Unpublished Randomised Controlled Trials Research Articles

Effectiveness of musculoskeletal manipulations in patients with neck pain: a protocol for a systematic review and network meta-analysis

IntroductionNeck pain is a common problem that severely affects physical and mental health. While musculoskeletal manipulations are recommended as the first-line treatment for adults with neck pain, the comparative effectiveness...

Antithrombotic therapy in patients after transcatheter aortic valve implantation: a network meta-analysis.

The optimal antithrombotic therapy to balance the risk of thrombosis and bleeding in patients who undergo transcatheter aortic valve implantation (TAVI) is unknown. This systematic review/network meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the efficacy and safety of different oral anticoagulant (OAC) and antiplatelet regimens in patients post-TAVI. MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov were searched from inception to April 2023. Co-primary outcomes were all-cause death and major bleeding. We conducted Bayesian network meta-analyses to compare all interventions simultaneously. For each outcome, we generated odds ratios (ORs) with 95% credible intervals using a random-effects model with informative priors, and ranked interventions based on mean surface under the cumulative ranking curve. We included 11 RCTs (n=6415), including 1 unpublished RCT. Three trials enrolled patients with an indication for an OAC. Overall risk of bias was low or with some concerns. Median age was 81 years. Median follow-up was 6 months. The combination of OAC plus single antiplatelet therapy (SAPT) increased the risk of all-cause death compared with dual antiplatelet therapy (DAPT) (OR 1.78, 95% credible interval 1.15-2.77). No other comparisons for all-cause death were significantly different. For major bleeding, SAPT reduced the risk compared with DAPT, direct-acting OAC, and OAC+SAPT (OR 0.20-0.40), and DAPT reduced the risk compared with OAC+SAPT. SAPT and DAPT ranked best for all-cause death, while SAPT ranked best for major bleeding. In post-TAVI patients, SAPT may provide the optimal balance of reducing thrombotic events while minimizing the risk of bleeding.

Endometrial scratching in women undergoing IVF/ICSI: an individual participant data meta-analysis.

In IVF/ICSI treatment, the process of embryo implantation is the success rate-limiting step. Endometrial scratching has been suggested to improve this process, but it is unclear if this procedure increases the chance of implantation and live birth (LB) and, if so, for whom, and how the scratch should be performed. This individual participant data meta-analysis (IPD-MA) aims to answer the question of whether endometrial scratching in women undergoing IVF/ICSI influences the chance of a LB, and whether this effect is different in specific subgroups of women. After its incidental discovery in 2000, endometrial scratching has been suggested to improve embryo implantation. Numerous randomized controlled trials (RCTs) have been conducted, showing contradicting results. Conventional meta-analyses were limited by high within- and between-study heterogeneity, small study samples, and a high risk of bias for many of the trials. Also, the data integrity of several trials have been questioned. Thus, despite numerous RCTs and a multitude of conventional meta-analyses, no conclusion on the clinical effectiveness of endometrial scratching could be drawn. An IPD-MA approach is able to overcome many of these problems because it allows for increased uniformity of outcome definitions, can filter out studies with data integrity concerns, enables a more precise estimation of the true treatment effect thanks to adjustment for participant characteristics and not having to make the assumptions necessary in conventional meta-analyses, and because it allows for subgroup analysis. A systematic literature search identified RCTs on endometrial scratching in women undergoing IVF/ICSI. Authors of eligible studies were invited to share original data for this IPD-MA. Studies were assessed for risk of bias (RoB) and integrity checks were performed. The primary outcome was LB, with a one-stage intention to treat (ITT) as the primary analysis. Secondary analyses included as treated (AT), and the subset of women that underwent an embryo transfer (AT+ET). Treatment-covariate interaction for specific participant characteristics was analyzed in AT+ET. Out of 37 published and 15 unpublished RCTs (7690 participants), 15 RCTs (14 published, one unpublished) shared data. After data integrity checks, we included 13 RCTs (12 published, one unpublished) representing 4112 participants. RoB was evaluated as 'low' for 10/13 RCTs. The one-stage ITT analysis for scratch versus no scratch/sham showed an improvement of LB rates (odds ratio (OR) 1.29 [95% CI 1.02-1.64]). AT, AT+ET, and low-RoB-sensitivity analyses yielded similar results (OR 1.22 [95% CI 0.96-1.54]; OR 1.25 [95% CI 0.99-1.57]; OR 1.26 [95% CI 1.03-1.55], respectively). Treatment-covariate interaction analysis showed no evidence of interaction with age, number of previous failed embryo transfers, treatment type, or infertility cause. This is the first meta-analysis based on IPD of more than 4000 participants, and it demonstrates that endometrial scratching may improve LB rates in women undergoing IVF/ICSI. Subgroup analysis for age, number of previous failed embryo transfers, treatment type, and infertility cause could not identify subgroups in which endometrial scratching performed better or worse. The timing of endometrial scratching may play a role in its effectiveness. The use of endometrial scratching in clinical practice should be considered with caution, meaning that patients should be properly counseled on the level of evidence and the uncertainties.

