicines with much greater supportive evidence are available. There may be a role for desipramine in patients who have not obtained pain relief from other treatments.

Five small studies, each with 24 to 54 participants, included 177 participants in total with painful diabetic neuropathy or postherpetic neuralgia. Studies were randomised and double-blind, but all had one or more sources of potential major bias that could lead to overestimation of efficacy. It was not possible to combine information from the different studies, but individually they indicated some benefit from desipramine (usually at a dose between 100 mg and 150 mg daily), compared with placebo, at the expense of increased adverse events. There was not enough information about other comparators to draw any conclusions. There was too little information, which was of inadequate quality, to be sure that desipramine works as a pain medicine in painful diabetic neuropathy or postherpetic neuralgia, and no information about other types of neuropathic pain. Other medicines have been shown to be effective as treatments of first choice.

10.1002/14651858.CD011003.pub2

cochrane-simplification-train-841

cochrane-simplification-train-841

Twenty-three randomised controlled trials were identified. A total of 3872 and 2915 participants in the intervention and in the control group, respectively, were analysed. The weighted mean difference (WMD) for the level of glycosylated haemoglobin was -0.08 (95% confidence interval (CI) -0.12 to -0.04) in favour of the long acting insulin arm. The WMD between the groups in fasting plasma and blood glucose levels was -0.63 (95% CI -0.86 to -0.40) and -0.86 (95% CI -1.00 to -0.72) in favour of the long acting insulins. The odds ratio for a patient on long acting insulin to develop any type of hypoglycaemia was 0.93 (95% CI 0.8 to 1.08) compared to that of a patient on intermediate acting insulins. The OR for severe hypoglycaemic episodes was 0.73 (95% CI 0.61 to 0.87), and 0.70 (95% CI of 0.63 to 0.79) for nocturnal episodes. The WMD between the long and intermediate insulin groups for hypoglycaemic events per 100 patient follow up days was -0.77 (95% CI -0.89 to -0.65), -0.0 (95% CI -0.02 to 0.02) and -0.40 (95% CI -0.45 to -0.34) for overall, severe, and nocturnal hypoglycaemic episodes. Weight gain was more prominent in the control group. No difference was noted in the quantity or quality of severe adverse events or deaths. Long acting insulin preparations seem to exert a beneficial effect on nocturnal glucose levels. Their effect on the overall diabetes control is clinically unremarkable. Their use as a basal insulin regimen for type 1 diabetes mellitus warrants further substantiation.

Twenty-three studies fulfilled our inclusion criteria with a total of 3872 and 2915 participants in the intervention and in the control group, respectively. The methodological quality of all the studies was rated intermediate to low. Trials duration was no longer than one year. The level of glycosylated haemoglobin, a marker of diabetes control, was lower in the long acting insulin group, but the observed difference was of doubtful clinical significance. Longer acting insulins were superior mostly in their nocturnal effect, which resulted in a lower level of fasting glucose levels and fewer episodes of nocturnal hypoglycaemia. No data on long term complications were available. The currently available data can not substantiate conclusions on the benefits and risks of long acting insulins, and long-term data are of need.

10.1002/14651858.CD006297.pub2

cochrane-simplification-train-842

cochrane-simplification-train-842

Intra-arterial delivery of thrombolytic agents appeared to be more effective than intravenous administration. Thrombolysis was more effective when the angiographic catheter was placed within the thrombus. Although 'high dose' and 'forced infusion' techniques achieved vessel patency in less time than 'low dose infusion', there were more bleeding complications, and no increase in patency rates or improvement in limb salvage at 30 days. Implications for practice Thrombolysis should be reserved for patients with limb threatening ischaemia, due to the high risk of haemorrhage or death. Greater benefit is seen when the thrombolytic agent is delivered into the thrombus. Systemic intravenous thrombolysis is less effective than intra-arterial thrombolysis and is associated with an increase in bleeding complications. 'High dose' and 'forced infusion' techniques, or adjunctive agents such as platelet glycoprotein IIb/IIIa inhibitors may speed up thrombolysis, but these are not accompanied by lower amputation rates or a decreased need for adjunctive endovascular or surgical procedures. 'Low dose continuous infusion', following initial lacing of the thrombus with a high dose of the thrombolytic agent, is the least labour intensive technique. Implications for research Only large multicentre trials with carefully controlled inclusion criteria will be sufficiently powerful to demonstrate genuine benefit for a particular thrombolytic regime.

This review found evidence suggesting that arterial infusion is more effective than intravenous infusion. The risk of haemorrhage with intravenous infusion is high. However, none of the different arterial infusion techniques studied have been shown to be more effective in preventing limb loss, amputation or death. More research is needed to confirm these findings.

10.1002/14651858.CD000985.pub2

cochrane-simplification-train-843

cochrane-simplification-train-843

A total of 59 RCTs with 8924 participants were included. The mean age of included participants ranged from 59.0 to 74.1 years. Mean prostate volume ranged from 39 mL to 82.6 mL. Primary outcomes BTURP probably results in little to no difference in urological symptoms, as measured by the International Prostate Symptom Score (IPSS) at 12 months on a scale of 0 to 35, with higher scores reflecting worse symptoms (mean difference (MD) -0.24, 95% confidence interval (CI) -0.39 to -0.09; participants = 2531; RCTs = 16; I² = 0%; moderate certainty of evidence (CoE), downgraded for study limitations), compared to MTURP. BTURP probably results in little to no difference in bother, as measured by health-related quality of life (HRQoL) score at 12 months on a scale of 0 to 6, with higher scores reflecting greater bother (MD -0.12, 95% CI -0.25 to 0.02; participants = 2004; RCTs = 11; I² = 53%; moderate CoE, downgraded for study limitations), compared to MTURP. BTURP probably reduces transurethral resection (TUR) syndrome events slightly (risk ratio (RR) 0.17, 95% CI 0.09 to 0.30; participants = 6745; RCTs = 44; I² = 0%; moderate CoE, downgraded for study limitations), compared to MTURP. This corresponds to 20 fewer TUR syndrome events per 1000 participants (95% CI 22 fewer to 17 fewer). Secondary outcomes BTURP may carry a similar risk of urinary incontinence at 12 months (RR 0.20, 95% CI 0.01 to 4.06; participants = 751; RCTs = 4; I² = 0%; low CoE, downgraded for study limitations and imprecision), compared to MTURP. This corresponds to four fewer events of urinary incontinence per 1000 participants (95% CI five fewer to 16 more). BTURP probably slightly reduces blood transfusions (RR 0.42, 95% CI 0.30 to 0.59; participants = 5727; RCTs = 38; I² = 0%; moderate CoE, downgraded for study limitations), compared to MTURP. This corresponds to 28 fewer events of blood transfusion per 1000 participants (95% CI 34 fewer to 20 fewer). BTURP may result in similar rates of re-TURP (RR 1.02, 95% CI 0.44 to 2.40; participants = 652; RCTs = 6; I² = 0%; low CoE, downgraded for study limitations and imprecision). This corresponds to one more re-TURP per 1000 participants (95% CI 19 fewer to 48 more). Erectile function as measured by the International Index of Erectile Function score (IIEF-5) at 12 months on a scale from 5 to 25, with higher scores reflecting better erectile function, appears to be similar (MD 0.88, 95% CI -0.56 to 2.32; RCTs = 3; I² = 68%; moderate CoE, downgraded for study limitations) for the two approaches. BTURP and MTURP probably improve urological symptoms, both to a similar degree. BTURP probably reduces both TUR syndrome and postoperative blood transfusion slightly compared to MTURP. The impact of both procedures on erectile function is probably similar. The moderate certainty of evidence available for the primary outcomes of this review suggests that there is no need for further RCTs comparing BTURP and MTURP.

We searched the medical literature for clinical trials up to 19 March 2019. We found 59 randomised trials that compared BTURP with MTURP. These studies included a total of 8924 patients. The longest period of follow-up for the outcomes of interest was 12 months after treatment. Compared to MTURP, BTURP probably results in similar reduction in urinary symptoms and bother. It probably slightly reduces both the risk of TUR syndrome and the need for blood transfusion. Erectile function is probably similar after both procedures, as is the risk of urinary incontinence and the need for a repeat procedure. The quality of evidence for the outcomes of ability to pass urine, patient bother, TUR syndrome, need for blood transfusion, and erectile function was considered to be moderate. The quality of evidence for the outcomes of urinary leakage after the procedure and need for a repeat procedure was low.

10.1002/14651858.CD009629.pub4

cochrane-simplification-train-844

cochrane-simplification-train-844

Seven RCTs were included in the review, totalling 1385 patients. Four of these trials met the criteria for good quality studies. For any antiplatelet agent there were reductions of a poor outcome (RR 0.79, 95% confidence interval (CI) 0.62 to 1.01) and secondary brain ischaemia (RR 0.79, 95% CI 0.56 to 1.22) and more intracranial haemorrhagic complications (RR 1.36, 95% CI 0.59 to 3.12), but none of these differences were statistically significant. There was no effect on case fatality (RR 1.01, 95% CI 0.74 to 1.37) or aneurysmal rebleeding (RR 0.98, 95% CI 0.78 to 1.38). For individual antiplatelet agents, only ticlopidine was associated with statistically significant fewer occurrences of a poor outcome (RR 0.37, 95% CI 95% CI 0.14 to 0.98) but this estimate was based on only one small RCT. This review shows a trend towards better outcome in patients treated with antiplatelet agents, possibly due to a reduction in secondary ischaemia. However, results were not statistically significant, thus no definite conclusions can be drawn. Also, antiplatelet agents could increase the risk of haemorrhagic complications. On the basis of the current evidence treatment with antiplatelet agents in order to prevent secondary ischaemia or poor outcome cannot be recommended.

Therefore, trials have been performed with agents that prevent clotting of blood platelets (antiplatelet agents). In this review of seven trials, including 1385 patients, that studied the effects of antiplatelet agents on the outcome after SAH, we found that patients who were treated with antiplatelet agents had a poor outcome less often, and secondary ischaemia less often than patients that received no antiplatelet agent, but the results were not statistically significant and so no definite conclusion can be drawn. Moreover, patients who are treated with antiplatelet agents might have a slightly higher risk of bleeding. Based on these results we conclude that antiplatelet agents after SAH cannot be recommended at the present time.

10.1002/14651858.CD006184.pub2

cochrane-simplification-train-845

cochrane-simplification-train-845

Three RCTs, with a total of 154 participants were included in this review. None of the studies reported data on prostate cancer mortality. All of the included studies differed with respect to design, participants included and allocation of lycopene. This clinical heterogeneity limits the value on the pooled estimated of the meta-analyses. The methodological quality of two of the three included studies was assessed as posing a 'high' risk of bias. Meta-analysis indicated no statistical difference in PSA levels between men randomised to receive lycopene and the comparison group (MD (mean difference) -0.34, 95% CI (confidence interval) -2.01 to 1.32). Only one study reported incidence of prostate cancer (10% in the lycopene group versus 30% in control group). The level of lycopene was also not statistically different in men randomised to receive lycopene and the comparison group (MD 0.39 µg/mL (micrograms/millilitre), 95% CI -0.19 to 0.98). No other meta-analyses were possible since other outcomes assessed only had one study contributing data. Given that only three RCTs were included in this systematic review, and the high risk of bias in two of the three studies, there is insufficient evidence to either support, or refute, the use of lycopene for the prevention of prostate cancer. Similarly, there is no robust evidence from RCTs to identify the impact of lycopene consumption upon the incidence of prostate cancer, prostate symptoms, PSA levels or adverse events.

The objective of this systematic review was to identify the effectiveness of lycopene in the prevention of prostate cancer. This review identified 3 relevant studies, comprising 154 participants in total. Two of the studies were assessed to be of 'high' risk of bias. Meta-analysis of two studies indicated no statistical difference in prostate specific antigen (PSA) levels between men randomised to receive lycopene and the comparison group (MD -0.34, 95% CI -2.01 to 1.32). None of the studies assessed prostate cancer mortality. No other meta-analyses were possible since other outcomes assessed only had one study contributing data.

10.1002/14651858.CD008007.pub2

cochrane-simplification-train-846

cochrane-simplification-train-846

We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials. We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome. There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference. DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result. Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score). There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result. None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.

We included 138 randomised clinical trials. All included trials were at high risk of bias. The 138 trials used 51 different DAAs. Of these, 84 trials assessed DAAs on the market or under development; 57 trials were on DAAs withdrawn from development or the market. Trials were conducted from 2004 to 2016. The trials were from all over the world including 34 different countries. We included 17 trials where all the participants had previously been treated for hepatitis C (treatment-experienced) before being included in the trial. There were 95 trials that included only participants who had not been previously treated for hepatitis C (treatment-naive). The intervention periods ranged from one day to 48 weeks with an average of 14 weeks. The combined intervention period and follow-up period ranged from one day to 120 weeks with an average of 34 weeks. We could not reliably determine the effect of DAAs on hepatitis C-related morbidity or death from any cause. There were no data on hepatitis C-related morbidity and very few deaths occurred over the course of the trials (15 deaths/2377 direct-acting antiviral participants (0.63%) versus 1 death/617 control participants (0.16%), very low quality evidence). Based on very low quality evidence, 5.2% people treated with DAAs had one or more serious adverse events versus 5.6% participants who were untreated during the observation period. When analysed separately, simeprevir was the only direct-acting antiviral that showed evidence of a beneficial effect when assessing risk of a serious adverse event. Our analyses, however, showed that the validity of this result is questionable and that 'play of chance' might be the cause for the difference. There was not enough information to determine if there was any effect of DAAs on other clinically relevant outcomes. Our results confirm that DAAs seem to reduce the number of people who have the hepatitis C virus in their blood from 54.1% in untreated people to 23.8% in those who were treated. Because the loss of detectable hepatitis C virus in the blood stream is only a blood test, the studies could not tell what this result means in the long term. Due to several limitations (e.g. lack of blinding, lack of relevant data, missing data, no published protocol) we assessed the quality of the evidence in this review as very low or low quality. First, all trials and outcome results were at high risk of bias, which means that our results presumably overestimate the beneficial effects of DAAs and underestimate any potential harmful effects. Second, there were limited data on most of our clinical outcomes, that is, there were only relevant clinical data for meta-analyses on all-cause mortality and serious adverse events, and for these, data were sparse. There are no long-term trials that have assessed whether or not DAA treatment improves morbidity or mortality.

10.1002/14651858.CD012143.pub3

cochrane-simplification-train-847

cochrane-simplification-train-847

Only one study met the criteria of inclusion in the review. This study compared oral zinc with placebo. Oral zinc was administered in a dose of 5 mL twice daily from day 2 to day 7 postpartum. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or with a spoon. Incidence of hyperbilirubinaemia, defined as serum total bilirubin (STB) ≥ 15 mg/dL, was similar between groups (N = 286; risk ratio (RR) 0.94, 95% confidence interval (CI) 0.58 to 1.52). Mean STB levels, mg/dL, at 72 ± 12 hours were comparable in both the groups (N = 286; mean difference (MD) -0.20; 95% CI -1.03 to 0.63). Although the duration of phototherapy in the zinc group was significantly shorter compared to the placebo group (N = 286; MD -12.80, 95% CI -16.93 to -8.67), the incidence of need for phototherapy was comparable across both the groups (N = 286; RR 1.20; 95% CI 0.66 to 2.18). Incidences of side effects like vomiting (N = 286; RR 0.65, 95% CI 0.19 to 2.25), diarrhoea (N = 286; RR 2.92, 95% CI 0.31 to 27.71), and rash (N = 286; RR 2.92, 95% CI 0.12 to 71.03) were found to be rare and statistically comparable between groups. The limited evidence available has not shown that oral zinc supplementation given to infants up to one week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.

Researchers from Cochrane searched for all available literature up to 30 November 2014. One randomised controlled trial met our inclusion criteria. In this review, the efficacy of oral zinc salt was compared with placebo. One study enrolling 294 infants was identified. This study evaluated oral zinc salt, given in a dose of 5 mg twice daily to infants between 25 and 168 hours old. The administration of oral zinc salt did not affect the incidence of jaundice (hyperbilirubinaemia) in these infants.

10.1002/14651858.CD008432.pub2

cochrane-simplification-train-848

cochrane-simplification-train-848

We identified 22 studies (3465 participants); 17 studies (3282 participants) compared statin with placebo or no treatment, and five studies (183 participants) compared two different statin regimens. From data generally derived from a single high-quality study, it was found that statins may reduce major cardiovascular events (1 study, 2102 participants: RR 0.84, CI 0.66 to 1.06), cardiovascular mortality (4 studies, 2322 participants: RR 0.68, CI 0.45 to 1.01), and fatal or non-fatal myocardial infarction (1 study, 2102 participants: RR 0.70, CI 0.48 to 1.01); although effect estimates lack precision and include the possibility of no effect. Statins had uncertain effects on all-cause mortality (6 studies, 2760 participants: RR 1.08, CI 0.63 to 1.83); fatal or non-fatal stroke (1 study, 2102 participants: RR 1.18, CI 0.85 to 1.63); creatine kinase elevation (3 studies, 2233 participants: RR 0.86, CI 0.39 to 1.89); liver enzyme elevation (4 studies, 608 participants: RR 0.62, CI 0.33 to 1.19); withdrawal due to adverse events (9 studies, 2810 participants: RR 0.89, CI 0.74 to 1.06); and cancer (1 study, 2094 participants: RR 0.94, CI 0.82 to 1.07). Statins significantly reduced serum total cholesterol (12 studies, 3070 participants: MD -42.43 mg/dL, CI -51.22 to -33.65); low-density lipoprotein cholesterol (11 studies, 3004 participants: MD -43.19 mg/dL, CI -52.59 to -33.78); serum triglycerides (11 studies, 3012 participants: MD -27.28 mg/dL, CI -34.29 to -20.27); and lowered high-density lipoprotein cholesterol (11 studies, 3005 participants: MD -5.69 mg/dL, CI -10.35 to -1.03). Statins had uncertain effects on kidney function: ESKD (6 studies, 2740 participants: RR 1.14, CI 0.94 to 1.37); proteinuria (2 studies, 136 participants: MD -0.04 g/24 h, CI -0.17 to 0.25); acute allograft rejection (4 studies, 582 participants: RR 0.88, CI 0.61 to 1.28); and GFR (1 study, 62 participants: MD -1.00 mL/min, CI -9.96 to 7.96). Due to heterogeneity in comparisons, data directly comparing differing statin regimens could not be meta-analysed. Evidence for statins in people who have had a kidney transplant were sparse and lower quality due to imprecise effect estimates and provided limited systematic evaluation of treatment harm. Statins may reduce cardiovascular events in kidney transplant recipients, although treatment effects are imprecise. Statin treatment has uncertain effects on overall mortality, stroke, kidney function, and toxicity outcomes in kidney transplant recipients. Additional studies would improve our confidence in the treatment benefits and harms of statins on cardiovascular events in this clinical setting.

The aim of this review was to find out whether statins prevent death and complications from heart disease in people who have had a kidney transplant. We included 17 studies in 3282 adults with a functioning kidney transplant which compared statin therapy to a placebo or standard treatment. Based largely on information from a single, large and well-conducted study, statins may reduce complications from heart disease although information from the available research is imprecise. The effects of statin treatment on death overall, stroke, kidney function and side-effects are uncertain in people with a kidney transplant. Large additional studies of statin therapy may improve our confidence that statin treatment can safely prevent serious complications from heart disease for people who have a kidney transplant.