Do mindfulness-based programmes improve the cognitive skills, behaviour and mental health of children and adolescents? An updated meta-analysis of randomised controlled trials

QuestionMindfulness-based programmes (MBPs) are an increasingly popular approach to improving mental health in young people. Our previous meta-analysis suggested that MBPs show promising effectiveness, but highlighted a lack of high-quality,...

Continuing, reducing, switching, or stopping antipsychotics in individuals with schizophrenia-spectrum disorders who are clinically stable: a systematic review and network meta-analysis

Although antipsychotic maintenance treatment is widely recommended to prevent relapse in chronic psychoses, evidence-based guidelines do not provide clear indications on different maintenance treatment strategies, including continuing the antipsychotic at standard doses, reducing the dose, switching to another antipsychotic, or even stopping the antipsychotic. We aimed to compare the effectiveness of these maintenance treatment strategies, hypothesising the superiority of all strategies over stopping, and of continuing at standard doses over both switching and reducing the dose. We did a systematic review and network meta-analysis of randomized controlled trials (RCTs) that investigated antipsychotics for relapse prevention in adults with schizophrenia-spectrum disorders who were clinically stable, and which compared four treatment strategies: continuing the current antipsychotic at standard doses recommended for acute treatment; reducing the current antipsychotic dose; switching to a different antipsychotic; and stopping the antipsychotic and replacing it with placebo. We excluded RCTs with fewer than 25 individuals, a prerandomisation washout period greater than 4 weeks, a follow-up shorter than 6 weeks, and those recruiting treatment-resistant individuals. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, CENTRAL, and online trial registers for published and unpublished RCTs from inception to Sept 1, 2021, combining terms describing all available antipsychotics, and terms describing continuation, maintenance, or long-term treatment for schizophrenia-spectrum disorders. Relative risks (RRs) and standardised mean differences were pooled using random-effects pairwise and network meta-analyses. We assessed risk of bias of each RCT with the Cochrane Risk-of-Bias 2 tool, and confidence of pooled estimates with CINeMA. The primary outcome was relapse prevention. The study protocol was registered in advance in the Open Science Forum registry. Of 3936 records identified, 119 records, reporting on 101 RCTs, were eligible, 98 of which (including 13 988 individuals) provided data that could be meta-analysed for at least one outcome. The mean proportion of female participants per study was 38% (range 0-100; median 39%, IQR 29-50), whereas for male participants it was 62% (range 0-100; median 61%, IQR 50-71), and the overall mean age was 38·8 years (range 23·2-63·9; median 39·3, IQR 35·0-43·9). Of the 98 RCTs meta-analysed, 89·8% were done in high-income and upper-middle-income countries. The ethnic group White or so-called Caucasian was the most represented (mean 56% participants per study), although this information was relatively scarce. All continuation strategies were significantly more effective in preventing relapse than stopping antipsychotic treatment, with a large risk reduction for continuing at standard doses (RR 0·37, 95% CI 0·32-0·43; number-needed-to-treat [NNT] 3·17, 95% CI 2·94-3·51) and antipsychotic switching (RR 0·44, 0·37-0·53; NNT 3·57, 3·17-4·25), and moderate risk reduction for dose reduction (RR 0·68, 0·51-0·90; NNT 6·25, 4·08-20·00). Continuing and switching antipsychotics did not differ significantly (RR 0·84, 0·69-1·02; with lower values favouring continuing), whereas reducing antipsychotic dose was outperformed by both continuing (RR 0·55, 0·42-0·71; NNT 4·44, 3·45-6·90) and switching (RR 0·65, 0·47-0·89; NNT 5·17, 3·77-18·18). Results were supported by moderate confidence of evidence and confirmed by secondary analyses and by several sensitivity and subgroup analyses, including removing studies with abrupt antipsychotic discontinuation or fast tapering (≤4 weeks). No tolerability differences emerged between treatment strategies. According to the Cochrane Risk-of-Bias tool, version 2, 16·8% of included RCTs had an overall high risk of bias for the primary outcome. We found moderate heterogeneity (τ2=0·13; I2=61%) and no overall incoherence for the primary analysis. Results were supported by moderate confidence of evidence and confirmed by secondary analyses. Contrary to our original hypothesis, we found that continuing antipsychotic treatment at standard doses or switching to a different antipsychotic are similarly effective treatment strategies, whereas reducing antipsychotic doses below standard doses is associated with higher risk of relapse than the other two maintenance treatment strategies and should therefore be limited to selected cases. Despite limitations, including moderate heterogeneity and moderate certainty of evidence, these results are of pragmatic relevance for clinicians, and should support the update of evidence-based guidelines. None.