10.1002/14651858.CD005019.pub4

cochrane-simplification-train-849

cochrane-simplification-train-849

We included three trials (2804 children), comparing cuffed with uncuffed ETTs. We rated the risks of bias in all three trials as high. Outcome data were limited. The largest trial was supported by Microcuff GmbH, who provided the cuffed tubes used. The other two trials were small, and should be interpreted with caution. Based on the GRADE approach, we rated the quality of evidence as low to very low. Two trials comparing cuffed versus uncuffed ETTs found no difference between the groups for postextubation stridor (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.65 to 1.33; 2734 children; quality of evidence very low). However, those two trials demonstrated a statistically significantly lower rate of endotracheal tube exchange in the cuffed ETT group (RR 0.07, 95% CI 0.05 to 0.10; 2734 children; quality of evidence very low). One trial with 70 participants found that costs per case were lower in the cuffed ETT group (mean difference (MD) EUR 19.0 lower; 95% CI 24.23 to 13.77 lower; quality of evidence low), since the higher cost of the cuffed tubes may be offset by the savings made with anaesthetic gases. No clear evidence emerged to suggest any difference between cuffed and uncuffed tubes for outcomes such as the need to treat postextubation stridor with tracheal re-intubation (RR 1.85, 95% CI 0.17 to 19.76; 115 children; 2 trials; quality of evidence very low), epinephrine (RR 0.70, 95% CI 0.38 to 1.28; 115 children; 2 trials; quality of evidence very low) or corticosteroid (RR 0.87, 95% CI 0.51 to 1.49; 102 children; 1 trial; quality of evidence very low), or need for intensive care unit (ICU) admission to treat postextubation stridor (RR 2.77, 95% CI 0.30 to 25.78; 102 children; 1 trial; quality of evidence very low). None of the trials included in this review evaluated the ability to deliver appropriate tidal volume. Implications for practice We are unable to draw definitive conclusions about the comparative effects of cuffed or non-cuffed endotracheal tubes in children undergoing general anaesthesia. Our confidence is limited by risks of bias, imprecision and indirectness. The lower requirement for exchange of tubes with cuffed ETTs was very low-quality evidence, and the requirement for less medical gas used and consequent lower cost was low-quality evidence. In some cases, tracheal re-intubation is required to guarantee an open airway when adequate oxygenation is difficult after removal of the tube, for a variety of reasons including stridor, muscle weakness or obstruction. No data were available to permit evaluation of whether appropriate tidal volumes were delivered. Implications for research Large randomized controlled trials of high methodological quality should be conducted to help clarify the risks and benefits of cuffed ETTs for children. Such trials should investigate the capacity to deliver appropriate tidal volume. Future trials should also address cost effectiveness and respiratory complications. Such studies should correlate the age of the child with the duration of intubation, and with possible complications. Studies should also be conducted in newborn babies. Future research should be conducted to compare the effects of the different types or brands of cuffed tubes used worldwide. Finally, trials should be designed to perform more accurate assessments and to diagnose the complications encountered with cuffed compared to uncuffed ETTs.

This review includes trials involving 2804 children up to eight years old, undergoing general anaesthesia. The trials assessed two types of cuffed tubes: conventional and Microcuff™ tubes (the latter consisting of a different type of balloon with low pressure levels that is more suitable for children's windpipes). The primary outcome was postextubation stridor. This is a potentially serious problem resulting from the narrowing of the airway and can be identified by a high-pitched noise following removal of the tube. Other factors assessed were the need to exchange the tube for another; to put the tube back in; to use drugs such as epinephrine (adrenaline) or corticosteroid (an anti-inflammatory); and to admit a child to an intensive care unit to treat stridor; the cost of medical gas per child; and the ability to deliver appropriate volumes of oxygen. Two trials (involving 2734 children) measured postextubation stridor and found no difference between the groups. The need to exchange tubes for others was 93% lower in the cuffed ETT group. One trial involving 70 children showed that cuffed tubes reduced the amount of anaesthetic gases required, and consequently the cost involved. The quality of evidence was low to very low, as there were problems with the study designs. Comparisons between cuffed and uncuffed tubes need to be interpreted with caution. Further studies are needed to evaluate the benefits and risks of the two types of tubes. Several gaps remain in the information available around this question. Large, well-conducted clinical trials should clarify factors such as the ability of these tubes to provide adequate amounts of oxygen, and the respiratory complications that occur with the wide use of cuffed tubes in children.

10.1002/14651858.CD011954.pub2

cochrane-simplification-train-850

cochrane-simplification-train-850

There are no nicotine vaccines currently licensed for public use, but there are a number in development. We found four trials which met our inclusion criteria, three comparing NicVAX to placebo and one comparing NIC002 (formerly NicQbeta) to placebo. All were smoking cessation trials conducted by pharmaceutical companies as part of the drug development process, and all trials were judged to be at high or unclear risk of bias in at least one domain. Overall, 2642 smokers participated in the included studies in this review. None of the four included studies detected a statistically significant difference in long-term cessation between participants receiving vaccine and those receiving placebo. The RR for 12 month cessation in active and placebo groups was 1.35 (95% Confidence Interval (CI) 0.82 to 2.22) in the trial of NIC002 and 1.74 (95% CI 0.73 to 4.18) in one NicVAX trial. Two Phase III NicVAX trials, for which full results were not available, reported similar quit rates of approximately 11% in both groups. In the two studies with full results available, post hoc analyses detected higher cessation rates in participants with higher levels of nicotine antibodies, but these findings are not readily generalisable. The two studies with full results showed nicotine vaccines to be well tolerated, with the majority of adverse events classified as mild or moderate. In the study of NIC002, participants receiving the vaccine were more likely to report mild to moderate adverse events, most commonly flu-like symptoms, whereas in the study of NicVAX there was no significant difference between the two arms. Information on adverse events was not available for the large Phase III trials of NicVAX. Vaccine candidates are likely to undergo significant changes before becoming available to the general public, and those included in this review may not be the first to reach market; this limits the external validity of the results reported in this review in terms of both effectiveness and tolerability. There is currently no evidence that nicotine vaccines enhance long-term smoking cessation. Rates of serious adverse events recorded in the two trials with full data available were low, and the majority of adverse events reported were at mild to moderate levels. The evidence available suggests nicotine vaccines do not induce compensatory smoking or affect withdrawal symptoms. No nicotine vaccines are currently licensed for use in any country but a number are under development. Further trials of nicotine vaccines are needed, comparing vaccines with placebo for smoking cessation. Further trials are also needed to explore the potential of nicotine vaccines to prevent relapse. Results from past, current and future research should be reported in full. Adverse events and serious adverse events should continue to be carefully monitored and thoroughly reported.

There are no nicotine vaccines currently licensed for public use, but there are a number in development. We found four trials (2642 participants) comparing nicotine vaccines to a placebo. These did not show that vaccines help people to stop smoking in the long term. All four trials were conducted by pharmaceutical companies as part of the drug development process and involved vaccines administered by injection. There were no trials testing whether nicotine vaccines helped keep people who had stopped smoking from starting to smoke again. Only two of the four trials had full results available. The two trials showed nicotine vaccines to be generally safe, with most side effects being mild or moderate. In one trial, flu-like symptoms were found to be a side effect of the nicotine vaccine. If nicotine vaccines become available to the general public they may have changed from the ones tested in these studies, meaning the results reported in this review, including those on side effects, may not apply to all nicotine vaccines.

10.1002/14651858.CD007072.pub2

cochrane-simplification-train-851

cochrane-simplification-train-851

We included nine industry-sponsored randomised controlled trials (3327 participants) in the review. Seven trials compared pregabalin to placebo. For the primary outcome, participants randomised to pregabalin were significantly more likely to attain a 50% or greater reduction in seizure frequency compared to placebo (RR 2.28, 95% CI 1.52 to 3.42, 7 trials, 2193 participants, low-certainty evidence). The odds of response doubled with an increase in dose from 300 mg/day to 600 mg/day (OR 1.99, 95% CI 1.74 to 2.28), indicating a dose-response relationship. Pregabalin was significantly associated with seizure freedom (RR 3.94, 95% CI 1.50 to 10.37, 4 trials, 1125 participants, moderate-certainty evidence). Participants were significantly more likely to withdraw from pregabalin treatment than placebo for any reason (RR 1.35, 95% CI 1.11 to 1.65, 7 trials, 2193 participants, moderate-certainty evidence) and for adverse effects (RR 2.65, 95% CI 1.88 to 3.74, 7 trials, 2193 participants, moderate-certainty evidence). Three trials compared pregabalin to three active-control drugs: lamotrigine, levetiracetam, and gabapentin. Participants allocated to pregabalin were significantly more likely to achieve a 50% or greater reduction in seizure frequency than those allocated to lamotrigine (RR 1.47, 95% CI 1.03 to 2.12, 1 trial, 293 participants) but not those allocated to levetiracetam (RR 0.94, 95% CI 0.80 to 1.11, 1 trial, 509 participants) or gabapentin (RR 0.96, 95% CI 0.82 to 1.12, 1 trial, 484 participants). We found no significant differences between pregabalin and lamotrigine (RR 1.39, 95% CI 0.40 to 4.83) for seizure freedom, however, significantly fewer participants achieved seizure freedom with add-on pregabalin compared to levetiracetam (RR 0.50, 95% CI 0.30 to 0.85). No data were reported for this outcome for pregabalin versus gabapentin. We found no significant differences between pregabalin and lamotrigine (RR 1.07, 95% CI 0.75 to 1.52), levetiracetam (RR 1.03, 95% CI 0.71 to 1.49), or gabapentin (RR 0.78, 95% CI 0.57 to 1.07) for treatment withdrawal due to any reason or due to adverse effects (pregabalin versus lamotrigine: RR 0.89, 95% CI 0.53 to 1.48; versus levetiracetam: RR 1.29, 95% CI 0.66 to 2.54; versus gabapentin: RR 1.07, 95% CI 0.54 to 2.11). Ataxia, dizziness, somnolence, weight gain, and fatigue were significantly associated with pregabalin. We rated the overall risk of bias in the included studies as low or unclear due to the possibility of publication bias and lack of methodological details provided. We rated the certainty of the evidence as very low to moderate using the GRADE approach. Pregabalin, when used as an add-on drug for treatment-resistant focal epilepsy, is significantly more effective than placebo at producing a 50% or greater seizure reduction and seizure freedom. Results demonstrated efficacy for doses from 150 mg/day to 600 mg/day, with increasing effectiveness at 600 mg doses, however issues with tolerability were noted at higher doses. The trials included in this review were of short duration, and longer-term trials are needed to inform clinical decision making.

This review examined data from 9 trials including a total of 3327 participants. Study participants were assigned using a random method to take pregabalin, placebo, or another antiepileptic drug in addition to their usual antiepileptic drugs. Participants taking pregabalin were more than twice as likely to have their seizure frequency reduced by 50% or more during a 12-week treatment period compared to those taking placebo, and were nearly four times more likely to be completely free of seizures. Pregabalin was shown to be effective across a range of doses (150 mg to 600 mg), with increasing effectiveness at higher doses. There was also an increased likelihood of treatment withdrawal with pregabalin. Side effects associated with pregabalin included ataxia, dizziness, fatigue, somnolence, and weight gain. When pregabalin was compared to three other antiepileptic drugs (lamotrigine, levetiracetam, and gabapentin), participants taking pregabalin were more likely to achieve a 50% reduction in seizure frequency than those taking lamotrigine. We found no significant differences between pregabalin and levetiracetam or gabapentin as add-on drugs. We rated all included studies as at low or unclear in risk of bias due to missing information about the methods used to conduct the trial and a suspicion of publication bias. Publication bias can occur when studies that report non-significant findings are not published. We suspected publication bias because the majority of included studies showed significant findings and were sponsored by the same drug company. We assessed the certainty of the evidence for the primary outcome of reduction in seizure frequency as low, meaning that we cannot be certain that the finding reported is accurate. However, we rated the certainty of the evidence for the outcomes seizure freedom and treatment withdrawal as moderate, so we can be fairly confident that these results are accurate. There were no data regarding the longer-term effectiveness of pregabalin, which should be investigated in future studies. The evidence is current to 5 July 2018.

10.1002/14651858.CD005612.pub4

cochrane-simplification-train-852

cochrane-simplification-train-852

There were no new included studies for this update. Eight studies (3118 participants) were included in this review. We found no evidence for difference in overall mortality between the groups treated with heparin and placebo (risk ratio (RR) = 0.84, 95% confidence interval (CI) 0.36 to 1.98). Heparins compared with placebo, reduced the occurrence of myocardial infarction in patients with unstable angina and NSTEMI (RR = 0.40, 95% CI 0.25 to 0.63, number needed to benefit (NNTB) = 33). There was a trend towards more major bleeds in the heparin studies compared to control studies (RR = 2.05, 95% CI 0.91 to 4.60). From a limited data set, there appeared to be no difference between patients treated with heparins compared to control in the occurrence of thrombocytopenia (RR = 0.20, 95% CI 0.01 to 4.24). Assessment of overall risk of bias in these studies was limited as most of the studies did not give sufficient detail to allow assessment of potential risk of bias. Compared with placebo, patients treated with heparins had a similar risk of mortality, revascularization, recurrent angina, and thrombocytopenia. However, those treated with heparins had a decreased risk of myocardial infarction and a higher incidence of minor bleeding. Overall, the evidence assessed in this review was classified as low quality according to the GRADE approach. The results presented in this review must therefore be interpreted with caution.

This review of trials found that UFH and LMWH when given to patients with high-risk unstable angina or NSTEMI in the acute phase of treatment, in addition to standard therapy with aspirin, prevent more heart attacks than placebo but do not reduce mortality, the need for revascularization procedures or recurrent angina. Although there was limited reporting of side-effects, heparins caused more cases of minor bleeding.

10.1002/14651858.CD003462.pub3

cochrane-simplification-train-853

cochrane-simplification-train-853

We included 38 trials that involved a total of 7924 children; seven trials were new for this update (1693 participants). Fifteen trials evaluated the effects of resin-based sealant versus no sealant (3620 participants in 14 studies plus 575 tooth pairs in one study); three trials with evaluated glass ionomer sealant versus no sealant (905 participants); and 24 trials evaluated one type of sealant versus another (4146 participants). Children were aged from 5 to 16 years. Trials rarely reported background exposure to fluoride of trial participants or baseline caries prevalence. Resin-based sealant versus no sealant: second-, third- and fourth-generation resin-based sealants prevented caries in first permanent molars in children aged 5 to 10 years (at 24 months follow-up: OR 0.12, 95% CI 0.08 to 0.19, 7 trials (5 published in the 1970s; 2 in the 2010s), 1548 children randomised, 1322 children evaluated; moderate-quality evidence). If we were to assume that 16% of the control tooth surfaces were decayed during 24 months of follow-up (160 carious teeth per 1000), then applying a resin-based sealant would reduce the proportion of carious surfaces to 5.2% (95% CI 3.13% to 7.37%). Similarly, assuming that 40% of control tooth surfaces were decayed (400 carious teeth per 1000), then applying a resin-based sealant would reduce the proportion of carious surfaces to 6.25% (95% CI 3.84% to 9.63%). If 70% of control tooth surfaces were decayed, there would be 19% decayed surfaces in the sealant group (95% CI 12.3% to 27.2%). This caries-preventive effect was maintained at longer follow-up but evidence quality and quantity was reduced (e.g. at 48 to 54 months of follow-up: OR 0.21, 95% CI 0.16 to 0.28, 4 trials, 482 children evaluated; RR 0.24, 95% CI 0.12 to 0.45, 203 children evaluated). Although studies were generally well conducted, we assessed blinding of outcome assessment for caries at high risk of bias for all trials (blinding of outcome assessment is not possible in sealant studies because outcome assessors can see and identify sealant). Glass ionomer sealant versus no sealant: was evaluated by three studies. Results at 24 months were inconclusive (very low-quality evidence). One sealant versus another sealant: the relative effectiveness of different types of sealants is unknown (very low-quality evidence). We included 24 trials that directly compared two different sealant materials. Comparisons varied in terms of types of sealant assessed, outcome measures chosen and duration of follow-up. Adverse events: only four trials assessed adverse events. No adverse events were reported. Resin-based sealants applied on occlusal surfaces of permanent molars are effective for preventing caries in children and adolescents. Our review found moderate-quality evidence that resin-based sealants reduced caries by between 11% and 51% compared to no sealant, when measured at 24 months. Similar benefit was seen at timepoints up to 48 months; after longer follow-up, the quantity and quality of evidence was reduced. There was insufficient evidence to judge the effectiveness of glass ionomer sealant or the relative effectiveness of different types of sealants. Information on adverse effects was limited but none occurred where this was reported. Further research with long follow-up is needed.

We included 38 studies that involved 7924 young people (aged 5 to 16 years) among whom a variety of dental sealants was used to prevent tooth decay. Young people in the studies represented the general population. The review includes studies available from a search of the literature up to 3 August 2016. We assessed all studies as being at high risk of bias because the dental professionals who are measuring the outcomes can see whether or not sealant has been used. Fifteen studies compared resin-based sealants to no sealants and found that children who had sealant applied to their back teeth were less likely to have tooth decay in their back teeth than children with no sealant. We were able to combine data from seven of these studies (including two published since 2010), which involved children who were aged from 5 to 10 years when the sealants were applied. This showed that if 40% of back teeth develop decay over 24 months, using sealant reduces this to 6%. Similar benefits for resin-based sealants were shown up to four years. The effect appeared to persist when measured up to nine years, but there was less evidence. Results were inconclusive when glass ionomer-based sealant was compared with no sealant and when one type of sealant material was compared with another. Four studies assessed possible problems from using sealants; none were reported. We found moderate-quality evidence that resin-based sealant is more effective than no sealant for preventing tooth decay, reducing it by between 11% and 51% more than in children without sealant (measured two years after application). 'Moderate quality' means we are reasonably certain of this finding, although it is possible that future research could change it. Most of the studies included in this analysis were carried out in the 1970s. We are not able to draw conclusions about the other comparisons included in our review as the available evidence is very low quality. More studies with long follow-up times are needed.

10.1002/14651858.CD001830.pub5

cochrane-simplification-train-854

cochrane-simplification-train-854

This review includes 15 trials with a total of 791 participants that have evaluated Pycnogenol® for the treatment of seven different chronic disorders. These included asthma (two studies; N = 86), attention deficit hyperactivity disorder (one study; N = 61), chronic venous insufficiency (two studies; N = 60), diabetes mellitus (four studies; N = 201), erectile dysfunction (one study; N = 21), hypertension (two studies; N = 69) and osteoarthritis (three studies; N = 293). Two of the studies were conducted exclusively in children; the others involved adults. Due to small sample size, limited numbers of trials per condition, variation in outcomes evaluated and outcome measures used, as well as the risk of bias in the included studies, no definitive conclusions regarding the efficacy or safety of Pycnogenol® are possible. Current evidence is insufficient to support Pycnogenol® use for the treatment of any chronic disorder. Well-designed, adequately powered trials are needed to establish the value of this treatment.

We chose to focus on Pycnogenol® as this supplement is a standardised product, many trials have been conducted, and it is extensively marketed internationally. Our review aimed to assess the efficacy and safety of Pycnogenol® as a treatment for chronic disorders. We identified 15 eligible randomised controlled trials with a total of 791 participants which addressed seven different chronic conditions: asthma (two studies); attention deficit hyperactivity disorder (one study), chronic venous insufficiency (two studies), diabetes (four studies), erectile dysfunction (one study), hypertension (two studies) and osteoarthritis (three studies). Due to small sample size, limited number of trials per condition, variation in outcomes evaluated and outcome measures used, as well as the risk of bias in the included studies, no definite conclusions regarding the efficacy and safety of Pycnogenol® are possible.

10.1002/14651858.CD008294.pub4

cochrane-simplification-train-855

cochrane-simplification-train-855

We included three trials, involving 496 participants, and defined four trials as waiting assessment. All three included trials were of edaravone plus another treatment compared with the other treatment alone. The dose of edaravone injections in the three trials was the same at 60 mg per day. The course of treatment in all three trials is 14 days. None of the included trials reported the pre-specified primary outcome of death or dependency defined using the modified Rankin scale during the follow-up period. The three trials evaluated the effect of edaravone at different times and using different methods. All three trials reported adverse events; there were no differences between the treatment group and the control group. Overall, edaravone appeared to increase the proportion of participants with marked neurological improvement compared with the control group, and the difference was significant (risk ratio (RR) 1.99, 95% confidence interval (CI) 1.60 to 2.49). The risk of bias in the included trials was moderate and the sample was small. Hence, although the data in this review show an effective treatment trend of edaravone for acute ischaemic stroke, further large, high-quality trials are required to confirm this trend.

Data from some experimental and human studies have suggested that edaravone, a neuroprotective agent, may be beneficial for people with acute ischaemic stroke. It has been widely used in China to treat stroke. To obtain a reliable assessment of the effects of edaravone in acute ischaemic stroke, we reviewed data from three studies involving 496 participants. The quality of the trials was moderate. It would appear that edaravone is an effective treatment for acute ischaemic stroke. However, more high-quality and bigger sample trials are needed to confirm this result.