Awake prone positioning for non-intubated patients with COVID-19-related acute hypoxaemic respiratory failure: a systematic review and meta-analysis

BackgroundAwake prone positioning has been broadly utilised for non-intubated patients with COVID-19-related acute hypoxaemic respiratory failure, but the results from published randomised controlled trials (RCTs) in the past year are contradictory. We aimed to systematically synthesise the outcomes associated with awake prone positioning, and evaluate these outcomes in relevant subpopulations.MethodsIn this systematic review and meta-analysis, two independent groups of researchers searched MEDLINE, Embase, PubMed, Web of Science, Scopus, MedRxiv, BioRxiv, and ClinicalTrials.gov for RCTs and observational studies (with a control group) of awake prone positioning in patients with COVID-19-related acute hypoxaemic respiratory failure published in English from Jan 1, 2020, to Nov 8, 2021. We excluded trials that included patients intubated before or at enrolment, paediatric patients (ie, younger than 18 years), or trials that did not include the supine position in the control group. The same two independent groups screened studies, extracted the summary data from published reports, and assessed the risk of bias. We used a random-effects meta-analysis to pool individual studies. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty and quality of the evidence. The primary outcome was the reported cumulative intubation risk across RCTs, and effect estimates were calculated as risk ratios (RR;95% CI). The analysis was primarily conducted on RCTs, and observational studies were used for sensitivity analyses. No serious adverse events associated with awake prone positioning were reported. The study protocol was prospectively registered with PROSPERO, CRD42021271285.FindingsA total of 1243 studies were identified, we assessed 138 full-text articles and received the aggregated results of three unpublished RCTs; therefore, after exclusions, 29 studies were included in the study. Ten were RCTs (1985 patients) and 19 were observational studies (2669 patients). In ten RCTs, awake prone positioning compared with the supine position significantly reduced the need for intubation in the overall population (RR 0·84 [95% CI 0·72–0·97]). A reduced need for intubation was shown among patients who received advanced respiratory support (ie, high-flow nasal cannula or non-invasive ventilation) at enrolment (RR 0·83 [0·71–0·97]) and in intensive care unit (ICU) settings (RR 0·83 [0·71–0·97]) but not in patients receiving conventional oxygen therapy (RR 0·87 [0·45–1·69]) or in non-ICU settings (RR 0·88 [0·44–1·76]). No obvious risk of bias and publication bias was found among the included RCTs for the primary outcome.InterpretationIn patients with COVID-19-related acute hypoxaemic respiratory failure, awake prone positioning reduced the need for intubation, particularly among those requiring advanced respiratory support and those in ICU settings. Awake prone positioning should be used in patients who have acute hypoxaemic respiratory failure due to COVID-19 and require advanced respiratory support or are treated in the ICU.FundingOpenAI, Rice Foundation, National Institute for Health Research, and Oxford Biomedical Research Centre.

Inhaled corticosteroids for the treatment of COVID-19.

Inhaled corticosteroids for the treatment of COVID-19.