10.1002/14651858.CD007230.pub2

cochrane-simplification-train-856

cochrane-simplification-train-856

Three randomised controlled trials and one quasi-randomised controlled trial were included. These involved a total of 292 participants with ankle fractures. All studies were at high risk of bias from lack of blinding. Additionally, loss to follow-up or inappropriate exclusion of participants put two trials at high risk of attrition bias. The trials used different and incompatible outcome measures for assessing function and pain. Only limited meta-analysis was possible for early treatment failure, some adverse events and radiological signs of arthritis. One trial, following up 92 of 111 randomised participants, found no statistically significant differences between surgery and conservative treatment in patient-reported symptoms (self assessed ankle "troubles": 11/43 versus 14/49; risk ratio (RR) 0.90, 95% CI 0.46 to 1.76) or walking difficulties at seven years follow-up. One trial, reporting data for 31 of 43 randomised participants, found a statistically significantly better mean Olerud score in the surgically treated group but no difference between the two groups in pain scores after a mean follow-up of 27 months. A third trial, reporting data for 49 of 96 randomised participants at 3.5 years follow-up, reported no difference between the two groups in a non-validated clinical score. Early treatment failure, generally reflecting the failure of closed reduction (criteria not reported in two trials) probably or explicitly leading to surgery in patients allocated conservative treatment, was significantly higher in the conservative treatment group (2/116 versus 19/129; RR 0.18, 95% CI 0.06 to 0.54). Otherwise, there were no statistically significant differences between the two groups in any of the reported complications. Pooled results from two trials of participants with radiological signs of osteoarthritis at averages of 3.5 and 7.0 years follow-up showed no between-group differences (44/66 versus 50/75; RR 1.05, 95% CI 0.83 to 1.31). There is currently insufficient evidence to conclude whether surgical or conservative treatment produces superior long-term outcomes for ankle fractures in adults. The identification of several ongoing randomised trials means that better evidence to inform this question is likely to be available in future.

This review included four trials, involving a total of 292 participants. All four trials had flawed methods that could affect the reliability of their findings. No data could be pooled for long-term measures of function or pain. The largest trial found no evidence of differences between surgery and conservative treatment in patient-reported symptoms or walking difficulties at seven years follow-up. The second trial found better results for the surgical group for function but not pain at 27 months, while the third trial reported no difference between the two groups in clinical outcome at 3.5 years. In all four trials, there were some patients in the conservative treatment group who were treated surgically because the repositioning of the fractured bone was judged unsuccessful. Otherwise, there were no significant differences between the two groups in any of the reported complications nor in radiological signs of osteoarthritis. Overall, there was not enough reliable evidence to draw conclusions about whether surgery or conservative treatment is more appropriate for treating broken ankles in adults.

10.1002/14651858.CD008470.pub2

cochrane-simplification-train-857

cochrane-simplification-train-857

We included two RCTs, enrolling a total of 102 participants. Both trials evaluated the effect of DBS on the internal globus pallidus nucleus, and assessed outcomes after three and six months of stimulation. One of the studies included participants with generalised and segmental dystonia; the other included participants with focal (cervical) dystonia. We assessed both studies at high risk for performance and for-profit bias. One study was retrospectively registered with a clinical trial register, we judged the second at high risk of detection bias. Low-quality evidence suggests that DBS of the internal globus pallidus nucleus may improve overall cervical dystonia-related symptoms (mean difference (MD) 9.8 units, 95% CI 3.52 to 16.08 units; 1 RCT, 59 participants), cervical dystonia-related functional capacity (MD 3.8 units, 95% CI 1.41 to 6.19; 1 RCT, 61 participants), and mood at three months (MD 3.1 units, 95% CI 0.73 to 5.47; 1 RCT, 61 participants). Low-quality evidence suggests that In people with cervical dystonia, DBS may slightly improve the overall clinical status (MD 2.3 units, 95% CI 1.15 to 3.45; 1 RCT, 61 participants). We are uncertain whether DBS improves quality of life in cervical dystonia (MD 3 units, 95% CI -7.71 to 13.71; 1 RCT, 57 participants; very low-quality evidence), or emotional state (MD 2.4 units, 95% CI -6.2 to 11.00; 1 RCT, 56 participants; very low-quality evidence). Low-quality evidence suggests that DBS of the internal globus pallidus nucleus may improve generalised or segmental dystonia-related symptoms (MD 14.4 units, 95% CI 8.0 to 20.8; 1 RCT, 40 participants), overall clinical status (MD 3.5 units, 95% CI 2.33 to 4.67; 1 RCT, 37 participants), physical functioning-related quality of life (MD 6.3 units, 95% CI 1.06 to 11.54; 1 RCT, 33 participants), and overall dystonia-related functional capacity at three months (MD 3.1 units, 95% CI 1.71 to 4.48; 1 RCT, 39 participants). We are uncertain whether DBS improves physical functioning-related quality of life (MD 5.0 units, 95% CI -2.14 to 12.14, 1 RCT, 33 participants; very low-quality evidence), or mental health-related quality of life (MD -4.6 units, 95% CI -11.26 to 2.06; 1 RCT, 30 participants; very low-quality evidence) in generalised or segmental dystonia. We pooled outcomes related to safety and tolerability, since both trials used the same intervention and comparison. We found very low-quality evidence of inconclusive results for risk of adverse events (relative risk (RR) 1.58, 95% 0.98 to 2.54; 2 RCTs, 102 participants), and tolerability (RR 1.86, 95% CI 0.16 to 21.57; 2 RCTs,102 participants). DBS of the internal globus pallidus nucleus may reduce symptom severity and improve functional capacity in adults with cervical, segmental or generalised moderate to severe dystonia (low-quality evidence), and may improve quality of life in adults with generalised or segmental dystonia (low-quality evidence). We are uncertain whether the procedure improves quality of life in cervical dystonia (very low-quality evidence). We are also uncertain about the safety and tolerability of the procedure in adults with either cervical and generalised, or segmental dystonia (very-low quality evidence). We could draw no conclusions for other populations with dystonia (i.e. children and adolescents, and adults with other types of dystonia), or for other DBS protocols (i.e. other target nuclei or stimulation paradigms). Further research is needed to establish the long-term efficacy and safety of DBS of the internal globus pallidus nucleus.

We conducted a literature search on 29 May 2018 for studies that compared DBS with sham stimulation (same surgical procedure, but no electrical impulses are delivered through the electrodes placed in the brain), best medical therapy, and placebo (a pretend medicine). We found two studies that compared DBS with sham stimulation, and included a total of 102 participants. One study included participants with dystonia of the limbs and trunk, and the other with dystonia of the neck. Participants received active DBS for a total of six months. The average age of people in the studies was 50 years; the average duration of the disease was 16 years. Both studies were funded by a DBS device manufacturer with possible interests in the results of the studies. For limb and trunk dystonia, DBS may improve symptoms, self-assessed clinical status, and functioning. The results showed that for neck dystonia, DBS may improve symptoms, clinical status, functioning, and mood. For either type of dystonia, we are uncertain about the impact that DBS has on harmful or undesired events, or treatment tolerability. The overall quality of the evidence for neck, limb, and trunk dystonia was low to very low. Further research is needed to draw conclusions about the clinical efficacy, safety, and tolerability of DBS in people with dystonia, especially beyond the three- to six-month duration of the included studies.

10.1002/14651858.CD012405.pub2

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cochrane-simplification-train-858

Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias. One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months. Combining the trial results suggests that patients with PFAPA likely experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution) (moderate-certainty evidence). Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Surgery probably results in a large overall reduction in the average number of episodes over the total length of follow-up (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years (moderate-certainty evidence). Surgery also likely reduces severity, as indicated by the length of PFAPA symptoms during these episodes. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group (moderate-certainty evidence). The evidence suggests that the proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92) (low-certainty evidence). Other outcomes such as absence from school and quality of life were not measured or reported. The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate certainty (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.

We searched for and included any randomised controlled trials published up to October 2019. We found two small randomised controlled trials, with a low risk of bias, comparing tonsillectomy or adenotonsillectomy against non-surgical interventions (total of 67 participants, with data from 65 analysed). One study (39 participants) used the adenotonsillectomy procedure in the intervention group and followed up patients for 18 months. This study applied stringent criteria for diagnosing PFAPA when recruiting patients. The other trial (28 participants) only removed the tonsils and followed up patients for up to six months. Less stringent recruitment criteria were applied and it was possible that patients with other types of recurrent sore throats might have been recruited and included in the trial. Neither study masked participants and investigators to the type of treatment received. Participants in the control groups of both studies received standard medical treatment. The two trials showed that children with PFAPA are likely to benefit from tonsillectomy. The results showed that children who had surgery were about four times more likely to be free of PFAPA symptoms from the point of surgery until the end of the follow-up periods for these studies. There was an overall decrease in the number or frequency of PFAPA episodes experienced by the children in the surgery group. While the average child in the control arm had an average of one episode every two months, this was reduced to less than one-tenth of that; i.e. about one episode every two years among children who had surgery. In addition, the length of each episode was also shortened by an average of 1.8 days (reduced from an average of 3.5 days to 1.7 days per episode) for children who had surgery. Courses of corticosteroids can be used to treat episodes of symptoms in children with PFAPA. One trial reported that the proportion of children given a course of corticosteroids was lower in children who received surgery. The trials reported no complications of surgery. However, these studies might be too small to detect important but rarer types of complications such as bleeding from the surgery. Other outcomes such as absence from school or quality of life were not reported. The certainty of the evidence is moderate (that is, further research is likely to have an important impact on our confidence in the estimates of effects and may change these estimates). The studies are very small. Studies with larger numbers of patients are required to estimate the effects more precisely. There is also some uncertainly about whether the effects observed in these studies can be replicated in most children with PFAPA for two reasons. It is unclear whether some children who did not have PFAPA had been included in the study that applied less stringent inclusion criteria for PFAPA diagnosis. Secondly, it is uncertain whether the treatment received in the control arms of the studies was adequate and represented current practice.

10.1002/14651858.CD008669.pub3

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cochrane-simplification-train-859

Of 2332 publications obtained through the search strategy, seven studies met the inclusion criteria; one study was ongoing and six studies of 435 participants were eligible for inclusion in the updated review. Data show a significant difference in immediate success rates of procedures favouring tube drainage over simple aspiration for management of primary spontaneous pneumothorax (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.69 to 0.89; 435 participants, 6 studies; moderate-quality evidence). Duration of hospitalization however was significantly less for patients treated by simple aspiration (mean difference (MD) -1.66, 95% CI -2.28 to -1.04; 387 participants, 5 studies; moderate-quality evidence). A narrative synthesis of evidence revealed that simple aspiration led to fewer adverse events (245 participants, 3 studies; low-quality evidence), but data suggest no differences between groups in terms of one-year success rate (RR 1.07, 95% CI 0.96 to 1.18; 318 participants, 4 studies; moderate-quality evidence), hospitalization rate (RR 0.60, 95% CI 0.25 to 1.47; 245 participants, 3 studies; very low-quality evidence), and patient satisfaction (median between-group difference of 0.5 on a scale from 1 to 10; 48 participants, 1 study; low-quality evidence). No studies provided data on cost-effectiveness. Available trials showed low to moderate-quality evidence that intercostal tube drainage produced higher rates of immediate success, while simple aspiration resulted in a shorter duration of hospitalization. Although adverse events were reported more commonly for patients treated with tube drainage, the low quality of the evidence warrants caution in interpreting these findings. Similarly, although this review observed no differences between groups when early failure rate, one-year success rate, or hospital admission rate was evaluated, this too needs to be put into the perspective of the quality of evidence, specifically, for evidence of very low and low quality for hospitalization rate and patient satisfaction, respectively. Future adequately powered research is needed to strengthen the evidence presented in this review.

We searched the medical literature (January 2017) and identified seven studies that met the inclusion criteria; one study was ongoing and six studies were eligible for inclusion in the updated review. The six included studies comprised a total of 435 participants with primary spontaneous pneumothorax; 208 of these underwent simple aspiration and 227 underwent intercostal tube drainage. Study results show that tube drainage produced a better rate of immediate treatment success when compared with simple aspiration for primary spontaneous pneumothorax. However, simple aspiration was associated with shorter duration of hospitalization and may have led to fewer adverse events. Researchers noted no significant differences between the two treatments with regard to hospitalization rate, early failure rate, one-year success rate, or patient satisfaction. However, the quality of evidence presented in this review ranged between very low and moderate, making it difficult for review authors to come to definitive conclusions. Results of this review indicate that tube drainage has a better immediate success rate than simple aspiration for treating people with primary spontaneous pneumothorax. However, simple aspiration results in a shorter hospital stay and, although the evidence presented for this outcome is of low quality, may lead to fewer adverse events than are reported with tube drainage. The overall quality of evidence ranges from very low to moderate, and future research is needed to strengthen the evidence presented in this review.

10.1002/14651858.CD004479.pub3

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cochrane-simplification-train-860

Five trials that randomly assigned 144 participants with overt hepatic encephalopathy that were published during 1979 to 1982 were included. Three trials assessed levodopa, and two trials assessed bromocriptine. The mean daily dose was 4 grams for levodopa and 15 grams for bromocriptine. The median duration of treatment was 14 days (range seven to 56 days). None of the trials followed participants after the end of treatment. Only one trial reported adequate bias control; the remaining four trials were considered to have high risk of bias. Random-effects model meta-analyses showed that dopamine agents had no beneficial or detrimental effect on hepatic encephalopathy in the primary analyses (15/80 (19%) versus 14/80 (18%); odds ratio (OR) 2.99, 95% confidence interval (CI) 0.09 to 100.55; two trials) or when paired data from cross-over trials were included (OR 1.04, 95% CI 0.75 to 1.43). Clear evidence of intertrial heterogeneity was identified both in the primary analysis (I2 = 65%) and when paired data from cross-over trials were included (I2 = 40%). Dopamine agents had no beneficial or harmful effect on mortality (42/144 (29%) versus 38/144 (26%); OR 1.11, 95% CI 0.35 to 3.54; five trials). Trial sequential analyses demonstrated that we lacked information to refute or recommend the interventions for all outcomes. Dopamine agonists did not seem to increase the risk of adverse events. This review found no evidence to recommend or refute the use of dopamine agents for hepatic encephalopathy. More randomised placebo-controlled clinical trials without risks of systematic errors and risks of random errors seem necessary to permit firm decisions on dopamine agents for patients with hepatic encephalopathy.

We performed the present systematic review to determine the beneficial and harmful effects of dopamine agents for patients with hepatic encephalopathy. Our analyses included five small trials published in 1982 or earlier. All trials but one had high risks of bias (i.e., risks of systematic errors or risks of overestimation of beneficial effects or risks of underestimation of harmful effects). Only 144 patients were included in the five trials, and accordingly risks of random errors (i.e., play of chance) are present. Our analyses showed no significant differences regarding symptoms of hepatic encephalopathy or mortality in patients treated with dopamine agents compared with patients who received an inactive placebo or no intervention. The number of patients with adverse events seemed comparable in the two intervention groups. Based on the available evidence, we conclude that no evidence can be found to recommend or refute the use of dopamine agents for hepatic encephalopathy. More randomised placebo-controlled clinical trials without risks of systematic errors and risks of random errors seem necessary to obtain firm evidence on dopamine agents for patients with hepatic encephalopathy.

10.1002/14651858.CD003047.pub3

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cochrane-simplification-train-861

We identified 14 studies (1390 participants), nine enrolled adults without a known access stenosis (primary prophylaxis; three studies including people using fistulas) and five enrolled adults with a documented stenosis in a non-dysfunctional access (secondary prophylaxis; three studies in people using fistulas). Study follow-up ranged from 6 to 38 months, and study size ranged from 58 to 189 participants. In low- to moderate-quality evidence (based on GRADE criteria) in adults treated with haemodialysis, relative to no surveillance and deferred correction, surveillance with pre-emptive correction of an AV stenosis reduced the risk of thrombosis (RR 0.79, 95% CI 0.65 to 0.97; I² = 30%; 18 study comparisons, 1212 participants), and probably improves the longevity of AV access (RR 0.80, 95% CI 0.64 to 0.99; I² = 0%; 11 study comparisons, 972 participants). In analyses subgrouped by access type, pre-emptive stenosis correction did not reduce the risk of thrombosis (RR 0.95, 95% CI 0.8 to 1.12; I² = 0%; 11 study comparisons, 697 participants) or access loss in grafts (RR 0.87, 95% CI 0.69 to 1.11; I² = 0%; 7 study comparisons; 662 participants), but did reduce the risk of thrombosis (RR 0.5, 95% CI 0.35 to 0.71; I² = 0%; 7 study comparisons, 515 participants) and the risk of access loss in fistulas (RR 0.5, 95% CI 0.29 to 0.86; I² = 0%; 4 studies; 310 participants). Three of the four studies reporting access loss data in fistulas (199 participants) were conducted in the same centre. Insufficient data were available to assess whether benefits vary by prophylaxis aim in fistulas (i.e. primary and secondary prophylaxis). Although the magnitude of the effects of pre-emptive stenosis correction was considerable for patient-centred outcomes, results were either heterogeneous or imprecise. While pre-emptive stenosis correction may reduce the rates of hospitalisation (IRR 0.54, 95% CI 0.31 to 0.93; I² = 67%; 4 study comparisons, 219 participants) and use of catheters (IRR 0.58, 95% CI 0.35 to 0.98; I² = 53%; 6 study comparisons, 394 participants), it may also increase the rates of diagnostic procedures (IRR 1.78, 95% CI 1.18 to 2.67; I² = 62%; 7 study comparisons, 539 participants), infection (IRR 1.74, 95% CI 0.78 to 3.91; I² = 0%; 3 studies, 248 participants) and mortality (RR 1.38, 95% CI 0.91 to 2.11; I² = 0%; 5 studies, 386 participants). In general, risk of bias was high or unclear in most studies for many domains we assessed. Four studies were published after 2005 and only one had evidence of registration within a trial registry. No study reported information on authorship and/or involvement of the study sponsor in data collection, analysis, and interpretation. Pre-emptive correction of a newly identified or known stenosis in a functional AV access does not improve access longevity. Although pre-emptive stenosis correction may be promising in fistulas existing evidence is insufficient to guide clinical practice and health policy. While pre-emptive stenosis correction may reduce the risk of hospitalisation, this benefit is uncertain whereas there may be a substantial increase (i.e. 80%) in the use of access-related procedures and procedure-related adverse events (e.g. infection, mortality). The net effects of pre-emptive correction on harms and resource use are thus unclear.

In this review we included 14 studies, randomising 1390 participants to either a pre-emptive correction of an access stenosis (i.e. before the access became dysfunctional) or a deferred correction of an access stenosis (i.e. if and when the access became dysfunctional). This review shows that pre-emptive correction of an arteriovenous access stenosis does not improve longevity of the access overall. In people using grafts pre-emptive correction does not reduce the risk of thrombosis or access loss. In people using fistulas pre-emptive stenosis correction reduces the risk of thrombosis and may prolong the longevity of the access. However, this surveillance and pre-emptive correction strategy may increase the number of access-related procedures and procedure-related adverse events. This systematic review presents, to clinicians and patients, evidence-based data that do not support the use of access surveillance and pre-emptive correction of stenosis in grafts. Although surveillance and pre-emptive correction of stenosis reduce the risk of thrombosis and may reduce the risk of access loss in fistulas, they may also increase the risk of procedure-related adverse events and health-care cost. Large multicentre clinical trials are necessary in this patient population to better clarify potential harms and expected benefits of routine surveillance and pre-emptive correction of fistula stenosis.

10.1002/14651858.CD010709.pub2

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cochrane-simplification-train-862

We included seven trials randomising 556 patients. The comparisons include CUSA (cavitron ultrasound surgical aspirator) versus clamp-crush (two trials); radiofrequency dissecting sealer (RFDS) versus clamp-crush (two trials); sharp dissection versus clamp-crush technique (one trial); and hydrojet versus CUSA (one trial). One trial compared CUSA, RFDS, hydrojet, and clamp-crush technique. The infective complications and transection blood loss were greater in the RFDS than clamp-crush. There was no difference in the blood transfusion requirements, intensive therapy unit (ITU) stay, or hospital stay in this comparison. There was no significant differences in the mortality, morbidity, markers of liver parenchymal injury or liver dysfunction, ITU, or hospital stay in the other comparisons. The blood transfusion requirements were lower in the clamp-crush technique than CUSA and hydrojet. There was no difference in the transfusion requirements of clamp-crush technique and sharp dissection. Clamp-crush technique is quicker than CUSA, hydrojet, and RFDS. The transection speed of sharp dissection and clamp-crush technique was not compared. There was no clinically or statistically significant difference in the operating time between sharp dissection and clamp-crush techniques. Clamp-crush technique is two to six times cheaper than the other methods depending upon the number of surgeries performed each year. Clamp-crush technique is advocated as the method of choice in liver parenchymal transection because it avoids special equipment, whereas the newer methods do not seem to offer any benefit in decreasing the morbidity or transfusion requirement.