Safety evaluation of revefenacin at the approved dose in patients with chronic obstructive pulmonary disease: A meta-analysis

BackgroundRevefenacin is the first once-daily long-acting muscarinic antagonist (LAMA) for nebulization use in maintenance therapy for patients with chronic obstructive pulmonary disease (COPD). ObjectiveTo investigate the safety and tolerability profile of revefenacin at the approved dose (175 μg), compared with placebo and a lower dose (88 μg), for the treatment of COPD. MethodsAvailable randomized controlled trials (RCTs), both published and unpublished, were identified via databases. Risk differences (RDs) and risk ratios (RRs), with their corresponding 95% confidence intervals (CIs) were calculated as effect sizes. ResultsOne unpublished RCT and four articles containing 5 RCTs were included. Combined results showed that there were no significant differences between COPD patients receiving 175 μg revefenacin and those receiving a placebo, concerning the risk of discontinuation due to adverse events (AEs), any all-grade AE, or any serious AE. 175 μg revefenacin also did not significantly increase the risk of antimuscarinic-related AEs, cardiovascular AEs, or 12 commonly reported AEs. Plus, a lower dose of 88 μg was shown to share a comparable safety profile with the 175 μg revefenacin. A non-significant trend towards a decrease in risks of AEs for 175 μg revefenacin was observed. The most frequently reported AE for each group was COPD worsening/exacerbation. ConclusionRevefenacin at the approved dose is generally well-tolerated and safe with minimal AEs, which supports its use as a once-daily nebulized LAMA for the treatment of moderate to severe stable COPD. Additional studies are needed to complete the safety and tolerability profile.

Continuous versus bolus intermittent intragastric tube feeding for preterm and low birth weight infants with gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease is a particularly common condition among preterm and low birth weight infants. These infants are more likely to have excessive regurgitation, as they do not have a fully developed antireflux mechanism. Preterm and low birth weight infants who are unable to suck oral feeds are required to be fed via an intragastric tube for varying lengths of time. Intragastric tube feeding can be delivered by the intermittent bolus method or by the continuous feeding method. Use of continuous or intermittent bolus intragastric feeding may have a positive or negative effect on the incidence or severity of gastro-oesophageal reflux disease. • To determine whether continuous or intermittent bolus intragastric tube feeding reduces the number of episodes and the duration of gastro-oesophageal reflux disease (GORD) in preterm and low birth weight infants • To perform subgroup analyses for gestational age; birth weight; age in days from birth at full enteral feeding via intragastric tube (breast versus bottle); frequency of intermittent bolus feed; and type of medication for treatment of GORD (only if medication was prescribed and was given similarly to both intervention groups) SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 8 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. Published and unpublished RCTs and quasi-RCTs were eligible for inclusion in this review, as were cluster-randomised and cross-over randomised trials that compared the effects of continuous versus intermittent bolus intragastric tube feeding on gastro-oesophageal reflux disease in preterm and low birth weight infants. Two review authors independently assessed study eligibility and quality. We planned to use the GRADE approach to assess the certainty of evidence. We found no trials that met the inclusion criteria for this review. We did not identify any randomised trials that evaluated the effects of continuous versus intermittent bolus intragastric tube feeding on gastro-oesophageal reflux disease in preterm and low birth weight infants. Well-designed and adequately powered trials are needed.

Hybrid repair versus conventional open repair for aortic arch dissection

A dissection of the aorta is a separation or tear of the intima from the media. This tear allows blood to flow not only through the original aortic flow channel (known as the true lumen), but also through a second channel between the intima and media (known as the false lumen). Aortic dissection is a life-threatening condition which can be rapidly fatal. There is debate on the optimal surgical approach for aortic arch dissection. People with ascending aortic dissection have poor rates of survival. Currently open surgical repair is regarded as the standard treatment for aortic arch dissection. We intend to review the role of hybrid and open repair in aortic arch dissection.To assess the effectiveness and safety of a hybrid technique of treatment over conventional open repair in the management of aortic arch dissection.The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 8 February 2021. We also undertook reference checking for additional studies.We included randomised controlled trials (RCTs) and clinical controlled trials (CCTs), which compared the effects of hybrid repair techniques versus open surgical repair of aortic arch dissection. Outcomes of interest were dissection-related mortality and all-cause mortality, neurological deficit, cardiac injury, respiratory compromise, renal ischaemia, false lumen thrombosis (defined by partial or complete thrombosis) and mesenteric ischaemia.Two review authors independently screened all records identified by the literature searches to identify those that met our inclusion criteria. We planned to undertake data collection and analysis in accordance with recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions. We planned to assess the certainty of the evidence using GRADE.We identified one ongoing study and two unpublished studies that met the inclusion criteria for the review. Due to a lack of study data, we could not compare the outcomes of hybrid repair to conventional open repair for aortic arch dissection.This review revealed one ongoing RCT and two unpublished RCTs evaluating hybrid versus conventional open repair for aortic arch surgery. Observational data suggest that hybrid repair for aortic arch dissection could potentially be favourable, but conclusions can not be drawn from these studies, which are highly selective, and are based on the clinical status of the patient, the presence of comorbidities and the skills of the operators. However, a conclusion about its definitive benefit over conventional open surgical repair cannot be made from this review without published RCTs or CCTs. Future RCTs or CCTs need to have adequate sample sizes and follow-up, and assess clinically-relevant outcomes, in order to determine the optimal treatment for people with aortic arch dissection. It must be noted that this may not be feasible, due to the reasons mentioned.