In this systematic review of seven randomised clinical trials including 556 patients, various methods of parenchymal transection techniques were compared. The infective complications and transection blood loss were greater in the radio frequency dissecting sealer (RFDS ) than clamp-crush technique. There were no significant differences in the mortality or in the morbidity between the other techniques of parenchymal transection. There was also no difference in the markers of liver parenchymal injury or liver dysfunction between the different methods used. Intensive therapy unit stay and hospital stay were similar. The blood transfusion requirements were lower in the clamp-crush technique than CUSA (cavitron ultrasonic surgical aspirator) and hydrojet. There was no difference in the transfusion requirements of clamp-crush technique and sharp dissection. Clamp-crush technique is quicker than CUSA, hydrojet, and RFDS. The transection speed of sharp dissection and clamp-crush technique was not compared. There was no clinically or statistically significant difference in the operating time between sharp dissection and clamp-crush techniques. Clamp-crush technique is two to six times cheaper than the other methods depending upon the number of surgeries performed each year. Clamp-crush technique is advocated as the method of choice in liver parenchymal transection because it avoids the need for special equipment and the newer methods do not seem to offer any benefit in decreasing the morbidity or transfusion requirement.

10.1002/14651858.CD006880.pub2

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cochrane-simplification-train-863

This review now includes 73 randomised studies, with 4870 participants. Overall, the quality of the evidence is low to very low. Compared with placebo, use of fluphenazine decanoate does not result in any significant differences in death, nor does it reduce relapse over six months to one year, but one longer-term study found that relapse was significantly reduced in the fluphenazine arm (n = 54, 1 RCT, RR 0.35, CI 0.19 to 0.64, very low quality evidence). A very similar number of people left the medium-term studies (six months to one year) early in the fluphenazine decanoate (24%) and placebo (19%) groups, however, a two-year study significantly favoured fluphenazine decanoate (n = 54, 1 RCT, RR 0.47, CI 0.23 to 0.96, very low quality evidence). No significant differences were found in mental state measured on the Brief Psychiatric Rating Scale (BPRS) or in extrapyramidal adverse effects, although these outcomes were only reported in one small study each. No study comparing fluphenazine decanoate with placebo reported clinically significant changes in global state or hospital admissions. Fluphenazine decanoate does not reduce relapse more than oral neuroleptics in the medium term (n = 419, 6 RCTs, RR 1.46 CI 0.75 to 2.83, very low quality evidence). A small study found no difference in clinically significant changes in global state. No difference in the number of participants leaving the study early was found between fluphenazine decanoate (17%) and oral neuroleptics (18%), and no significant differences were found in mental state measured on the BPRS. Extrapyramidal adverse effects were significantly less for people receiving fluphenazine decanoate compared with oral neuroleptics (n = 259, 3 RCTs, RR 0.47 CI 0.24 to 0.91, very low quality evidence). No study comparing fluphenazine decanoate with oral neuroleptics reported death or hospital admissions. No significant difference in relapse rates in the medium term between fluphenazine decanoate and fluphenazine enanthate was found (n = 49, 1 RCT, RR 2.43, CI 0.71 to 8.32, very low quality evidence), immediate- and short-term studies were also equivocal. One small study reported the number of participants leaving the study early (29% versus 12%) and mental state measured on the BPRS and found no significant difference for either outcome. No significant difference was found in extrapyramidal adverse effects between fluphenazine decanoate and fluphenazine enanthate. No study comparing fluphenazine decanoate with fluphenazine enanthate reported death, clinically significant changes in global state or hospital admissions. There are more data for fluphenazine decanoate than for the enanthate ester. Both are effective antipsychotic preparations. Fluphenazine decanoate produced fewer movement disorder effects than other oral antipsychotics but data were of low quality, and overall, adverse effect data were equivocal. In the context of trials, there is little advantage of these depots over oral medications in terms of compliance but this is unlikely to be applicable to everyday clinical practice.

This review aimed to investigate the effects of fluphenazine (decanoate and enanthate) for schizophrenia. Searches for relevant randomised controlled trials was run in February 2011 and October 16, 2013. Authors could include and extract data from 73 studies with a total of 4870 participants. There were more studies on fluphenazine decanoate than enanthate.The review authors rated the quality of the evidence in the included trials to be low or very low. A long-term result from only one trial indicated fluphenazine decanoate reduces the rate of relapse when compared with placebo (‘dummy treatment’). Three studies found that fluphenazine decanoate produced fewer general movement disorders than oral antipsychotics. However, other results showed, overall, the effects and outcomes, including adverse effects for fluphenazine (decanoate and enanthate) are similar to other oral and depot antipsychotics. Important outcomes and information about use of services, going into hospital, satisfaction with care and costs were not reported in any study. Depot injections may offer an advantage over tablets (oral medication) in terms of people taking their medication (complying and adhering to treatment). However, this needs to be balanced with the likelihood of serious side effects, such as involuntary shaking, muscle stiffness, the inability to sit still and lowering in people’s mood. Results did not show any strong evidence that depot fluphenazine produced more adverse effects than other antipsychotics. This should be addressed in future large scale and high quality studies. This plain language summary has been written by a consumer Ben Gray from Rethink Mental Illness.

10.1002/14651858.CD000307.pub2

cochrane-simplification-train-864

cochrane-simplification-train-864

We included five trials in the review, with 190 participants in total. We did not identify any new studies for inclusion from the updated search in January 2016. Three trials were related to dental treatment, i.e. restorative and extraction treatments; two trials related to orthodontic treatment. We did not judge any of the included trials to be at low risk of bias. Three of the included trials compared paracetamol with placebo, only two of which provided data for analysis (presence or absence of parent-reported postoperative pain behaviour). Meta-analysis of the two trials gave arisk ratio (RR) for postoperative pain of 0.81 (95% confidence interval (CI) 0.53 to 1.22; two trials, 100 participants; P = 0.31), which showed no evidence of a benefit in taking paracetamol preoperatively (52% reporting pain in the placebo group versus 42% in the paracetamol group). One of these trials was at unclear risk of bias, and the other was at high risk. The quality of the evidence is low. One study did not have any adverse events; the other two trials did not mention adverse events. Four of the included trials compared ibuprofen with placebo. Three of these trials provided useable data. One trial reported no statistical difference in postoperative pain experienced by the ibuprofen group and the control group for children undergoing dental treatment. We pooled the data from the other two trials, which included participants who were having orthodontic separator replacement without a general anaesthetic, to determine the effect of preoperative ibuprofen on the severity of postoperative pain. There was a statistically significant mean difference in severity of postoperative pain of -13.44 (95% CI -23.01 to -3.88; two trials, 85 participants; P = 0.006) on a visual analogue scale (0 to 100), which indicated a probable benefit for preoperative ibuprofen before this orthodontic procedure. However, both trials were at high risk of bias. The quality of the evidence is low. Only one of the trials reported adverse events (one participant from the ibuprofen group and one from the placebo group reporting a lip or cheek biting injury). From the available evidence, we cannot determine whether or not preoperative analgesics are of benefit in paediatric dentistry for procedures under local anaesthetic. There is probably a benefit in using preoperative analgesics prior to orthodontic separator placement. The quality of the evidence is low. Further randomised clinical trials should be completed with appropriate sample sizes and well defined outcome measures.

We searched several electronic databases to 5 January 2016, as well as doing some searching by hand. We included five studies in the review, which had 190 participants in total. We did not find any new studies between the previous Cochrane review in 2012 and our updated search in January 2016. Three included studies related to dental treatment (fillings and tooth extractions) and two related to orthodontic treatment (braces). Three of the five included studies compared paracetamol to a placebo (sugar tablet) and four of them compared ibuprofen to a placebo. From the available evidence, we could not determine whether or not painkillers before treatment are of benefit for children and adolescents having dental procedures under local anaesthetic. There is probably a benefit in giving painkillers before braces are fitted. Only one study reported an adverse event (one participant in each group had a lip or cheek biting injury). More research is needed. None of the included studies were at low risk of bias. The quality of the evidence is low.

10.1002/14651858.CD008392.pub3

cochrane-simplification-train-865

cochrane-simplification-train-865

We identified a single cross-over RCT (enrolling 9 participants) that compared home haemodialysis (long hours: 6 to 8 hours, 3 times/week) with in-centre haemodialysis (short hours: 3.5 to 4.5 hours, 3 times/weeks) for 8 weeks in prevalent home haemodialysis patients. Outcome data were limited and not available for the end of the first phase of treatment in this cross-over study which was at risk of bias due to differences in dialysate composition between the two treatment comparisons. Overall, home haemodialysis reduced 24 hour ambulatory blood pressure and improved uraemic symptoms, but increased treatment-related burden of disease and interference in social activities. Insufficient data were available for mortality, hospitalisation or dialysis vascular access complications or treatment durability. Insufficient randomised data were available to determine the effects of home haemodialysis on survival, hospitalisation, and quality of life compared with in-centre haemodialysis. Given the consistently observed benefits of home haemodialysis on quality of life and survival in uncontrolled studies, and the low prevalence of home haemodialysis globally, randomised studies evaluating home haemodialysis would help inform clinical practice and policy.

We found that only one study that involved nine patients had compared home haemodialysis with in-centre haemodialysis. There was insufficient information to understand the effects of home haemodialysis on survival or need for hospital admission in this study. Home haemodialysis may improve blood pressure and physical symptoms, but may increase the burden of care for families and patients. Given the potential benefits of home haemodialysis in non-randomised studies, larger randomised trials of home haemodialysis could help inform clinical care and policy.

10.1002/14651858.CD009535.pub2

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cochrane-simplification-train-866

Ten RCTs were included. One trial reported near final height in girls and found that girls treated with GH were 7.5 cm taller than untreated controls (GH group, 155.3 cm ± 6.4; control, 147.8 cm ± 2.6; P = 0.003); another trial which reported adult height standard deviation score found that children treated with GH were 3.7 cm taller than children in a placebo-treated group (95% confidence intervals 0.03 to 1.10; P < 0.04). The other trials reported short term outcomes. Results suggest that short-term height gains can range from none to approximately 0.7 SD over one year. One study reported health related quality of life and showed no significant improvement in GH treated children compared with those in the control group, whilst another found no significant evidence that GH treatment impacts psychological adaptation or self-perception in children with ISS. No serious adverse effects of treatment were reported. GH therapy can increase short-term growth and improve (near) final height. Increases in height are such that treated individuals remain relatively short when compared with peers of normal stature. Large, multicentre RCTs are required which should focus on final height and address quality of life and cost issues.

Ten studies included altogether 741 children and lasted between six months and 6.2 years. Results showed that individuals treated with growth hormone remain relatively short when compared with peers of normal stature. Girls treated with growth hormone were 7.5 cm taller than untreated controls (growth hormone treated group 155.3 cm and control group 147.8 cm); another trial found that children treated with growth hormone were 3.7 cm taller than children in a placebo-treated group. No serious adverse effects were reported in the included studies. Although serious adverse effects (there has been concern that growth hormone would induce new tumours or increase the likelihood of tumour relapse) may be rare, their possibility must also be taken into consideration.

10.1002/14651858.CD004440.pub2

cochrane-simplification-train-867

cochrane-simplification-train-867

Twelve studies involving 27,482 participants met the inclusion criteria. Interventions were either mandatory or voluntary and included up to 10 discrete components in varying combinations. All but one study took place in North America. Although we searched for parental health outcomes, the vast majority of the sample in all included studies were female. Therefore, we describe adult health outcomes as 'maternal' throughout the results section. We downgraded the quality of all evidence at least one level because outcome assessors were not blinded. Follow-up ranged from 18 months to six years. The effects of welfare-to-work interventions on health were generally positive but of a magnitude unlikely to have any tangible effects. At T1 there was moderate-quality evidence of a very small negative impact on maternal mental health (standardised mean difference (SMD) 0.07, 95% Confidence Interval (CI) 0.00 to 0.14; N = 3352; studies = 2)); at T2, moderate-quality evidence of no effect (SMD 0.00, 95% CI 0.05 to 0.05; N = 7091; studies = 3); and at T3, low-quality evidence of a very small positive effect (SMD −0.07, 95% CI −0.15 to 0.00; N = 8873; studies = 4). There was evidence of very small positive effects on maternal physical health at T1 (risk ratio (RR) 0.85, 95% CI 0.54 to 1.36; N = 311; 1 study, low quality) and T2 (RR 1.06, 95% CI 0.95 to 1.18; N = 2551; 2 studies, moderate quality), and of a very small negative effect at T3 (RR 0.97, 95% CI 0.91 to 1.04; N = 1854; 1 study, low quality). At T1, there was moderate-quality evidence of a very small negative impact on child mental health (SMD 0.01, 95% CI −0.06 to 0.09; N = 2762; studies = 1); at T2, of a very small positive effect (SMD −0.04, 95% CI −0.08 to 0.01; N = 7560; studies = 5), and at T3, there was low-quality evidence of a very small positive effect (SMD −0.05, 95% CI −0.16 to 0.05; N = 3643; studies = 3). Moderate-quality evidence for effects on child physical health showed a very small negative effect at T1 (SMD −0.05, 95% CI −0.12 to 0.03; N = 2762; studies = 1), a very small positive effect at T2 (SMD 0.07, 95% CI 0.01 to 0.12; N = 7195; studies = 3), and a very small positive effect at T3 (SMD 0.01, 95% CI −0.04 to 0.06; N = 8083; studies = 5). There was some evidence of larger negative effects on health, but this was of low or very low quality. There were small positive effects on employment and income at 18 to 48 months (moderate-quality evidence), but these were largely absent at 49 to 72 months (very low to moderate-quality evidence), often due to control group members moving into work independently. Since the majority of the studies were conducted in North America before the year 2000, generalisabilty may be limited. However, all study sites were similar in that they were high-income countries with developed social welfare systems. The effects of WtW on health are largely of a magnitude that is unlikely to have tangible impacts. Since income and employment are hypothesised to mediate effects on health, it is possible that these negligible health impacts result from the small effects on economic outcomes. Even where employment and income were higher for the lone parents in WtW, poverty was still high for the majority of the lone parents in many of the studies. Perhaps because of this, depression also remained very high for lone parents whether they were in WtW or not. There is a lack of robust evidence on the health effects of WtW for lone parents outside North America.

We found 12 studies involving 27,482 participants that compared groups of lone parents in WtW interventions with lone parents who continued to receive welfare benefits in the normal way. All of the studies were at high risk of bias because the staff who collected the data knew when respondents were in the intervention group. In some studies, lone parents who were not in the intervention group were affected by similar changes to welfare policy that applied to all lone parents. We used statistical techniques to combine the results of different studies.These analyses suggest that WtW does not have important effects on health. Employment and income were slightly higher 18 to 48 months after the start of the intervention, but there was little difference 49 to 72 months after the studies began. In a number of studies, lone parents who were not in WtW interventions found jobs by themselves over time. It is possible that effects on health were small because there was not much change in employment or income. Even when employment and income were higher for the lone parents in WtW, most participants continued to be poor. Perhaps because of this, depression also remained very high for lone parents whether they were in WtW or not. All but one of the studies took place in the United States or Canada before the year 2000. This means it is difficult to be sure whether WtW would have the same effects in different countries at other times.

10.1002/14651858.CD009820.pub3

cochrane-simplification-train-868

cochrane-simplification-train-868

For early mortality where there was evidence of heterogeneity, a fixed-effect meta-analysis showed no difference between magensium and placebo groups (OR 0.99, 95%CI 0.94 to 1.04), while a random-effects meta-analysis showed a significant reduction comparing magnesium with placebo (OR 0.66, 95% CI 0.53 to 0.82). Stratification by timing of treatment (< 6 hrs, 6+ hrs) reduced heterogeneity, and in both fixed-effect and random-effects models no significant effect of magnesium was found. In stratified analyses, early mortality was reduced for patients not treated with thrombolysis (OR=0.73, 95% CI 0.56 to 0.94 by random-effects model) and for those treated with less than 75 mmol of magnesium (OR=0.59, 95% CI 0.49 to 0.70) in the magnesium compared with placebo groups. Meta-analysis for the secondary outcomes where there was no evidence of heterogeneity showed reductions in the odds of ventricular fibrillation (OR=0.88, 95% CI 0.81 to 0.96), but increases in the odds of profound hypotension (OR=1.13, 95% CI 1.09 to 1.19) and bradycardia (OR=1.49, 95% CI 1.26 to 1.77) comparing magnesium with placebo. No difference was observed for heart block (OR=1.05, 95% CI 0.97-1.14). For those outcomes where there was evidence of heterogeneity, meta-analysis with both fixed-effect and random-effects models showed that magnesium could decrease ventricular tachycardia (OR=0.45, 95% CI 0.31 to 0.66 by fixed-effect model; OR=0.40, 95% CI 0.19 to 0.84 by random-effects model) and severe arrhythmia needing treatment or Lown 2-5 (OR=0.72, 95% CI 0.60 to 0.85 by fixed-effect model; OR=0.51, 95% CI 0.33 to 0.79 by random-effects model) compared with placebo. There was no difference on the effect of cardiogenic shock between the two groups. Owing to the likelihood of publication bias and marked heterogeneity of treatment effects, it is essential that the findings are interpreted cautiously. From the evidence reviewed here, we consider that: (1) it is unlikely that magnesium is beneficial in reducing mortality both in patients treated early and in patients treated late, and in patients already receiving thrombolytic therapy; (2) it is unlikely that magnesium will reduce mortality when used at high dose (>=75 mmol); (3) magnesium treatment may reduce the incidence of ventricular fibrillation, ventricular tachycardia, severe arrhythmia needing treatment or Lown 2-5, but it may increase the incidence of profound hypotension, bradycardia and flushing; and (4) the areas of uncertainty regarding the effect of magnesium on mortality remain the effect of low dose treatment (< 75 mmol) and in patients not treated with thrombolysis.

Several small trials appeared to support the practice. But the authors of this review found that other trials went unpublished once they produced unfavorable results. A controversy erupted in 1995, when a large well-designed trial with 58,050 participants did not demonstrate any beneficial effect to IV magnesium, contradicting earlier meta-analyses of the smaller trials. This review includes 26 clinical trials that had randomly assigned heart attack patients to receive either IV magnesium or an inactive substance (placebo). Their results were mixed: IV magnesium reduced the incidence of serious arrhythmias, but this treatment also increased the incidence of profound hypotension, bradycardia and flushing. However, any apparent beneficial effects of magnesium may simply reflect various biases in these trials. Additionally, there was a lack of uniformity in these trials in terms of dosage and the timing of the IV magnesium regimen, which in some trials also included anti-clotting drugs. The evidence produced by this review does not support continued use of IV magnesium. Other effective treatments (aspirin, beta-blockers) should be used to treat heart attack.

10.1002/14651858.CD002755.pub2

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cochrane-simplification-train-869

Four studies enrolling 318 infants were included. All studies enrolled preterm infants on the basis of gestational age criteria. All studies commenced treatment in the first 48 hours, but used different regimens, dose and durations of treatment. All four studies used thyroxine (T4). Valerio 2004 incorporated one arm with an early short course of T3, then T4 for 6 weeks. Only two studies with neurodevelopmental follow-up were of good methodology (van Wassenaer 1997; Vanhole 1997). All studies were small with the largest (van Wassenaer 1997) enrolling 200 infants. No significant difference was found in neonatal morbidity, mortality or neurodevelopmental outcome in infants who received thyroid hormones compared to control. van Wassenaer 1997 reported no significant difference in abnormal mental development at 6, 12, 24 months (RR 0.67, 95% CI 0.28, 1.56) or five years (RR 0.66, 95% CI 0.22, 1.99) or cerebral palsy assessed at five years (RR 0.72, 95% CI 0.28, 1.84). Meta-analysis of two studies (van Wassenaer 1997, Vanhole 1997) found no significant difference in the Bayley MDI (WMD -1.14, 95% CI -5.46, 3.19) and PDI (WMD 0.22, 95% CI -4.80, 5.24) at 7 - 12 months. van Wassenaer 1997 reported no significant difference in the Bayley MDI (MD -3.50, 95% CI -11.21, 4.21) and PDI (MD 3.10, 95% CI -3.31, 9.51) at 24 months, IQ scores at 5 years (MD -2.10, 95% CI -7.91, 3.71) and children in special schooling at 10 years (RR 0.88, 95% CI 0.43, 1.83). Meta-analysis of all four trials found no significant difference in mortality to discharge (typical RR 0.76, 95% CI 0.46 to 1.24). van Wassenaer 1997 reported no significant difference in death or cerebral palsy at five years (RR 0.70, 95% CI 0.43 to 1.14). No significant differences were reported for neonatal morbidities, including the need for mechanical ventilation, duration of mechanical ventilation, air leak, CLD in survivors at 28 days or 36 weeks, intraventricular haemorrhage, severe intraventricular haemorrhage, periventricular leucomalacia, patent ductus arteriosus, sepsis, necrotising enterocolitis or retinopathy of prematurity. This review does not support the use of prophylactic thyroid hormones in preterm infants to reduce neonatal mortality, neonatal morbidity or improve neurodevelopmental outcomes. An adequately powered clinical trial of thyroid hormone supplementation with the goal of preventing the postnatal nadir of thyroid hormone levels seen in very preterm infants is required.