Surgical decompression for space-occupying hemispheric infarction.

Surgical decompression for space-occupying hemispheric infarction.

Effects of antidepressants on QT interval in people with mental disorders.

IntroductionDrug-induced QT prolongation is associated with higher cardiovascular mortality.Material and methodsWe conducted a protocol-based comprehensive review of antidepressant-induced QT prolongation in people with mental disorders.ResultsBased on findings from 47 published randomized controlled trials (RCTs), 3 unpublished RCTs, 14 observational studies, 662 case reports of torsades de pointes, and 168 cases of QT prolongation, we conclude that all antidepressants should be used only with licensed doses, and that all patients receiving antidepressants require monitoring of QT prolongation and clinical symptoms of cardiac arrhythmias. Large observational studies suggest increased mortality associated with all antidepressants (RR = 1.62, 95% CI: 1.60–1.63, number of adults: 1,716,552), high doses of tricyclic antidepressants (OR = 2.11, 85% CI 1.10–4.22), selective serotonin reuptake inhibitors (OR = 2.78, 95% CI: 1.24–6.24), venlafaxine (OR = 3.73, 95% CI: 1.33–10.45, number of adults: 4,040), and nortriptyline (OR = 4.60, 95% CI: 1.20–18.40, number of adults: 5,298).ConclusionsEvidence regarding the risk of QT prolongation in children is sparse.

Comparative efficacy and safety of treatments for secondary Raynaud's phenomenon: a systematic review and network meta-analysis of randomised trials.

Several pharmacological treatments are available for secondary Raynaud's phenomenon, but there is uncertainty regarding the best options. We aimed to assess and compare the benefits and harms of treatments available for secondary Raynaud's phenomenon. We did a systematic review and network meta-analysis of randomised controlled trials (RCTs) of pharmacological treatments. We searched for systematic reviews published in MEDLINE and the Cochrane Database of Systematic Reviews up to Jan 31, 2017, and for RCTs published from inception to Sept 24, 2019 in MEDLINE, Embase, and ClinicalTrials.gov. We included double-blind RCTs (parallel or crossover) that compared two or more pharmacological treatments or placebo in patients with secondary Raynaud's phenomenon. Individual patient data were obtained for one unpublished RCT. Three researchers independently screened the texts and extracted the data. Efficacy outcomes included severity (on a ten-point scale), daily frequency, and mean duration of Raynaud's phenomenon attacks. We also examined tolerability and acceptability. Pairwise meta-analyses and Bayesian random-effects network meta-analyses were used to synthesise data. This study is registered with PROSPERO (CRD42017057518). We included 58 RCTs in the analysis, comprising 3867 patients (3540 [91·5%] with secondary Raynaud's phenomenon) and 15 classes of drugs. Phosphodiesterase 5 (PDE5) inhibitors were more effective than placebo for frequency (mean difference -0·36 [95% credibility interval -0·69 to -0·04]), severity (-0·34 [-0·66 to -0·03]), and duration (-3·42 [-6·62 to -0·29]) of attacks (low to moderate level of evidence). Calcium channel blockers (CCBs) were superior to placebo for frequency (-0·35 [-0·67 to -0·02]) and severity (-0·84 [-1·25 to -0·45]) of attacks (low level of evidence). For severity of attacks, selective serotonin-reuptake inhibitors (-1·54 [-2·68 to -0·41]; very low level of evidence) and oral prostacyclin receptor agonists (-0·48 [-0·80 to -0·16]; low level of evidence) were superior to placebo. No other drug classes were significantly superior to placebo with regard to efficacy outcomes. Compared with placebo, tolerability was lower for PDE5 inhibitors (incidence rate ratio for serious adverse events or early study exit due to adverse events 3·30 [95% CrI 1·49 to 7·55]) and CCBs (3·13 [1·33 to 7·04]). For all outcomes, global heterogeneity and between-study variance ranged from low (I2=0% and τ2=0·0 for attack severity and duration) to moderate (I2=41% and τ2=0·2 for tolerability). The overall risk of bias was judged to be low in 22 (38%), high in ten (17%), and unclear in 26 (45%) RCTs. PDE5 inhibitors and CCBs are the most effective pharmacological options, albeit with moderate efficacy and a low level of evidence. Current evidence does not support the use of any other drug in secondary Raynaud's phenomenon. None.

Efficacy of pressure ulcer prevention interventions in adult intensive care units: a protocol for a systematic review and network meta-analysis

IntroductionPressure ulcers (PUs) are associated with substantial health burden. Patients in intensive care units (ICUs) are at high risk for developing PU. In the absence of large randomised controlled trials...

Interventions for infantile seborrhoeic dermatitis (including cradle cap).

Interventions for infantile seborrhoeic dermatitis (including cradle cap).

Efficacy and acceptability of psychosocial interventions in asylum seekers and refugees: systematic review and meta-analysis.

We used Cochrane procedures for conducting a systematic review and meta-analysis of RCTs. We searched for published and unpublished RCTs assessing the efficacy and acceptability of psychosocial interventions in adults and children asylum seekers and refugees with psychological distress. Post-traumatic stress disorder (PTSD), depressive and anxiety symptoms at post-intervention were the primary outcomes. Secondary outcomes include: PTSD, depressive and anxiety symptoms at follow-up, functioning, quality of life and dropouts due to any reason. We included 26 studies with 1959 participants. Meta-analysis of RCTs revealed that psychosocial interventions have a clinically significant beneficial effect on PTSD (standardised mean difference [SMD] = -0.71; 95% confidence interval [CI] -1.01 to -0.41; I2 = 83%; 95% CI 78-88; 20 studies, 1370 participants; moderate quality evidence), depression (SMD = -1.02; 95% CI -1.52 to -0.51; I2 = 89%; 95% CI 82-93; 12 studies, 844 participants; moderate quality evidence) and anxiety outcomes (SMD = -1.05; 95% CI -1.55 to -0.56; I2 = 87%; 95% CI 79-92; 11 studies, 815 participants; moderate quality evidence). This beneficial effect was maintained at 1 month or longer follow-up, which is extremely important for populations exposed to ongoing post-migration stressors. For the other secondary outcomes, we identified a non-significant trend in favour of psychosocial interventions. Most evidence supported interventions based on cognitive behavioural therapies with a trauma-focused component. Limitations of this review include the limited number of studies collected, with a relatively low total number of participants, and the limited available data for positive outcomes like functioning and quality of life. Considering the epidemiological relevance of psychological distress and mental health conditions in refugees and asylum seekers, and in view of the existing data on the effectiveness of psychosocial interventions, these interventions should be routinely made available as part of the health care of distressed refugees and asylum seekers. Evidence-based guidelines and implementation packages should be developed accordingly.

Protein supplementation of human milk for promoting growth in preterm infants.