A systematic review of the data from randomised controlled trials provides no evidence that routine thyroid hormone therapy is effective in preventing problems in preterm babies or improves their developmental outcomes. Thyroid hormones are needed for the normal growth and maturity of the central nervous system, as well as the heart and lungs. Children born without sufficient thyroid hormones can develop serious mental retardation. It is believed that low levels of thyroid hormones in the first few weeks after birth (transient hyperthyroxinaemia) in preterm babies born before 34 weeks may contribute to this abnormal development. The review of trials found no evidence that using thyroid hormones routinely in preterm babies is effective in reducing the risk of problems caused by transiently low levels of thyroid hormones.

10.1002/14651858.CD005948.pub2

cochrane-simplification-train-870

cochrane-simplification-train-870

Two RCTs (123 participants), both using amitriptyline, met the pre-specified inclusion criteria. These studies provided mixed findings on the efficacy of amitriptyline for the treatment of abdominal pain-related FGIDs. The larger, publicly-funded study reported no statistically significant difference in efficacy between amitriptyline and placebo in 90 children and adolescents with FGIDs after 4 weeks of treatment. On intention-to-treat (ITT)- analysis, 59% of the children reported feeling better in the amitriptyline group compared with 53% in the placebo group (RR 1.12; 95% CI: 0.77 to 1.63; P = 0.54). The risk of bias for this study was rated as low. The second RCT enrolled 33 adolescents with irritable bowel syndrome. Patients receiving amitriptyline experienced greater improvements in the primary outcome, overall quality of life, at weeks 6, 10, and 13 compared with those on placebo (P= 0.019, 0.004, and 0.013, respectively). No effect estimates were calculated for the quality of life outcome because mean quality of life scores and standard deviations were not reported. For most secondary outcomes no statistically significant differences between amitriptyline and placebo could be detected. The risk of bias for this study was rated as unclear for most items. However, it was rated as high for other bias due to multiple testing. The results of this study should be interpreted with caution due to the small number of patients and multiple testing. The larger study reported mild adverse events including fatigue, rash and headache and dizziness. On ITT analysis, 4% of the amitriptyline group experienced at least one adverse event compared to 2% of the placebo group. There was no statistically significant difference in the proportion of patients who experienced at least one adverse event (RR 1.91; 95% CI 0.18 to 20.35; P = 0.59). The smaller study reported no adverse events. The methods of adverse effects assessment was poorly reported in both studies and no clear conclusions on the risks of harms of amitriptyline can be drawn. Clinicians must be aware that for the majority of antidepressant medications no evidence exists that supports their use for the treatment of abdominal pain-related FGIDs in children and adolescents. The existing randomised controlled evidence is limited to studies on amitriptyline and revealed no statistically significant differences between amitriptyline and placebo for most efficacy outcomes. Amitriptyline does not appear to provide any benefit for the treatment of FGIDs in children and adolescents. Studies in children with depressive disorders have shown that antidepressants can lead to substantial, sometimes life-threatening adverse effects. Until better evidence evolves, clinicians should weigh the potential benefits of antidepressant treatment against known risks of antidepressants in paediatric patients.

Abdominal pain-related functional gastrointestinal disorders (FGIDs) are common in childhood and adolescence. In most cases no medical reason for the pain can be found. Various drug treatment approaches for the different types of abdominal pain-related FGIDs exist. These drug treatments include: prokinetics and antisecretory agents for functional dyspepsia; pizotifen, propranolol, cyproheptadine or sumatriptane for abdominal migraine; and antispasmodic and antidiarrhoeal regimen for irritable bowel syndrome. Antidepressants have been shown to be effective in some studies of adults with functional gastrointestinal disorders. As a result young patients with similar complaints are sometimes treated with antidepressants. The purpose of this review was to examine the evidence assessing the advantages and disadvantages of such an approach. Only two studies met the inclusion criteria. Both of these studies were randomised controlled trials and assessed the effectiveness and safety of amitriptyline in children with FGIDs. Amitriptyline is a first generation antidepressant (tricyclic antidepressant). Amitriptyline is no longer an agent of first choice for the treatment of depressive disorders because of potentially serious side effects including overdose. Amitriptyline has not been approved for the treatment of functional abdominal pain in children or adolescents. The larger study (n = 90) showed no difference in the proportion of patients feeling better between the treatment - and the placebo (sugar pill) groups. Side effects were mild and included fatigue, rash and headache and dizziness.The authors of the other, much smaller study (n = 33) reported a significant improvement in overall quality of life and a reduction in pain for specific areas of the abdomen and certain follow up times. However, the results of this study should be interpreted with caution due to poor methodological quality and the small number of patients enrolled. Amitriptyline does not appear to provide any benefit for the treatment of FGIDs in children and adolescents. At present, the evidence for the treatment of children and adolescents with abdominal pain-related diseases with antidepressants does not support the use of antidepressant agents in this group of patients. We suggest considering alternative treatments that are supported by stronger evidence. There is need for larger, well-conducted trials with adequate patient relevant outcomes such as quality of life and pain relief to provide more information regarding this common condition.

10.1002/14651858.CD008013.pub2

cochrane-simplification-train-871

cochrane-simplification-train-871

We included five RCTs (285 participants). Three studies were included in the original review and two more in the update. The authors of the included studies reported benefits of acupuncture in managing pancreatic cancer pain; no difference between real and sham electroacupuncture for pain associated with ovarian cancer; benefits of acupuncture over conventional medication for late stage unspecified cancer; benefits for auricular (ear) acupuncture over placebo for chronic neuropathic pain related to cancer; and no differences between conventional analgesia and acupuncture within the first 10 days of treatment for stomach carcinoma. All studies had a high risk of bias from inadequate sample size and a low risk of bias associated with random sequence generation. Only three studies had low risk of bias associated with incomplete outcome data, while two studies had low risk of bias associated with allocation concealment and one study had low risk of bias associated with inadequate blinding. The heterogeneity of methodologies, cancer populations and techniques used in the included studies precluded pooling of data and therefore meta-analysis was not carried out. A subgroup analysis on acupuncture for cancer-induced bone pain was not conducted because none of the studies made any reference to bone pain. Studies either reported that there were no adverse events as a result of treatment, or did not report adverse events at all. There is insufficient evidence to judge whether acupuncture is effective in treating cancer pain in adults.

We searched a wide range of electronic medical databases up to July 2015 for relevant studies. We included studies written in any language that included adults and compared treatment with acupuncture for cancer pain against no treatment, or usual treatment, or sham acupuncture, or other treatments. Since we were only interested in robust research, we restricted our search to randomised controlled trials (in which participants are randomly allocated to the methods being tested). We found five studies (with a total of 285 participants) that compared acupuncture against either sham acupuncture or pain-killing medicines. All five identified studies had small sample sizes, which reduces the quality of their evidence. One pilot study was well designed, but was too small to identify any differences in pain in women with ovarian cancer after electroacupuncture or a sham treatment. One study found that auricular (ear) acupuncture reduced cancer pain when compared with sham auricular acupuncture that was given at non-acupuncture points. However, the people in the sham acupuncture group could have been aware that they were not in the real acupuncture group and this could have affected the level of pain they reported. Another study found a difference between an electroacupuncture group and sham group in people with pancreatic cancer but again, there was no reported attempt to conceal which group people were in. One study found that acupuncture was as effective as pain-killing medication, and one study found that acupuncture was more effective than medication, but both studies were poorly designed and the study reports lacked detail. None of the studies described in this review were big enough to produce reliable results. None of the studies reported any harm to the participants. We conclude that there is insufficient evidence to judge whether acupuncture is effective in relieving cancer pain in adults. Larger, well-designed studies are needed to provide evidence in this area.

10.1002/14651858.CD007753.pub3

cochrane-simplification-train-872

cochrane-simplification-train-872

We did not identify any new trials for inclusion in this 2017 update. We included 17 trials with 5099 participants in the primary analysis. The quality of trials was generally good. At follow-up there was no difference in participants described as being clinically improved between the antibiotic and placebo groups (11 studies with 3841 participants, risk ratio (RR) 1.07, 95% confidence interval (CI) 0.99 to 1.15). Participants given antibiotics were less likely to have a cough (4 studies with 275 participants, RR 0.64, 95% CI 0.49 to 0.85; number needed to treat for an additional beneficial outcome (NNTB) 6) and a night cough (4 studies with 538 participants, RR 0.67, 95% CI 0.54 to 0.83; NNTB 7). Participants given antibiotics had a shorter mean cough duration (7 studies with 2776 participants, mean difference (MD) -0.46 days, 95% CI -0.87 to -0.04). The differences in presence of a productive cough at follow-up and MD of productive cough did not reach statistical significance. Antibiotic-treated participants were more likely to be improved according to clinician's global assessment (6 studies with 891 participants, RR 0.61, 95% CI 0.48 to 0.79; NNTB 11) and were less likely to have an abnormal lung exam (5 studies with 613 participants, RR 0.54, 95% CI 0.41 to 0.70; NNTB 6). Antibiotic-treated participants also had a reduction in days feeling ill (5 studies with 809 participants, MD -0.64 days, 95% CI -1.16 to -0.13) and days with impaired activity (6 studies with 767 participants, MD -0.49 days, 95% CI -0.94 to -0.04). The differences in proportions with activity limitations at follow-up did not reach statistical significance. There was a significant trend towards an increase in adverse effects in the antibiotic group (12 studies with 3496 participants, RR 1.20, 95% CI 1.05 to 1.36; NNT for an additional harmful outcome 24). There is limited evidence of clinical benefit to support the use of antibiotics in acute bronchitis. Antibiotics may have a modest beneficial effect in some patients such as frail, elderly people with multimorbidity who may not have been included in trials to date. However, the magnitude of this benefit needs to be considered in the broader context of potential side effects, medicalisation for a self limiting condition, increased resistance to respiratory pathogens, and cost of antibiotic treatment.

We included randomised controlled trials comparing any antibiotic therapy with placebo or no treatment in people with acute bronchitis or acute productive cough and no underlying chronic lung condition. We included 17 trials with 5099 participants. Co-treatments with other medications to relieve symptoms were allowed if they were given to all participants in the study. Our evidence is current to 13 January, 2017. We found limited evidence of clinical benefit to support the use of antibiotics for acute bronchitis. Some people treated with antibiotics recovered a bit more quickly with reduced cough-related outcomes. However, this difference may not be of practical importance as it amounted to a difference of half a day over an 8- to 10-day period. There was a small but significant increase in adverse side effects in people treated with antibiotics. The most commonly reported side effects included nausea, vomiting, diarrhoea, headache, and rash. This review suggests that there is limited benefit to the patient in using antibiotics for acute bronchitis in otherwise healthy individuals. More research is needed on the effects of using antibiotics for acute bronchitis in frail, elderly people with multiple chronic conditions who may not have been included in the existing trials. Antibiotic use needs to be considered in the context of the potential side effects, medicalisation for a self limiting condition, cost of antibiotic treatment, and in particular associated population-level harms due to increasing antibiotic resistance. The quality of these trials was generally good, particularly for more recent studies.

10.1002/14651858.CD000245.pub4

cochrane-simplification-train-873

cochrane-simplification-train-873

There was one trial with 20 participants (16 females) included in the review. The mean age of participants was 13.1 years. The trial was a double-blinded, randomised cross-over trial which had a duration of 12 months in total and compared high-dose and low-dose pancreatic enzyme therapy. As only the abstract of the trial was available, the overall risk of bias was judged to be unclear. The trial did not address either of our primary outcomes (time until resolution of DIOS and treatment failure rate), but reported episodes of acute DIOS, presence of abdominal mass and abdominal pain. There were no numerical data available for these outcomes, but the authors stated that there was no difference between treatment with high-dose or low-dose pancreatic enzymes. The overall quality of the evidence was found to be very low. There is a clear lack of evidence for the treatment of DIOS in people with cystic fibrosis. The included abstract did not address our primary outcome measures and did not provide numerical data for the two secondary outcomes it did address. Therefore, we cannot justify the use of high-dose pancreatic enzymes for treating DIOS, nor can we comment on the efficacy and safety of other laxative agents. From our findings, it is clear that more randomised controlled trials need to be conducted in this area.

We found the overall quality of the evidence to be very low. The trial itself was only published as an abstract from a conference which did not include numerical data and it was not published as a full report. This meant that we do not know many details about the trial. We thought that the overall risk of bias was unclear, as the trial authors did not describe how participants were put into the treatment groups, whether any participants dropped out or whether the planned outcomes were the same as the reported outcomes. The trial also had a very small number of participants and a limited age range, making it difficult to draw conclusions about the relevance of the treatment for all people with cystic fibrosis.

10.1002/14651858.CD012798.pub2

cochrane-simplification-train-874

cochrane-simplification-train-874

We included two cluster-randomised trials that compared interventions aimed at communities to routine immunisation practices. In one study from India, families, teachers, children and village leaders were encouraged to attend information meetings where they received information about childhood vaccination and could ask questions. In the second study from Pakistan, people who were considered to be trusted in the community were invited to meetings to discuss vaccine coverage rates in their community and the costs and benefits of childhood vaccination. They were asked to develop local action plans and to share the information they had been given and continue the discussions in their communities. The trials show low certainty evidence that interventions aimed at communities to inform and educate about childhood vaccination may improve knowledge of vaccines or vaccine-preventable diseases among intervention participants (adjusted mean difference 0.121, 95% confidence interval (CI) 0.055 to 0.189). These interventions probably increase the number of children who are vaccinated. The study from India showed that the intervention probably increased the number of children who received vaccinations (risk ratio (RR) 1.67, 95% CI 1.21 to 2.31; moderate certainty evidence). The study from Pakistan showed that there is probably an increase in the uptake of both measles (RR 1.63, 95% CI 1.03 to 2.58) and DPT (diptheria, pertussis and tetanus) (RR 2.17, 95% CI 1.43 to 3.29) vaccines (both moderate certainty evidence), but there may be little or no difference in the number of children who received polio vaccine (RR 1.01, 95% CI 0.97 to 1.05; low certainty evidence). There is also low certainty evidence that these interventions may change attitudes in favour of vaccination among parents with young children (adjusted mean difference 0.054, 95% CI 0.013 to 0.105), but they may make little or no difference to the involvement of mothers in decision-making regarding childhood vaccination (adjusted mean difference 0.043, 95% CI -0.009 to 0.097). The studies did not assess knowledge among participants of vaccine service delivery; participant confidence in the vaccination decision; intervention costs; or any unintended harms as a consequence of the intervention. We did not identify any studies that compared interventions aimed at communities to inform and/or educate with interventions directed to individual parents or caregivers, or studies that compared two interventions aimed at communities to inform and/or educate about childhood vaccination. This review provides limited evidence that interventions aimed at communities to inform and educate about early childhood vaccination may improve attitudes towards vaccination and probably increase vaccination uptake under some circumstances. However, some of these interventions may be resource intensive when implemented on a large scale and further rigorous evaluations are needed. These interventions may achieve most benefit when targeted to areas or groups that have low childhood vaccination rates.’

The review found two studies. The first study took place in India. Here, families, teachers, children and village leaders were encouraged to attend information meetings where they were given information about childhood vaccination and could ask questions. Posters and leaflets were also distributed in the community. The second study was from Pakistan. Here, people who were considered to be trusted in the community were invited to meetings where they discussed the current rates of vaccine coverage in their community and the costs and benefits of childhood vaccination. They were also asked to develop local action plans, to share the information they had been given and continue the discussions with households in their communities. What happens when members of the community are informed or educated about vaccines? The studies showed that community-based information or education: - may improve knowledge of vaccines or vaccine-preventable diseases; - probably increases the number of children who get vaccinated (both the study in India and the study in Pakistan showed that there is probably an increase in the number of vaccinated children); - may make little or no difference to the involvement of mothers in decision-making about vaccination; - may change attitudes in favour of vaccination among parents with young children; We assessed all of this evidence to be of low or moderate certainty. The studies did not assess whether this type of information or education led to better knowledge among participants about vaccine service delivery or increased their confidence in the decision made. Nor did the studies assess how much this information and education cost or whether it led to any unintended harms.

10.1002/14651858.CD010232.pub2

cochrane-simplification-train-875

cochrane-simplification-train-875

We included one study that met our selection criteria; a double-masked, placebo-controlled, randomised trial of high dose intravenous steroids in patients with indirect TON diagnosed within seven days of the initial injury. A total of 31 eligible participants were randomised to receive either high dose intravenous steroids (n = 16) or placebo (n = 15), and they were all followed-up for three months. Mean final best corrected visual acuity (BCVA) was 1.78±1.23 Logarithm of the Minimum Angle of Resolution (LogMAR) in the placebo group, and 1.11±1.14 LogMAR in the steroid group. The mean difference in BCVA between the placebo and steroid groups was 0.67 LogMAR (95% confidence interval -1.54 to 0.20), and this difference was not statistically significant (P = 0.13). At three months follow-up, an improvement in BCVA of 0.40 LogMAR occurred in eight eyes (8/15, 53.3%) in the placebo group, and in 11 eyes (11/16, 68.8%) in the treatment group. This difference was not statistically significant (P = 0.38). There is a relatively high rate of spontaneous visual recovery in TON and there is no convincing data that steroids provide any additional visual benefit over observation alone. Recent evidence also suggests a possible detrimental effect of steroids in TON and further studies are urgently needed to clarify this important issue. Each case therefore needs to be assessed on an individual basis and proper informed consent is paramount.

The recommendations in this review are based on a critical analysis of the available evidence in the medical literature. We found only one, relatively small, randomised controlled trial of steroids in TON, which included 31 participants within seven days of their initial injury. These participants received either high dose intravenous steroids (n = 16) or placebo (n = 15). At three months follow-up, no significant difference in best corrected visual acuity was found between these two groups. There is a relatively high rate of spontaneous visual recovery in TON and no convincing data that steroids provide any additional benefit over observation alone. Each case needs to be assessed on an individual basis and the patient needs to be made fully aware of the possibility of a serious adverse reaction, although rare, to steroids. Furthermore, recent studies have highlighted possible detrimental effects of steroids when used in brain and spinal cord injuries and these new lines of evidence need to be considered seriously.

10.1002/14651858.CD006032.pub4

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cochrane-simplification-train-876

Fifty-three double-blind RCTs evaluating a thiazide in 15129 hypertensive patients (baseline BP of 156/101 mmHg) were included. Hydrochlorothiazide was the thiazide used in 49/53 (92%) of the included studies. The additional BP reduction caused by the thiazide as a second drug was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. Thiazides as a second-line drug reduced BP by 6/3 and 8/4 mmHg at doses of 1 and 2 times the manufacturer's recommended starting dose respectively. The BP lowering effect was dose related. The effect was similar to that obtained when thiazides are used as a single agent. Only 3 double-blind RCTs evaluating loop diuretics were identified. These RCTs showed a BP lowering effect of a starting dose of about 6/3 mmHg. Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are added as a first-line drug. This means that the BP lowering effect of thiazides is additive. Loop diuretics appear to have a similar blood pressure lowering effect as thiazides at 1 times the recommended starting dose. Because of the short duration of the trials and lack of reporting of adverse events, this review does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug.

We performed a search of the available scientific literature to find all trial evidence to assess this question. Fifty-six trials were found. Fifty-three trials involved thiazide diuretics (92% with the drug hydrochlorothiazide) and included a total of 15310 participants. Adding a thiazide to another anti-hypertensive drug further reduces the BP by an additional 6/3 mmHg when given at the starting dose and reduces BP by 8/4 mmHg at 2 times the starting dose. This is approximately the same effect as when the drugs are used alone. A good estimate of the harms associated with diuretics cannot be estimated in this review because of the lack of reporting and the short duration of the trials.

10.1002/14651858.CD007187.pub2

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cochrane-simplification-train-877

This review included three studies. However, data for progestogen-releasing intrauterine systems were available from only one study that compared 29 women with a levonorgestrel (LNG)-IUS versus 29 women with a combined oral contraceptive (COC) for treating uterine fibroids. There was a significant reduction of menstrual blood loss (MBL) in women receiving the LNG-IUS compared to the COC using the alkaline hematin test (mean difference (MD) 77.5%, 95% CI 71.3% to 83.67%, 58 women) and a pictorial assessment chart (PBAC) (MD 34.5%, 95% CI 14.9% to 54.1%, 58 women). The reduction in uterine fibroid size was significantly greater in the leuprorelin group at 16 weeks compared to the progestogen lynestrenol group (MD -15.93 mm, 95% CI -18.02 to -13.84 mm, 46 women). There was no RCT evaluating the effect of DMPA on uterine fibroids. Progestogen-releasing intrauterine systems appear to reduce menstrual blood loss in premenopausal women with uterine fibroids. Oral progestogens did not reduce fibroid size or fibroid- related symptoms. However, there was a methodological limitation and the one included study with data had a small sample size. This evidence is insufficient to support the use of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids.