Preterm infants require high protein intake to achieve adequate growth and development. Although breast milk feeding has many benefits for this population, the protein content is highly variable, and inadequate to support rapid infant growth. This is a 2018 update of a Cochrane Review first published in 1999. To determine whether protein-supplemented human milk compared with unsupplemented human milk, fed to preterm infants, improves growth, body composition, cardio-metabolic, and neurodevelopmental outcomes, without significant adverse effects. We used the standard search strategy of Cochrane Neonatal to search CENTRAL, MEDLINE via PubMed, Embase, and CINAHL (February 2018). We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials. Published and unpublished RCTs were eligible if they used random or quasi-random methods to allocate hospitalised preterm infants who were being fed human milk, to additional protein supplementation or no supplementation. Two review authors independently abstracted data, assessed risk of bias and the quality of evidence at the outcome level, using GRADE methodology. We performed meta-analyses, using risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data, with their respective 95% confidence intervals (CIs). We used a fixed-effect model and had planned to explore potential causes of heterogeneity via subgroup or sensitivity analyses. We included six RCTs, involving 204 preterm infants. Low-quality evidence showed that protein supplementation of human milk increased in-hospital rates of growth in weight (MD 3.82 g/kg/day, 95% CI 2.94 to 4.7; five RCTs, 101 infants; I² = 73%), length (MD 0.12 cm/wk, 95% CI 0.07 to 0.17; four RCTs, 68 infants; I² = 89%), and head circumference (MD 0.06 cm/wk, 95% CI 0.01 to 0.12; four RCTs, 68 infants; I² = 84%). There was no evidence of a clear difference in rate of growth of skin fold thickness between the supplemented and unsupplemented groups (triceps MD 0.06 mm/wk, 95% CI -0.09 to 0.21; one RCT, 20 infants; or subscapular MD 0.00 mm/wk, 95% CI -0.17 to 0.17; one RCT, 20 infants). Protein supplementation led to longer hospital stays (MD 18.5 days, 95% CI 4.39 to 32.61; one RCT, 20 infants; very low-quality evidence), and higher blood urea nitrogen concentrations compared to the unsupplemented group (MD 0.95 mmol/L, 95% CI 0.81 to 1.09; four RCTs, 81 infants; I² = 56%). Very low-quality evidence did not show that protein supplementation clearly increased the risk of feeding intolerance (RR 2.70, 95% CI 0.13 to 58.24; one RCT, 17 infants), or necrotizing enterocolitis (RR 1.11, 95% CI 0.07 to 17.12; one RCT, 76 infants), or clearly altered serum albumin concentrations (MD 2.5 g/L, 95% CI -5.66 to 10.66; one RCT, 11 infants), compared with the unsupplemented groups. No data were available about the effects of protein supplementation on long-term growth, body mass index, body composition, neurodevelopmental, or cardio-metabolic outcomes. Low-quality evidence showed that protein supplementation of human milk, fed to preterm infants, increased short-term growth. However, the small sample sizes, low precision, and very low-quality evidence regarding duration of hospital stay, feeding intolerance, and necrotising enterocolitis precluded any conclusions about these outcomes. There were no data on outcomes after hospital discharge. Our findings may not be generalisable to low-resource settings, as none of the included studies were conducted in these settings.Since protein supplementation of human milk is now usually done as a component of multi-nutrient fortifiers, future studies should compare different amounts of protein in multi-component fortifiers, and be designed to determine the effects on duration of hospital stay and safety, as well as on long-term growth, body composition, cardio-metabolic, and neurodevelopmental outcomes.

Efficacy of antidepressants over placebo is similar in two-armed versus three-armed or more-armed randomized placebo-controlled trials.

Previous studies have reported that effect sizes of antidepressants were larger in two-armed than in three-armed or more-armed (multiarmed) randomized trials, where the probability of being allocated to placebo is lower. However, these studies have not taken into account the publication bias, differences among antidepressants, or covariance in multiarmed studies, or examined sponsorship bias. We searched published and unpublished randomized-controlled trials that compared placebo with 21 antidepressants for the acute treatment of major depression in adults. We calculated the ratio of odds ratios (ROR) of drug response over placebo in two-armed versus multiarmed trials for each antidepressant, and then synthesized RORs across all the included antidepressants using the multivariate meta-analysis. A random-effects model was used throughout. Two hundred and fifty-eight trials (66 two-armed and 192 multiarmed trials; 80 454 patients; 43.0% with unpublished data) were included in the present analyses. The pooled ROR for response of two-armed trials over multiarmed trials was 1.09 (95% confidence interval: 0.96-1.24). The ROR did not materially change between types of antidepressants, publication year, or sponsorship. The differences between two-armed versus multiarmed studies were much smaller than were suggested in previous studies and were not significant.

WITHDRAWN: Celecoxib for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic auto-immune disorder, involving persistent joint inflammation. NSAIDs are used to control the symptoms of RA, but are associated with significant gastro-intestinal toxicity, including a risk of potentially life threatening gastroduodenal perforations, ulcers and bleeds. The NSAIDs known as the selective Cox II inhibitors, of which celecoxib is a member, were developed in order to reduce the GI toxicity, but are more expensive. To establish the efficacy and safety of celecoxib in the management of RA by systematic review of available evidence. We searched the following databases up to August 2002: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment Database. The bibliographies of retrieved papers and content experts were consulted for additional references. All eligible randomised controlled trials (RCTs) were included. No unpublished RCTs were included in this edition of the review. Data were abstracted independently by two reviewers. Data was analysed using a fixed effects model. A validated checklist was used to score the quality of the RCTs. The planned analysis was to pool, where appropriate continuous outcomes using mean differences and dichotomous outcomes using relative risk ratios. This was not however possible due to the lack of data. Five RCTs were included (4465 participants); three of the studies also enrolled individuals with OA. The comparators were placebo, naproxen, diclofenac and ibuprofen. The evidence reviewed suggests that celecoxib controls the symptoms of RA to a similar degree to that of the active comparators examined (naproxen, diclofenac and ibuprofen). When compared to placebo, the percentage of patients showing improvement according to ACR 20 criteria at week 4 were 42/82 (51%) in the twice daily celecoxib 200mg group and 43/82 (52%) in the twice daily celecoxib 400mg group; these were significantly different from the placebo group in which 25/85 (29%) improved. The six month data reviewed support a reduced rate of UGI complications with celecoxib but there is also evidence to suggest that these benefits may not be evident in the long-term and that celecoxib offers no additional benefit in patients who are also receiving cardio-prophylactic low dose aspirin. For an individual with RA the potential benefits of celecoxib need to be balanced against the uncertainty that the short-term reduced incidence of upper GI complications are maintained in the long-term and its increased cost in comparison to traditional NSAIDs.

Antifibrinolytic therapy to reduce haemoptysis from any cause.

Haemoptysis is a common pathology around the world, occurring with more frequency in low-income countries. It has different etiologies, many of which have infectious characteristics. Antifibrinolytic agents are commonly used to manage bleeding from different sources, but their usefulness in pulmonology is unclear. To evaluate the effectiveness and safety of antifibrinolytic agents in reducing the volume and duration of haemoptysis in adult and paediatric patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE) in The Cochrane Library, EMBASE and LILACS for publications that describe randomized controlled trials (RCTs) of antifibrinolytic therapy in patients presenting with haemoptysis. We also performed an independent search in MEDLINE for relevant trials not yet included in CENTRAL or DARE. Searches are up to date to the 19th September 2016. We conducted electronic and manual searches of relevant national and international journals. We reviewed the reference lists of included studies to locate relevant randomized controlled trials (RCTs). An additional search was carried out to find unpublished RCTs. We included RCTs designed to evaluate the effectiveness and safety of antifibrinolytic agents in reducing haemoptysis in adult and paediatric patients of both genders presenting with haemoptysis of any etiology and severity. The intervention of interest was the administration of antifibrinolytic agents compared with placebo or no treatment. All reviewers independently assessed methodological quality and extracted data tables pre-designed for this review. The electronic literature search identified 1 original study that met the eligibility criteria. One unpublished study was also identified through manual searches. Therefore two randomized controlled trials met the inclusion criteria: Tscheikuna 2002 (via electronic searches) and Ruiz 1994 (via manual searches). Tscheikuna 2002, a double-blind RCT performed in Thailand, evaluated the effectiveness of tranexamic acid (TXA, an antifibrinolytic agent) administered orally in 46 hospital in- and outpatients with haemoptysis of various etiologies. Ruiz 1994, a double-blind RCT performed in Peru, evaluated the effectiveness of intravenous TXA in 24 hospitalised patients presenting with haemoptysis secondary to tuberculosis.Pooled together, results demonstrated a significant reduction in bleeding time between patients receiving TXA and patients receiving placebo with a weighted mean difference (WMD) of -19.47 (95% CI -26.90 to -12.03 hours), but with high heterogeneity (I² = 52%). TXA did not affect remission of haemoptysis evaluated at seven days after the start of treatment. Adverse effects caused by the drug's mechanism of action were not reported. There was no significant difference in the incidence of mild side effects between active and placebo groups (OR 3.13, 95% CI 0.80 to 12.24). There is insufficient evidence to judge whether antifibrinolytics should be used to treat haemoptysis from any cause, though limited evidence suggests they may reduce the duration of bleeding.