The progestogen-releasing (levonorgestrel) intrauterine system (LNG-IUS) is a device placed inside the uterus that releases the hormone progesterone and can cause endometrial suppression. In this review, three randomised controlled studies were included. Two randomised controlled studies included 131 women and evaluated the beneficial and harmful effects of the LNG-IUS compared with hysterectomy or a low dose combined oral contraceptive (COC). However, the results were from only one study that compared 29 women with an LNG-IUS versus 29 women with COC for treating uterine fibroids. The LNG-IUS appeared to reduce menstrual blood loss and increase haemoglobin levels in premenopausal women with uterine fibroids. Reduction of fibroid size was not significant. In one study that included 56 women treated with preoperative oral progestogens (lynestrenol) compared with gonadotropin-releasing hormone (GnRH) agonist, the uterine fibroid size was not different. There was no randomised controlled study of DMPA to treat uterine fibroids. The included studies were of poor quality and had small numbers of participants. Indeed, the authors did not recommend the use of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. More high quality randomized controlled studies evaluating progestogens or progestogen-releasing intrauterine systems for treating uterine fibroids that have an adequate sample size are needed.

10.1002/14651858.CD008994.pub2

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cochrane-simplification-train-878

Nine randomised controlled trials were identified as meeting the inclusion criteria. The nine trials enrolled 2,159 participants but looked at a multiplicity of drug combinations. Despite this, a reasonably robust literature suggests no statistically significant difference between the two drug combinations, including severe adverse events and adherence/tolerance/retention. The quality of the literature was found overall to be low to very low for all key outcomes. Only one study reported on drug resistance, and no studies reported on sexual transmission of HIV. The length of follow-up time and study settings varied greatly. While ideally future research would focus on direct comparison of standard therapeutic combinations of d4T+3TC+an NNRTI and AZT+3TC+an NNRTI to compare these regimens more directly, it is unlikely that additional trials will be mounted. Observational studies should focus on understanding outcomes, including toxicity and tolerability, in low- and middle-income countries.

The purpose of this review was to assess which of these two medications was the best for initial treatment for people living with HIV, and through our search we identified nine randomised controlled trials. Overall, these studies showed no critical difference between d4T and AZT. Future studies and recommendations should focus on specific toxicities and tolerability when comparing these two medications.

10.1002/14651858.CD008651

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cochrane-simplification-train-879

We included eight randomized controlled trials (four of which were cross-over trials) with 510 participants (443 boys, 67 girls) in this review. Participants in these studies were children with both ADHD and a chronic tic disorder. All studies took place in the USA and ranged from three to 22 weeks in duration. Five of the eight studies were funded by charitable organizations or government agencies, or both. One study was funded by the drug manufacturer. The other two studies did not specify the source of funding. Risk of bias of included studies was low for blinding; low or unclear for random sequence generation, allocation concealment, and attrition bias; and low or high for selective outcome reporting. We were unable to combine any of the studies in a meta-analysis due to important clinical heterogeneity and unit-of-analysis issues. Several of the trials assessed multiple agents. Medications assessed included methylphenidate, clonidine, desipramine, dextroamphetamine, guanfacine, atomoxetine, and deprenyl. There was low-quality evidence for methylphenidate, atomoxetine, and clonidine, and very low-quality evidence for desipramine, dextroamphetamine, guanfacine and deprenyl in the treatment of ADHD in children with tics. All studies, with the exception of a study using deprenyl, reported improvement in symptoms of ADHD. Tic symptoms also improved in children treated with guanfacine, desipramine, methylphenidate, clonidine, and a combination of methylphenidate and clonidine. In one study, tics limited further dosage increases of methylphenidate. High-dose dextroamphetamine appeared to worsen tics in one study, although the length of this study was limited to three weeks. There was appetite suppression or weight loss in association with methylphenidate, dextroamphetamine, atomoxetine, and desipramine. There was insomnia associated with methylphenidate and dextroamphetamine, and sedation associated with clonidine. Following an updated search of potentially relevant studies, we found no new studies that matched our inclusion criteria and thus our conclusions have not changed. Methylphenidate, clonidine, guanfacine, desipramine, and atomoxetine appear to reduce ADHD symptoms in children with tics though the quality of the available evidence was low to very low. Although stimulants have not been shown to worsen tics in most people with tic disorders, they may, nonetheless, exacerbate tics in individual cases. In these instances, treatment with alpha agonists or atomoxetine may be an alternative. Although there is evidence that desipramine may improve tics and ADHD in children, safety concerns will likely continue to limit its use in this population.

We included eight studies with 510 participants (443 boys, 67 girls) in our review. Participants in these studies were children with both ADHD and a chronic tic disorder. The included studies evaluated several different medications for ADHD, including stimulants (methylphenidate, dextroamphetamine) and non-stimulants (clonidine, guanfacine, desipramine, atomoxetine, and deprenyl). All studies took place in the USA and ranged from three to 22 weeks in duration. Five of the eight studies were funded by charitable organizations or government agencies, or both. One study was funded by the drug manufacturer. The other two studies did not specify the source of funding for the study. The trials in this review suggested that several stimulant and non-stimulant medications may improve ADHD symptoms in children with ADHD and tics. At high doses, dextroamphetamine may initially worsen tics in some children, and dose increases of both dextroamphetamine and methylphenidate may be limited due to tic exacerbation. However, for most children, both tics and ADHD symptoms can improve with use of stimulant medications. There is low-quality evidence for methylphenidate, atomoxetine, and clonidine, and very low-quality evidence for desipramine, dextroamphetamine, guanfacine, and deprenyl in the treatment of ADHD in children with tics. The evidence was limited by the small number of trials, small number of participants, and risk of bias of the included studies.

10.1002/14651858.CD007990.pub3

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cochrane-simplification-train-880

We identified seven randomized studies involving 450 European participants with LNB for inclusion in this systematic review. We found no trials conducted in the United States. Marked heterogeneity among these studies prevented meta-analysis. None of the studies included a placebo control on the initial antibiotic treatment, and only one was blinded. None were delayed-start studies. All were active comparator studies, and most were not adequately powered for non-inferiority comparison. The trials investigated four antibiotics: penicillin G and ceftriaxone in four studies, doxycycline in three studies, and cefotaxime in two studies. One study tested a three-month course of oral amoxicillin versus placebo following initial treatment with intravenous ceftriaxone. One study was limited to children. The trials measured efficacy using heterogeneous physician- or patient-reported outcomes, or both. In some cases cerebrospinal fluid analysis was included as an indirect biomarker of disease and outcome. None of the studies reported on our proposed primary outcome, 'Improvement in a measure of overall disability in the long term (three or more months).' None of the trials revealed any between-group differences in symptom resolution in response to active treatment. In general, treatment was tolerated well. The quality of adverse event reporting, however, was low. There is mostly low- to very low-quality clinical evidence from a limited number of mostly small, heterogeneous trials with diverse outcome measures, comparing the relative efficacy of central nervous system-penetrant antibiotics for the treatment of LNB. The few existing randomized studies have limited power and lack consistent and well-defined entry criteria and efficacy endpoints. It is not possible to draw firm conclusions on the relative efficacy of accepted antibiotic drug regimens for the treatment of LNB. The majority of people are reported to have good outcomes, and symptoms resolve by 12 months regardless of the antibiotic used. A minority of participants did not improve sufficiently, and some were retreated. These randomized studies provide some evidence that doxycycline, penicillin G, ceftriaxone, and cefotaxime are efficacious in the treatment of European LNB. No evidence of additional efficacy was observed when, in one study, an initial antibiotic treatment with intravenous ceftriaxone was followed by additional longer treatment with oral amoxicillin. There is a lack of evidence identified through our high-quality search strategy on the efficacy of antibiotics for treatment of LNB in the United States.

We found seven trials studying antibiotic treatments for neurological Lyme disease. All but one trial compared different antibiotics. The other trial compared the treatment effects of oral amoxicillin to placebo following initial ceftriaxone treatment. The trials included 450 Europeans. The antibiotics tested were penicillin G, doxycycline, ceftriaxone, and cefotaxime. One of the trials involved children only, while the others included mostly adults. We only selected studies in which treatment allocation was determined by chance (randomly), as such studies provide the best information for comparing the effects of different treatments. Most studies were not blinded (meaning that those taking part and the study staff knew the treatment being given). We could not find any studies of antibiotic treatments for neurological Lyme disease from the United States. No studies assessed the effects of delaying the start of treatment. The seven studies were too different for their results to be combined, so we analyzed them individually. None of the studies provided clear evidence that one antibiotic was better than another. One study failed to find evidence that a second and longer treatment with an oral antibiotic (amoxicillin) offered any extra benefit following initial intravenous treatment with ceftriaxone. As none of the other studies used a dummy treatment (placebo), the extra benefit offered by antibiotic treatment over recovery that occurs naturally is unknown. In general, the treatment was tolerated well, although the quality of adverse event reporting in most studies appeared to be low. The results indicate that treatment with any of the four antibiotics produced similarly good outcomes for treatment of neurological Lyme disease in Europe. A second treatment with amoxicillin does not appear to provide added benefit to ceftriaxone. We found no trials of antibiotics for treatment of neurological Lyme disease in the United States. The evidence is current to October 2016.

10.1002/14651858.CD006978.pub2

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cochrane-simplification-train-881

Thirteen studies with a total of 1344 participants met the inclusion criteria of the review. They were of varying quality. There was no significant difference between salmeterol and theophylline in FEV1 predicted (6.5%; 95% CI -0.84 to 13.83). However, salmeterol treatment led to significantly better morning PEF (mean difference 16.71 L/min, 95% CI 8.91 to 24.51) and evening PEF (mean difference 15.58 L/min, 95% CI 8.33 to 22.83). Salmeterol also reduced the use of rescue medication. Formoterol, used in two studies was reported to be as effective as theophylline. Bitolterol, used in only one study, was reported to be less effective than theophylline. Participants taking salmeterol experienced fewer adverse events than those using theophylline (Parallel studies: Relative Risk 0.44; 95% CI 0.30 to 0.63, Risk Difference -0.11; 95% CI -0.16 to -0.07, Numbers Needed to Treat (NNT) 9; 95% CI 6 to 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95% CI 0.29 to 0.86, Risk Difference -0.07; 95% CI -0.12 to -0.02, NNT 14; 95% CI 8 to 50) and gastrointestinal adverse events (Relative Risk 0.30; 95% CI 0.17 to 0.55, Risk Difference -0.11; 95% CI -0.16 to -0.06, NNT 9; 95% CI 6 to 16). Long-acting beta-2 agonists, particularly salmeterol, are more effective than theophylline in improving morning and evening PEF, but are not significantly different in their effect on FEV1. There is evidence of decreased daytime and nighttime short-acting beta-2 agonist requirement with salmeterol. Fewer adverse events occurred in participants using long-acting beta-2 agonists (salmeterol and formoterol) as compared to theophylline.

This review compared three asthma medications, salmeterol, formoterol (both long acting beta-agonists) and theophylline. These medications are used to help control symptoms of asthma, especially those which occur during the night. This review found that salmeterol showed a greater improvement in lung function, and reduced the need for extra short-term inhalers in the day and the night. Salmeterol and formoterol are less likely to produce side-effects (such as headaches and nausea) when compared to theophylline.

10.1002/14651858.CD001281.pub2

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cochrane-simplification-train-882

Six trials involving 907 patients were identified. For 'death (all causes)' the Peto odds ratio of 0.77 with a 95% confidence interval (CI) of 0.48 to 1.24 did not show a statistically significant difference between both treatment groups. For 'stroke (any)' the Peto odds ratio of 0.58 (95% CI: 0.34 to 0.98) indicated a statistically significant benefit in favour of antiplatelet drugs (P = 0.04). For 'vascular death', 'stroke or vascular death', 'serious vascular events', 'death or dependency', 'myocardial infarction', 'major extracranial haemorrhage', 'local haemorrhage requiring surgery', 'restenosis', 'TIA or amaurosis fugax', neither any benefit nor any hazard of antiplatelet drugs could be shown. For the outcome events 'intracranial haemorrhage', 'ischaemic stroke' and 'occurrence or progression of contralateral stenosis', data were either too sparse for meaningful analyses, or not available at all. Our results may indicate that antiplatelet drugs did not significantly change the odds of death but reduce the outcome 'stroke of any cause' in patients undergoing carotid endarterectomy. However, it can not be excluded that the beneficial effect in reducing stroke is due to chance. There is a suggestion that antiplatelets may increase the odds of haemorrhage, but there are currently too few data to quantify this effect.

This review showed that antiplatelet drugs can also reduce the risk of stroke in patients undergoing carotid endarterectomy. There was limited information on bleeding risk. The review's conclusions supported the routine use of antiplatelet drugs such as aspirin in patients having carotid endarterectomy.

10.1002/14651858.CD001458

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cochrane-simplification-train-883

We included ten studies with a total of 1592 patients. Eight included studies reported sufficiently detailed results to enter into analyses related to antidepressant efficacy. We split one study which included two different antidepressants and therefore had nine groups of patients treated with antidepressants compared with nine groups receiving placebo treatment. Information needed to make 'Risk of bias' judgements was often missing. We found high-quality evidence of little or no difference in scores on depression symptom rating scales between the antidepressant and placebo treated groups after 6 to 13 weeks (standardised mean difference (SMD) -0.10, 95% confidence interval (CI) -0.26 to 0.06; 614 participants; 8 studies). There was probably also little or no difference between groups after six to nine months (mean difference (MD) 0.59 point, 95% CI -1.12 to 2.3, 357 participants; 2 studies; moderate-quality evidence). The evidence on response rates at 12 weeks was of low quality, and imprecision in the result meant we were uncertain of any effect of antidepressants (antidepressant: 49.1%, placebo: 37.7%; odds ratio (OR) 1.71, 95% CI 0.80 to 3.67; 116 participants; 3 studies). However, the remission rate was probably higher in the antidepressant group than the placebo group (antidepressant: 40%, placebo: 21.7%; OR 2.57, 95% CI 1.44 to 4.59; 240 participants; 4 studies; moderate-quality evidence). The largest of these studies continued for another 12 weeks, but because of imprecision of the result we could not be sure of any effect of antidepressants on remission rates after 24 weeks. There was evidence of no effect of antidepressants on performance of activities of daily living at weeks 6 to 13 (SMD -0.05, 95% CI -0.36 to 0.25; 173 participants; 4 studies; high-quality evidence) and probably also little or no effect on cognition (MD 0.33 point on the Mini-Mental State Examination, 95% CI -1.31 to 1.96; 194 participants; 6 studies; moderate-quality evidence). Participants on antidepressants were probably more likely to drop out of treatment than those on placebo over 6 to 13 weeks (OR 1.51, 95% CI 1.07 to 2.14; 836 participants; 9 studies). The meta-analysis of the number of participants suffering at least one adverse event showed a significant difference in favour of placebo (antidepressant: 49.2%, placebo: 38.4%; OR 1.55, 95% CI 1.21 to 1.98, 1073 participants; 3 studies), as did the analyses for participants suffering one event of dry mouth (antidepressant: 19.6%, placebo: 13.3%; OR 1.80, 95% CI 1.23 to 2.63, 1044 participants; 5 studies), and one event of dizziness (antidepressant: 19.2%, placebo: 12.5%; OR 2.00, 95% CI 1.34 to 2.98, 1044 participants; 5 studies). Heterogeneity in the way adverse events were reported in studies presented a major difficulty for meta-analysis, but there was some evidence that antidepressant treatment causes more adverse effects than placebo treatment does. The available evidence is of variable quality and does not provide strong support for the efficacy of antidepressants for treating depression in dementia, especially beyond 12 weeks. On the only measure of efficacy for which we had high-quality evidence (depression rating scale scores), antidepressants showed little or no effect. The evidence on remission rates favoured antidepressants but was of moderate quality, so future research may find a different result. There was insufficient evidence to draw conclusions about individual antidepressant drugs or about subtypes of dementia or depression. There is some evidence that antidepressant treatment may cause adverse events.

We found ten studies with 1592 people to include in the review. On average, the studies lasted only 12 weeks, although one study ran for nine months. Each of them used a set of formal criteria to diagnose both depression and dementia and compared an antidepressant against a dummy pill (placebo). The older studies used more old-fashioned antidepressants (imipramine, clomipramine, and moclobemide) and the newer studies used more modern ones, such as venlafaxine, mirtazapine and so-called SSRI antidepressants (sertraline, fluoxetine, citalopram and escitalopram). The people taking part in the studies had an average age of 75 and they had mild or moderate dementia. With the exception of two studies, they were being treated as outpatients. We found that there was little or no difference in scores on depression rating scales between people treated with antidepressants and those treated with placebo for 12 weeks. The evidence to support this finding was of high quality, which suggests that further research is unlikely to find a different result. There was probably also little or no difference after six to nine months of treatment. Another way to assess the effect of antidepressants is to count the number of people in the antidepressant and placebo groups who show significant clinical improvement (response) or who recover from depression (remission). There was low-quality evidence on the number of people showing a significant clinical improvement and the result was imprecise so we were unable to be sure of any effect on this measure. People taking an antidepressant were probably more likely to recover from depression than were those taking placebo (antidepressant: 40%, placebo: 21.7%). There was moderate-quality evidence for this finding, so it is possible that further research could find a different result. We found that antidepressants did not affect the ability to manage daily activities and probably had little or no effect on a test of cognitive function (which includes attention, memory, and language). People taking an antidepressant were probably more likely to drop out of treatment and to have at least one unwanted side effect. The quality of the evidence varied, mainly due to poorly conducted studies and problems with the relevance of the outcome measures used. This should be taken into consideration when interpreting the different results on depression rating scales and recovery rates, as evidence was of a higher quality for the former than for the latter. Another major problem is that side effects are very rarely well-reported in studies. Therefore, further research will still be useful to reach conclusions that are more reliable and can better help doctors and patients to know what works for whom.

10.1002/14651858.CD003944.pub2

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cochrane-simplification-train-884

We included four studies (five publications) involving 302 participants with idiopathic non-allergic rhinitis. All the included studies described patients with moderately severe, idiopathic non-allergic rhinitis who were between the ages of 16 and 65. Studies had follow-up periods ranging from four to 38 weeks. The overall risk of bias in the studies was either high or unclear (two studies had overall high risk of bias, while two others had low to unclear risk of bias). Using the GRADE system we assessed the evidence as being of low to moderate quality. A meta-analysis was not possible, given lack of similarity of the reported outcomes. Two studies compared capsaicin with placebo. One study reported that capsaicin resulted in an improvement of overall nasal symptoms (a primary outcome) measured on a visual analogue scale (VAS) of 0 to 10. There was a mean difference (MD) of -3.34 (95% confidence interval (CI) -5.24 to -1.44), MD -3.73 (95% CI -5.45 to -2.01) and MD -3.52 (95% CI -5.55 to -1.48) at two, 12 and 36 weeks post-treatment, respectively. Another study reported that, compared to placebo, capsaicin (at 4 µg/puff) was more likely to produce overall symptom resolution (reduction in nasal blockage, sneezing/itching/coughing and nasal secretion measured with a daily record chart) at four weeks post-treatment (a primary outcome). The risk ratio (RR) was 3.17 (95% CI 1.38 to 7.29). One study compared capsaicin to budesonide (an intranasal corticosteroid). This study found that patients treated with capsaicin had a better overall symptom score compared to those treated with budesonide (MD 2.50, 95% CI 1.06 to 3.94, VAS of 0 to 10). However, there were no differences in the individual symptom scores for headache, postnasal drip, rhinorrhoea, nasal blockage, sneezing and sore throat assessed during the last three days of a four-week treatment. One study compared two different regimens of capsaicin administration: five treatments in one day versus five treatments given every two to three days during two weeks. Using daily record charts, the study reported significant improvement of individual symptom scores for rhinorrhoea in patients treated five times per day, however numerical data were not presented. There were no improvements in the other outcomes: rhinorrhoea, nasal obstruction, sneezing and overall nasal symptoms, measured on a VAS. Finally, one of these studies also compared three doses of capsaicin (to placebo). Patients treated with a 1 µg versus 4 µg per puff dose of capsaicin had a worse daily record chart overall symptom score resolution (RR 0.63, 95% CI 0.34 to 1.16). Only one study attempted to measure adverse effects (a primary outcome), however due to methodological issues with the assessment we are unable to draw any conclusions. We sought to include other secondary outcomes (e.g. quality of life measures, treatment dropouts, endoscopic scores, turbinate or mucosal size, cost of therapy), but none of these were measured or reported in the included studies. Capsaicin may be an option in the treatment of idiopathic non-allergic rhinitis. It is given in the form of brief treatments, usually during the same day. It appears to have beneficial effects on overall nasal symptoms up to 36 weeks after treatment, based on a few, small studies (low-quality evidence). Well-conducted randomised controlled trials are required to further advance our understanding of the effectiveness of capsaicin in non-allergic rhinitis, especially in patients with non-allergic rhinitis of different types and severity, and using different methods of capsaicin application.

We included four studies involving 302 patients with idiopathic non-allergic rhinitis. All the included studies described patients with moderately severe idiopathic non-allergic rhinitis, who were between the ages of 16 and 65. The studies had a follow-up ranging from four to 38 weeks after treatment. Individually, the studies reported that the overall function of the nose in patients with non-allergic rhinitis improved when treated with capsaicin compared to placebo. Capsaicin also seems to work better than another common type of nasal medication, budesonide (a steroid). The best knowledge that we have on capsaicin treatment supports giving it five times in one day, and to use doses of at least 4 micrograms in each puff. We could not combine the results together. The included studies did not have sufficient information to allow us to draw a conclusion about side effects. We also wanted to include other outcomes (e.g. quality of life measures, treatment dropouts, endoscopic scores, turbinate or mucosal size, cost of therapy), but none of these were measured or reported in the included studies. Overall, we judged the quality of the evidence to be of low to moderate quality. The evidence is up to date to June 2015. Given that many other options do not work well in non-allergic rhinitis, capsaicin is a reasonable option to try under physician supervision.

10.1002/14651858.CD010591.pub2

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cochrane-simplification-train-885

Thirteen trials performed between the years 1974 and 2008 were included, involving 1412 patients. Four trials included 520 children with acute lymphoblastic leukemia and the remaining trials included adults with acute leukemia, solid organ transplantation or autologous bone marrow transplantation. Compared to no treatment or treatment with fluoroquinolones (inactive against Pneumocystis), there was an 85% reduction in the occurrence of PCP in patients receiving prophylaxis with trimethoprim/sulfamethoxazole, RR of 0.15 (95% CI 0.04 to 0.62; 10 trials, 1000 patients). The evidence was graded as moderate due to possible risk of bias. PCP-related mortality was also significantly reduced, RR of 0.17 (95% CI 0.03 to 0.94; nine trials, 886 patients) (low quality of evidence due to possible risk of bias and imprecision), but in trials comparing PCP prophylaxis against placebo or no treatment there was no significant effect on all-cause mortality (low quality of evidence due to imprecision). Occurrence of leukopenia or neutropenia and their duration were not reported consistently. No significant differences in overall adverse events or events requiring discontinuation were seen comparing trimethoprim/sulfamethoxazole to no treatment or placebo (four trials, 470 patients, moderate quality evidence). No differences between once daily versus thrice weekly trimethoprim/sulfamethoxazole were seen (two trials, 207 patients). Given an event rate of 6.2% in the control groups of the included trials, prophylaxis for PCP using trimethoprim/sulfamethoxazole is highly effective among non-HIV immunocompromised patients, with a number needed to treat to prevent PCP of 19 patients (95% CI 17 to 42). Prophylaxis should be considered for patients with a similar baseline risk of PCP.

The patients included in the 13 trials we identified were adults with acute leukemia or solid organ transplantation and children with acute leukemia. This review of randomised controlled trials (RCTs) found that prophylaxis with trimethoprim/sulfamethoxazole, an antibiotic effective against PCP, significantly reduced the occurrence of PCP by 85%. We found no evidence for a reduction in all cause mortality. Confidence in the results for PCP was moderate to high, while for mortality it was low due to paucity of data. Preventive treatment was not associated with an increased rate of adverse events. Trimethoprim/sulfamethoxazole may be administered thrice weekly as effectively as once daily. Based on our results, the number of people that need to be treated with trimethoprim/sulfamethoxazole for a prolonged period of time (ranging between several weeks to three years in the included trials) in order to prevent one episode of PCP infection was 19; when PCP infection occurs at a rate of about 6% without prophylaxis. Given the low rate of adverse events, prophylaxis should be considered for patients at similar risk of PCP.

10.1002/14651858.CD005590.pub3

cochrane-simplification-train-886

cochrane-simplification-train-886

We screened a total of 1150 records. Seven RCTs involving 1763 patients were identified, but only five could be included in the two separate meta-analyses we performed. We judged the overall the quality of these trials as moderate to high. All trials were randomised and open-label studies. However, two trials were published as abstracts only, therefore we were unable to assess the potential risk of bias for these trials in detail. Three RCTs (N = 1421) assessed the efficacy of monoclonal anti-CD20 antibodies (i.e. rituximab) plus chemotherapy compared to chemotherapy alone. The meta-analyses showed a statistically significant OS (HR 0.78, 95% confidence interval (CI) 0.62 to 0.98, P = 0.03, the number needed to treat for an additional beneficial effect (NNTB) was 12) and PFS (HR 0.64, 95% CI 0.55 to 0.74, P < 0.00001) advantage for patients receiving rituximab. In the rituximab-arm occurred more AEs, World Health Organization (WHO) grade 3 or 4 (3 trials, N = 1398, RR 1.15, 95% CI 1.08 to 1.23, P < 0.0001; the number needed to harm for an additional harmful outcome (NNTH) was 9), but that did not lead to a statistically significant difference regarding TRM (3 trials, N = 1415, RR 1.19, 95% CI 0.70 to 2.01, P = 0.52). Two trials (N = 177) evaluated rituximab versus alemtuzumab. Neither study reported OS or PFS. There was no statistically significant difference between arms regarding complete response rate (CRR) (RR 1.21, 95% CI 0.94 to 1.58, P = 0.14) or TRM (RR 0.31, 95% CI 0.06 to 1.51, P = 0.15). However, the CLL2007FMP trial was stopped early owing to an increase in mortality in the alemtuzumab arm. More serious AEs occurred in this arm (43% with alemtuzumab versus 22% with rituximab; P = 0.006). Two trials assessed different dosages or time schedules of monoclonal anti-CD20 antibodies. One trial (N = 104) evaluated two different rituximab schedules (concurrent arm: fludarabine plus rituximab (Flu-R) plus rituximab consolidation versus sequential arm: fludarabine alone plus rituximab consolidation). The comparison of the concurrent versus sequential regimen of rituximab showed a statistically significant difference of the CRR with 33% in the concurrent-arm and 15% in the sequential-arm (P = 0.04), that did not lead to statistically significant differences regarding OS (HR 1.14, 95% CI 0.20 to 6.65, P = 0.30) or PFS (HR 0.96, 95% CI 0.43 to 2.15, P = 0.11). Furthermore results showed no differences in occurring AEs, except for neutropenia, which was more often observed in patients of the concurrent arm. The other trial (N = 61) investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to FluC. The arm investigating ofatumumab did not assess OS and a median PFS had not been reached owing to the short median follow-up of eight months. It showed no statistically significant differences between arms regarding CRR (32% in the FCO500 arm versus 50% in the FCO1000 arm; P = 0.10) or AEs (anaemia, neutropenia, thrombocytopenia). This meta-analysis showed that patients receiving chemotherapy plus rituximab benefit in terms of OS as well as PFS compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with FluC as an option for the first-line treatment as well as for the people with relapsed or refractory CLL. The available evidence regarding the other assessed comparisons was not sufficient to deduct final conclusions.

Three trials (N = 1421) were included in the meta-analysis assessing the efficacy of chemotherapy plus rituximab compared to chemotherapy without further therapy. The meta-analysis showed for patients receiving additional rituximab a statistically significant improvement of overall survival and a longer time without progression of the disease. Treatment with rituximab caused more adverse events, but this did not lead to a statistically significant difference regarding death caused by treatment. However, patients who were treated within these trials did not suffer from other severe health problems aside from CLL; therefore, it remains unclear whether patients with severe co-morbidities will benefit from this treatment option. In summary, this meta-analysis showed that patients receiving chemotherapy plus rituximab benefited in terms of survival compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with fludarabine and cyclophosphamide as an option for the first-line treatment as well as for people with relapsed or refractory CLL. Further research should focus on the evaluation of benefits of adding rituximab to other chemotherapy regimens than fludarabine with cyclophosphamide in the therapy of previously untreated, relapsed or refractory patients. It should also assess whether patients with serious co-morbidities will benefit from the addition of rituximab to chemotherapy. The available evidence regarding assessed comparisons from four other trials was not sufficient to deduct final conclusions.Two trials evaluated polychemotherapy in combination with rituximab versus alemtuzumab respectively. One trial evaluated two different rituximab schedules: rituximab given concurrently with primary treatment plus rituximab therapy given subsequently to the primary treatment versus primary treatment alone with subsequent administration of rituximab. One trial investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to fludarabine with cyclophosphamide. Randomised Controlled Trials (RCTs) are needed to determine the clinical effects of novel anti-CD20 antibodies, such as ofatumumab or GA101, compared to rituximab. We are aware of 16 ongoing studies, including three trials comparing ofatumumab with or without additional chemotherapy versus no treatment. The findings of these trials will be included in an update of this review and could lead to different conclusions and may allow a judgement on general efficacy and safety of monoclonal anti-CD20 antibody in the treatment of CLL.

10.1002/14651858.CD008079.pub2

cochrane-simplification-train-887

cochrane-simplification-train-887

Four randomised trials were eligible for inclusion in this systematic review - two studies with 83 adults comparing fluoroquinolones with β-lactams and two studies with 55 adults comparing aminoglycosides with polymyxins. None of the included studies reported information on exacerbations - one of our primary outcomes. Included studies reported no serious adverse events - another of our primary outcomes - and no deaths. We graded this evidence as low or very low quality. Included studies did not report quality of life. Comparison between fluoroquinolones and β-lactams (amoxicillin) showed fewer treatment failures in the fluoroquinolone group than in the amoxicillin group (OR 0.07, 95% CI 0.01 to 0.32; low-quality evidence) after 7 to 10 days of therapy. Researchers reported that Pseudomonas aeruginosa infection was eradicated in more participants treated with fluoroquinolones (Peto OR 20.09, 95% CI 2.83 to 142.59; low-quality evidence) but provided no evidence of differences in the numbers of participants showing improvement in sputum purulence (OR 2.35, 95% CI 0.96 to 5.72; very low-quality evidence). Study authors presented no evidence of benefit in relation to forced expiratory volume in one second (FEV₁). The two studies that compared polymyxins versus aminoglycosides described no clear differences between groups in the proportion of participants with P aeruginosa eradication (OR 1.40. 95% CI 0.36 to 5.35; very low-quality evidence) or improvement in sputum purulence (OR 0.16, 95% CI 0.01 to 3.85; very low-quality evidence). The evidence for changes in FEV₁ was inconclusive. Two of three trials reported adverse events but did not report the proportion of participants experiencing one or more adverse events, so we were unable to interpret the information. Limited low-quality evidence favours short-term oral fluoroquinolones over beta-lactam antibiotics for patients hospitalised with exacerbations. Very low-quality evidence suggests no benefit from inhaled aminoglycosides verus polymyxins. RCTs have presented no evidence comparing other modes of delivery for each of these comparisons, and no RCTs have included children. Overall, current evidence from a limited number of head-to-head trials in adults or children with bronchiectasis is insufficient to guide the selection of antibiotics for short-term or long-term therapy. More research on this topic is needed.

In April 2018, we looked for studies including adults or children with bronchiectasis that randomly allocated participants to receive one antibiotic or another by the same method of administration. We found only four studies, and they were very small. In total, they included 138 participants. This small sample makes it very difficult to draw clear conclusions. Four randomised trials were eligible for inclusion in this systematic review. None of the included studies reported information on flare-ups (exacerbations). Included studies reported no deaths and no serious adverse events. Treatment failures were fewer with fluoroquinolone antibiotics than with amoxicillin antibiotics. Reviewers considered the quality of the evidence provided by the four small included studies to be low or very low. Fluoroquinolone antibiotics may be more successful than amoxicillin antibiotics in treating exacerbations, but this finding is based on low-quality evidence. More evidence from high-quality clinical trials of short-term and long-term treatment with antibiotics is needed if clear conclusions are to be reached on the benefits of one antibiotic over another for people with bronchiectasis.

10.1002/14651858.CD012590.pub2

cochrane-simplification-train-888

cochrane-simplification-train-888

Ten studies were included in the review but only five reported data that could be used. Three of the ten studies were related to exercise-based psychological interventions. Seven were related to psychological interventions. No meta-analyses were possible due to diversity of participants, interventions and outcomes. Two studies compared a psychosocial intervention versus another intervention. Three studies compared a psychosocial intervention to a control group. Only one primary prevention trial reported data for the primary outcomes and, although this study found a significant difference in depression in favour of the intervention at endpoint, this difference was no longer evident at 18 months. No studies of primary prevention comparing different interventions and reporting primary outcomes of interest were identified. The methodological quality of the included studies was summarised. No study met our full quality criteria and one was regarded as low-quality. The remainder could not be rated because of incomplete data in the published reports and inadequate responses from the trialists. There is evidence only from individual small and low quality trials with minimal data suggesting that police officers benefit from psychosocial interventions, in terms of physical symptoms and psychological symptoms such as anxiety, depression, sleep problems, cynicism, anger, PTSD, marital problems and distress. No data on adverse effects were available. Meta-analyses of the available data were not possible. Further well-designed trials of psychosocial interventions are required. Research is needed on organization-based interventions to enhance psychological health among police officers.

In view of the importance of the functions performed by law enforcement officers, and the fact that there is no definitive approach to deal with psychological problems they may develop, a systematic review of the evidence is needed to determine the effectiveness of psychosocial interventions in preventing these problems in this select population. We found ten randomised trials, but not of all these contributed useful data for this review and quantitative meta-analyses were not possible. No data on adverse effects were available. The available evidence is, therefore, limited to the analysis of single, small and low quality trials. This suggests that police officers may benefit from psychosocial interventions in terms of psychological symptoms and physical symptoms. Further well-designed trials of psychosocial interventions to enhance the psychological health of police officers are required. Trials of organisation-based interventions are also needed.

10.1002/14651858.CD005601.pub2

cochrane-simplification-train-889

cochrane-simplification-train-889

The curves for the life-table cumulative pregnancy rates for the Prentif cap and the diaphragm did not differ. However, the Kaplan-Meier six-month cumulative pregnancy rates for the FemCap and the diaphragm were not clinically equivalent. The Prentif cap had more Class I to Class III cervical cytologic conversions than the diaphragm (OR 2.31; 95% CI 1.04 to 5.11). The FemCap trial did not find differences in Papanicolaou smear results between the groups. Fewer Prentif cap users had vaginal ulcerations or lacerations (OR 0.31; 95% CI 0.14 to 0.71) than diaphragm users. Fewer FemCap users had blood in the device (OR 2.29; 95% CI 1.27 to 4.14), but more had urinary tract infections (OR 0.59; 95% CI 0.39 to 0.95). In the FemCap trial, similar proportions of women reported liking their device. However, FemCap users were less likely to use the device alone after the trial (OR 0.47; 95% CI 0.31 to 0.71) or recommend it to a friend (OR 0.48; 95% CI 0.29 to 0.81). The Prentif cap was as effective as its comparison diaphragm in preventing pregnancy, but the FemCap was not. Both cervical caps appear to be medically safe.

In February 2012, we did a computer search for studies of cervical caps. We wrote to manufacturers and researchers for information about other trials. We included randomized controlled trials that compared a cervical cap with a diaphragm. We found two trials that compared the cervical cap with the diaphragm. Two types of cervical caps were studied: the Prentif cap and the FemCap. The Prentif cap prevented pregnancy as well as the diaphragm, but the FemCap did not. Women who used the Prentif cap had more abnormal changes in the cervix than diaphragm users. The FemCap users did not have more abnormal changes than the diaphragm users. Many women from both groups dropped out early from the two trials. Similar numbers of FemCap users and diaphragm users reported liking their assigned method. The Prentif cap worked as well as the diaphragm to prevent pregnancy. The FemCap did not prevent pregnancy as well as the diaphragm. Both cervical caps appear to be medically safe.

10.1002/14651858.CD003551

cochrane-simplification-train-890

cochrane-simplification-train-890

We found one RCT, which included 13 women, that met our inclusion criteria and this trial reported data on LARVH versus RAH. Women who underwent LARVH for treatment of early-stage cervical cancer appeared to have less blood loss compared with those who underwent RAH. The trial reported a borderline significant difference between the two types of surgery (median blood loss 400 mL (interquartile range (IQR): 325 to 1050) and 1000 mL (IQR: 800 to 1025) for LARVH and RAH, respectively, P value = 0.05). RAH was associated with significantly shorter operation time compared with LARVH (median: 180 minutes with LARVH versus 138 minutes with RAH, P value = 0.05). There was no statistically significant difference in the risk of perioperative complications in women who underwent LARVH and RAH. The trial reported two (29%) and four (57%) cases of intraoperative and postoperative complications, respectively, in the LARVH group and no (0%) reported cases of intraoperative complications and five (83%) cases of postoperative complications in the RAH group. There were no reported cases of severe perioperative complications. Bladder and bowel dysfunction of either a transient or chronic nature remain major morbidities after radical hysterectomy, and the one included study showed that there may be significantly less after LARVH. The included trial lacked statistical power due to the small number of women in each group and the low number of observed events. Therefore, the absence of reliable evidence, regarding the effectiveness and safety of the two surgical techniques for the management of early-stage cervical cancer, precludes any definitive guidance or recommendations for clinical practice. The trial did not report data on long-term outcomes, but was at moderate risk of bias due to very low numbers of included women.

We carried out a systematic review and searched for published and unpublished randomised controlled trials (RCTs) that compared open and laparoscopically assisted vaginal methods of performing radical hysterectomy in women with early cervical cancer. The evidence is current to July 2013. We found only one relevant trial. It included only 13 women; seven had a laparoscopically assisted radical vaginal hysterectomy (LARVH) and six had radical abdominal hysterectomy (RAH). Women who underwent LARVH appeared to have less blood loss, shorter hospital stay and less requirement for pain medication compared with those who underwent RAH. There was no statistically significant difference in the risk of complications related to the operation in women who underwent LARVH and RAH. However, RAH had a significantly shorter operation time compared with LARVH. The trial did not assess overall survival and progression-free survival (PFS; the time that a woman lives with the cancer but does not get worse) or quality of life (QoL) as the main focus of the trial was to examine short-term complications. Due to the small number of cases and the short-term scope of the trial, we were unable to reach any definite conclusions about the relative benefits and harms of the two forms of treatment and we were unable to identify subgroups of women who are likely to benefit from one treatment or the other.

10.1002/14651858.CD006651.pub3

cochrane-simplification-train-891

cochrane-simplification-train-891

No immediate mortality was reported. There was no significant difference in serious cardio-respiratory complications suffered by patients in either sedation group. Failure to complete the procedure due to sedation-related problems was reported in one study. Three studies found faster and better recovery in patients receiving propofol for their ERCP procedures. Study protocols regarding use of supplemental oxygen, intravenous fluid administration and capnography monitoring varied considerably. The studies showed either moderate or high risk of bias. Results from individual studies suggested that patients have a better recovery profile after propofol sedation for ERCP procedures than after midazolam and meperidine sedation. As there was no difference between the two sedation techniques as regards safety, propofol sedation is probably preferred for patients undergoing ERCP procedures. However, in all of the studies that were identified only non-anaesthesia personnel were involved in administering the sedation. It would be helpful if further research was conducted where anaesthesia personnel were involved in the administration of sedation for ERCP procedures. This would clarify the extent to which anaesthesia personnel should be involved in the administration of propofol sedation.

There was no significant difference between the sedation techniques as regards safety. There were no deaths in the trials and the number of major complications, such as lack of oxygen (hypoxaemia) and low blood pressure (hypotension), was comparable in both techniques. There was no difference in patient satisfaction in either group. However, the recovery of patients who received propofol was significantly better than for those who had received midazolam and meperidine for the procedure. In conclusion, patients undergoing ERCP procedures under propofol sedation recover faster and better than those patients receiving midazolam and meperidine sedation. This would make propofol the preferred choice for these procedures as there was no difference in the safety of either technique. Further research should focus on the safety of the sedative techniques and involve anaesthesia personnel in the administration of the sedation.

10.1002/14651858.CD007274.pub2

cochrane-simplification-train-892

cochrane-simplification-train-892

We identified 37 randomised controlled trials involving 11,948 participants. These trials compared lidocaine versus placebo or no intervention, disopyramide, mexiletine, tocainide, propafenone, amiodarone, dimethylammonium chloride, aprindine and pirmenol. Overall, trials were underpowered and had high risk of bias. Ninety-seven per cent of trials (36/37) were conducted without an a priori sample size estimation. Ten trials were sponsored by the pharmaceutical industry. Trials were conducted in 17 countries, and intravenous intervention was the most frequent route of administration. In trials involving participants with proven or non-proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences regarding all-cause mortality (213/5879 (3.62%) vs 199/5848 (3.40%); RR 1.02, 95% CI 0.82 to 1.27; participants = 11727; studies = 18; I2 = 15%); low-quality evidence), cardiac mortality (69/4184 (1.65%) vs 62/4093 (1.51%); RR 1.03, 95% CI 0.70 to 1.50; participants = 8277; studies = 12; I2 = 12%; low-quality evidence) and prophylaxis of ventricular fibrillation (76/5128 (1.48%) vs 103/4987 (2.01%); RR 0.78, 95% CI 0.55 to 1.12; participants = 10115; studies = 16; I2 = 18%; low-quality evidence). In terms of sinus bradycardia, lidocaine effect is imprecise compared with effects of placebo or no intervention (55/1346 (4.08%) vs 49/1203 (4.07%); RR 1.09, 95% CI 0.66 to 1.80; participants = 2549; studies = 8; I2 = 21%; very low-quality evidence). In trials involving only participants with proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences in all-cause mortality (148/2747 (5.39%) vs 135/2506 (5.39%); RR 1.01, 95% CI 0.79 to 1.30; participants = 5253; studies = 16; I2 = 9%; low-quality evidence). No significant differences were noted between lidocaine and any other antiarrhythmic drug in terms of all-cause mortality and ventricular fibrillation. Data on overall survival 30 days after myocardial infarction were not reported. Lidocaine compared with placebo or no intervention increased risk of asystole (35/3393 (1.03%) vs 14/3443 (0.41%); RR 2.32, 95% CI 1.26 to 4.26; participants = 6826; studies = 4; I2 = 0%; very low-quality evidence) and dizziness/drowsiness (74/1259 (5.88%) vs 16/1274 (1.26%); RR 3.85, 95% CI 2.29 to 6.47; participants = 2533; studies = 6; I2 = 0%; low-quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. Trial sequential analyses suggest that additional trials may not be needed for reliable conclusions to be drawn regarding these outcomes. This Cochrane review found evidence of low quality to suggest that prophylactic lidocaine has very little or no effect on mortality or ventricular fibrillation in people with acute myocardial infarction. The safety profile is unclear. This conclusion is based on randomised controlled trials with high risk of bias. However (disregarding the risk of bias), trial sequential analysis suggests that additional trials may not be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might require additional higher trials.

We identified 37 trials conducted between 1969 and 1999. The evidence is current up to April 2015. Trials were conducted in Australia, Belgium, Brazil, Canada, Denmark, France, Germany, Italy, New Zealand, Northern Ireland, Norway, Poland, Sweden, Switzerland, The Netherlands, United Kingdom and United States of America and included 11,948 participants. Trials were conducted in pre-hospital and in-hospital settings and included individuals with or without proved acute myocardial infarction. Some trials did not limit results to acute myocardial infarction only. Lidocaine was given by intravenous (bolus and/or infusion) and intramuscular (alone or in combination with intravenous dosage) routes. Overall, trials included small sample sizes and reported low numbers of events. All trials had high risk of bias. Ten trials were sponsored by the pharmaceutical industry. In people who had known or suspected heart attack, we found that lidocaine compared with placebo, no intervention or any other antiarrhythmic drug had very small or no effects on death, cardiac death and ventricular fibrillation. Our confidence in the results of this review is low because the included trials that we synthesised were of low quality (overestimation of benefits and underestimation of harms) and were conducted with a small number of participants, leading to imprecision of results.

10.1002/14651858.CD008553.pub2

cochrane-simplification-train-893

cochrane-simplification-train-893

Five trials involving 962 participants are included in this review. All trials were of relatively short duration (< 16 weeks). Due to the heterogenous aetiology of pulmonary hypertension in participants, results are best considered according to each pulmonary hypertension subtype. Pooled analysis shows a mean difference (MD) increase in six-minute walking distance (6MWD) of 30.13 metres (95% CI 5.29 to 54.96; participants = 659; studies = 3). On subgroup analysis, for pulmonary arterial hypertension (PAH) there was no effect noted (6MWD; MD 11.91 metres, 95% CI −44.92 to 68.75; participants = 398; studies = 2), and in chronic thromboembolic pulmonary hypertension (CTEPH) sGC stimulators improved 6MWD by an MD of 45 metres (95% CI 23.87 to 66.13; participants = 261; studies = 1). Data for left heart disease-associated PH was not available for pooling. Importantly, when participants receiving phosphodiesterase inhibitors were excluded, sGC stimulators increased 6MWD by a MD of 36 metres in PAH. The second primary outcome, mortality, showed no change on pooled analysis against placebo (Peto odds ratio (OR) 0.57, 95% CI 0.18 to 1.80). Pooled secondary outcomes include an increase in World Health Organization (WHO) functional class (OR 1.53, 95% CI 0.87 to 2.72; participants = 858; studies = 4), no effect on clinical worsening (OR 0.45, 95% CI 0.17 to 1.14; participants = 842; studies = 3), and a reduction in mean pulmonary artery pressure (MD −2.77 mmHg, 95% CI −4.96 to −0.58; participants = 744; studies = 5). There was no significant difference in serious adverse events on pooled analysis (OR 1.12, 95% CI 0.66 to 1.90; participants = 818; studies = 5) or when analysed at PAH (MD −3.50, 95% CI −5.54 to −1.46; participants = 344; studies = 1), left heart disease associated subgroups (OR 1.56, 95% CI 0.78 to 3.13; participants = 159; studies = 2) or CTEPH subgroups (OR 1.29, 95% CI 0.65 to 2.56; participants = 261; studies = 1). It is important to consider the results for PAH in the context of a person who is not also receiving a phosphodiesterase-V inhibitor, a contra-indication to sGC stimulator use. It should also be noted that CTEPH results are applicable to inoperable or recurrent CTEPH only. Evidence was rated according to the GRADE scoring system. One outcome was considered high quality, two were moderate, and eight were of low or very low quality, meaning that for many of the outcomes the true effect could differ substantially from our estimate. There were only minor concerns regarding the risk of bias in these trials, all being RCTs largely following the original protocol. Most trials employed an intention-to-treat analysis. sGC stimulators improve pulmonary artery pressures in people with PAH (who are treatment naive or receiving a prostanoid or endothelin antagonist) or those with recurrent or inoperable CTEPH. In these settings this can be achieved without notable complication. However, sGC stimulators should not be taken by people also receiving phosphodiestase-V inhibitors or nitrates due to the risks of hypotension, and there is currently no evidence supporting their use in pulmonary hypertension associated with left heart disease. There is no evidence supporting their use in children. These conclusions are based on data with limitations, including unavailable data from two of the trials.

This evidence is current to February 2016. Males and females of all ages diagnosed with PH were included in this review. We selected only randomised clinical trials. All trials used a comparison to no treatment. Trial durations ranged from 12 to 16 weeks. This review involves five trials on 962 participants. All included studies were sponsored by the maker of the drug. Soluble guanylate cyclase stimulators appear to reduce lung pressures and improve exercise capacity in PAH and recurrent or inoperable CTEPH, but not in PH due to left heart disease. It is uncertain if these drugs have an effect on death rates and general health decline, or if they may be associated with serious side effects. There is evidence that suggests these drugs should not be taken at the same time as phosphodiesterase-V inhibitors. One outcome was considered to be high quality according to the GRADE scoring system. Two were considered moderate strength and eight outcomes were considered low or very low strength. This means the results reported may not represent the true effect.

10.1002/14651858.CD011205.pub2

cochrane-simplification-train-894

cochrane-simplification-train-894

Three trials including 255 patients qualified for this review. In two of the trial, a total of 150 patients were randomised to absorbable clips (n = 75) and non-absorbable clips (n = 75). In the third trial, a total of 105 patients were randomised to absorbable ligatures (n = 53) and non-absorbable clips (n = 52). All three trials were of high risk of bias. There was no difference in the morbidity between the groups. There was statistically significant longer operating time (MD 12.00 minutes, 95% CI 1.59 to 22.41) in the absorbable ligature group than non-absorbable clips. The duration and method of follow-up were not adequate to determine the incidence of long-term complications. We are unable to determine the benefits and harms of different methods of cystic duct occlusion because of the small sample size, short period of follow-up, and lack of reporting of important outcomes in the included trials. Adequately powered randomised trials with low risk of bias and with long periods of follow-up and assessing all of the important outcomes for patients and professionals are necessary.

A total of three trials including 255 patients qualified for this review of randomised clinical trials. Two trials randomised 150 patients in total to absorbable clips (n = 75) and non-absorbable clips (n = 75). A third trial randomised a total of 105 patients to absorbable ligatures (n = 53) and non-absorbable clips (n = 52). All three trials were of high risk of bias. There was no difference in the morbidity between the groups. The operating time was 12 minutes longer in the absorbable ligature group than in the group randomised to non-absorbable clips.The duration and method of follow-up were not adequate to determine the incidence of long-term complications. We are unable to determine the benefits and harms of different methods of cystic duct occlusion because of the small sample size, short period of follow-up, and lack of reporting of important outcomes in the included trials. New trials with long periods of follow-up and assessing the important outcomes are necessary. Such trials should be designed well to decrease the risk of random errors and systematic errors.

10.1002/14651858.CD006807.pub2

cochrane-simplification-train-895

cochrane-simplification-train-895

We found two randomised clinical trials including 154 adult participants, aged between 18 years and 65 years, diagnosed with hepatosplenic schistosomiasis. One of the trials randomised participants to proximal splenorenal shunt versus distal splenorenal shunt versus oesophagogastric devascularisation with splenectomy, and the other randomised participants to distal splenorenal shunt versus oesophagogastric devascularisation with splenectomy. In both trials the diagnosis of hepatosplenic schistosomiasis was made based on clinical and biochemical assessments. The trials were conducted in Brazil and Egypt. Both trials were at high risk of bias. We are uncertain as to whether surgical portosystemic shunts improved all-cause mortality compared with oesophagogastric devascularisation with splenectomy due to imprecision in the trials (risk ratio (RR) 2.35, 95% confidence interval (CI) 0.55 to 9.92; participants = 154; studies = 2). We are uncertain whether serious adverse events differed between surgical portosystemic shunts and oesophagogastric devascularisation with splenectomy (RR 2.26, 95% CI 0.44 to 11.70; participants = 154; studies = 2). None of the trials reported on health-related quality of life. We are uncertain whether variceal rebleeding differed between surgical portosystemic shunts and oesophagogastric devascularisation with splenectomy (RR 0.39, 95% CI 0.13 to 1.23; participants = 154; studies = 2). We found evidence suggesting an increase in encephalopathy in the shunts group versus the devascularisation with splenectomy group (RR 7.51, 95% CI 1.45 to 38.89; participants = 154; studies = 2). We are uncertain whether ascites and re-interventions differed between surgical portosystemic shunts and oesophagogastric devascularisation with splenectomy. We computed Trial Sequential Analysis for all outcomes, but the trial sequential monitoring boundaries could not be drawn because of insufficient sample size and events. We downgraded the overall certainty of the body of evidence for all outcomes to very low due to risk of bias and imprecision. Given the very low certainty of the available body of evidence and the low number of clinical trials, we could not determine an overall benefit or harm of surgical portosystemic shunts compared with oesophagogastric devascularisation with splenectomy. Future randomised clinical trials should be designed with sufficient statistical power to assess the benefits and harms of surgical portosystemic shunts versus oesophagogastric devascularisations with or without splenectomy and with or without oesophageal transection.

We found two randomised clinical trials (types of studies in which participants are assigned to treatment group using a random method) involving a total of 154 adult participants who received either a non-selective shunt surgery, a selective shunt surgery, or devascularisation surgery. However, the design of both trials was of insufficient quality, as the numbers of trial participants were small, and some participant information was lacking. One of the trials was funded by an institutional grant, and how funding was obtained for the other trial was not clear. We assessed both trials as at high risk of bias. There were no significant differences in the number of participants who had repeat bleeding, adverse effects of treatment, or deaths between the shunt surgery and the devascularisation group, but participants who had devascularisation were less likely to suffer encephalopathy (disease of the brain due to damage from toxins produced by the liver). Neither of the trials addressed quality of life after treatment. Given the very low certainty of the evidence due to the way the clinical trials were performed, limited trial data and trial participants, we were unable to determine whether one treatment is better than the other. We suggest that future trials include a sufficient number of randomised participants to be able to obtain meaningful results on patient-relevant outcomes and allow objective comparison of these two surgery types.

10.1002/14651858.CD011717.pub2

cochrane-simplification-train-896

cochrane-simplification-train-896

The review currently includes eleven RCTs with 4144 participants on three second-generation antipsychotics (olanzapine, quetiapine, risperidone). Nine studies investigated the effects of second-generation antipsychotics in generalised anxiety disorder, only two studies investigated the effects in social phobia. There were no studies on panic disorder or any other primary anxiety disorder. Seven studies investigated the effects of quetiapine. Participants with generalised anxiety disorder responded significantly better to quetiapine than to placebo (4 RCTs, N = 2265, OR = 2.21, 95% CI 1.10 to 4.45). However, they were more likely to drop out due to adverse events, to gain weight, to suffer from sedation or to suffer from extrapyramidal side effects. When quetiapine was compared with antidepressants, there was no significant difference in efficacy-related outcomes, but more participants in the quetiapine groups dropped out due to adverse events, gained weight and feeling sedated. Only two very small studies with a total of 36 participants examined olanzapine and found no difference in response to treatment. Two trials compared adjunctive treatment with risperidone with placebo and found no difference in response to treatment. We identified eligible trials on quetiapine, risperidone and olanzapine. The available data on olanzapine and risperidone are too limited to draw any conclusions. Monotherapy with quetiapine seems to be efficacious in reducing symptoms of generalised anxiety disorder and this effect may be similar to that of antidepressants. However, quetiapine's efficacy must be weighed against its lower tolerability.

This systematic review evaluated the efficacy and tolerability of second-generation antipsychotics in the treatment of anxiety disorders. We found eleven randomised placebo-controlled trials, comparing quetiapine, olanzapine and risperidone with placebo and antidepressants. The vast majority of the available data was on quetiapine (> 3000 participants). Participants with generalised anxiety disorder responded significantly better to quetiapine than to placebo, measured as a reduction in the Hamilton Anxiety Scale (HAM-A). Participants treated with quetiapine were more likely to drop out due to adverse events, to gain weight, to suffer from sedation or to suffer from extrapyramidal side effects. The evidence on the other second-generation antipsychotics is currently too limited to draw any conclusions.

10.1002/14651858.CD008120.pub2

cochrane-simplification-train-897

cochrane-simplification-train-897

Overall 16 studies were identified and included. MR1: three trials (n=145). Some evidence of effectiveness of cognitive rehabilitation on cognitive outcomes, although this was difficult to interpret because of the large number of outcome measures used. MR2: three trials (n=80). One small trial suggesting psychotherapy may help with depression. MR3: seven studies (n=688). Some evidence that cognitive behavioural therapy may help people adjust to, and cope with, having MS (three trials). The other trials were diverse in nature and some difficult to interpret because of multiple outcome measures. MR4: three trials (n=93). Two small studies of cognitive behavioural therapy showed significant improvements in depression. The diversity of psychological interventions identified indicates the many ways in which they can potentially help people with MS. No definite conclusions can be made from this review. However there is reasonable evidence that cognitive behavioural approaches are beneficial in the treatment of depression, and in helping people adjust to, and cope with, having MS.

Sixteen relevant studies were identified and included in this review. They have researched a variety of different interventions, having different purposes, and so a single overall definite conclusion cannot be made. However the authors cautiously conclude that Cognitive Behavioural Therapy, a therapy that addresses thoughts and behaviours, can help people with MS adjust to, and cope with, having MS, and can help them if they get depressed. Psychological interventions can potentially help people with MS in many ways, including the management of symptoms such as pain and fatigue. Additional studies are needed, particularly those that include larger numbers of people.

10.1002/14651858.CD004431.pub2

cochrane-simplification-train-898

cochrane-simplification-train-898

Three randomised clinical trials were included in this review. All of them had a high risk of bias. One trial was conducted in Shanghai, China. There are several published reports on this trial, in which data were presented differently. According to the 2004 trial report, participants were randomised to screening every six months with alpha-foetoprotein and ultrasonography (n = 9373) versus no screening (n = 9443). We could not draw any definite conclusions from it. A second trial was conducted in Toronto, Canada. In this trial, there were 1069 participants with chronic hepatitis B. The trial compared screening every six months with alpha-foetoprotein alone (n = 532) versus alpha-foetoprotein and ultrasound (n = 538) over a period of five years. This trial was designed as a pilot trial; the small number of participants and the rare events did not allow an effective comparison between the two modes of screening that were studied. The remaining trial, conducted in Taiwan and published as an abstract, was designed as a cluster randomised trial to determine the optimal interval for screening using alpha foetoprotein and ultrasound. Screening intervals of four months and 12 months were compared in the two groups. Further details about the screening strategy were not available. The trial reported on cumulative four-year survival, cumulative three-year incidence of hepatocellular carcinoma, and mean tumour size. The cumulative four-year survival was not significantly different between the two screening intervals. The incidence of hepatocellular cancer was higher in the four-monthly screening group. The included trials did not report on adverse events. It appears that the sensitivity and specificity of the screening modes were poor, accounting for a substantial number of false-positive and false-negative screening results. There is not enough evidence to support or refute the value of alpha-foetoprotein or ultrasound screening, or both, of hepatitis B surface antigen (HBsAg) positive patients for hepatocellular carcinoma. More and better designed randomised trials are required to compare screening against no screening.

Only three trials could be included in this review. One of these trials was conducted in Shanghai, China. It compared screening twice yearly with ultrasound and alpha-foetoprotein against no screening. The trial has a high risk of systematic errors (bias) and several published reports of the trial provide different results. Another trial was conducted in Toronto, Canada. It compared screening with alpha-foetoprotein and ultrasound versus screening with alpha-foetoprotein alone. This trial had too few participants. As there were no participants who were not screened, we cannot assess whether screening is effective in reducing mortality. The remaining trial was published as an abstract only. It was designed to determine the optimal time interval for screening using alpha fetoprotein and ultrasound. The cumulative four-year survival was not significantly different between the two studied screening intervals of four months and 12 months. Thus, to date, there is insufficient evidence regarding screening for liver cancer among patients with chronic hepatitis B infection.

10.1002/14651858.CD002799.pub2

cochrane-simplification-train-899

cochrane-simplification-train-899

Ten studies (1785 participants) met the inclusion criteria. The two new studies in this update had been identified in the earlier update, but data were not available. There remain three potentially relevant unpublished studies for which data are not available at this time. The NNT for celecoxib 200 mg and 400 mg compared with placebo for at least 50% of maximum pain relief over four to six hours was 4.2 (95% confidence interval (CI) 3.4 to 5.6) and 2.6 (95% CI 2.3 to 3.0) respectively. The median time to use of rescue medication was 6.6 hours with celecoxib 200 mg, 8.4 hours with celecoxib 400 mg, and 2.3 hours with placebo. The proportion of participants requiring rescue medication over 24 hours was 74% with celecoxib 200 mg, 63% for celecoxib 400 mg, and 91% for placebo. The NNT to prevent one patient using rescue medication was 4.8 (95% CI 3.5 to 7.7) and 3.5 (95% CI 2.9 to 4.6) for celecoxib 200 mg and 400 mg respectively. Adverse events were generally mild to moderate in severity, and were experienced by a similar proportion of participants in the celecoxib and placebo groups. One serious adverse event that was probably related to celecoxib was reported. Single-dose oral celecoxib is an effective analgesic for postoperative pain relief. Indirect comparison suggests that the 400 mg dose has similar efficacy to ibuprofen 400 mg.

This review assessed information from 10 studies which used celecoxib for acute pain. Just over 3 in 10 people (33%) taking celecoxib 200 mg, and over 4 in 10 (43%) taking celecoxib 400 mg, experienced good pain relief (at least 50%) compared to about 1 in 10 (range 1% to 11%) with placebo. Comparing the results of the different studies showed that the 200 mg dose of celecoxib was at least as good as aspirin 600 to 650 mg and paracetamol (acetaminophen) 1000 mg for relieving postoperative pain, while a 400 mg dose was at least as good as ibuprofen 400 mg. The number of people who experienced negative (adverse) reactions was similar for celecoxib and placebo, and stopping the medication due to these adverse reactions also occurred at similar rates. One serious adverse event, muscle breakdown (rhabdomyolysis), was probably related to celecoxib.

10.1002/14651858.CD004233.pub4