Test For Subgroup Differences Research Articles

Achieved low-density lipoprotein cholesterol level and stroke risk: A meta-analysis of 23 randomised trials.

Lowering the low-density lipoprotein cholesterol level reduces the risk of stroke, but it has not been clear whether the stroke risk would continuously decrease by lowering low-density lipoprotein cholesterol to a very low level. The purpose of this study was to evaluate the association between achieved low-density lipoprotein cholesterol levels and stroke risk. A systematic search of MEDLINE, EMBASE and Cochrane Library databases was conducted to identify randomised controlled trials that tested cholesterol-lowering pharmacological therapies and reported both achieved low-density lipoprotein cholesterol levels and stroke outcomes. A meta-regression analysis was conducted to assess the linear association between the achieved low-density lipoprotein cholesterol levels and stroke risk. In addition, we evaluated pooled estimates of low-density lipoprotein cholesterol-lowering effect stratified by achieved low-density lipoprotein cholesterol levels of active arms. A total of 222,149 participants in 23 trials (52 arms of 26 studies) were included. The meta-regression analysis showed that each 1 mmol/L decrease in the achieved low-density lipoprotein cholesterol level (down to 0.78 mmol/L) was associated with a significant reduction of 23.5% (slope 0.235, 95% confidence interval 0.007-0.464, P = 0.044) in stroke risk. Irrespective of achieved low-density lipoprotein cholesterol levels in the active arms, the effects of lowering the low-density lipoprotein cholesterol level on stroke risk were significant and consistent (test for subgroup difference, P = 0.23, I2 = 31%). However, there was no significant increase in haemorrhagic stroke risk with lower achieved low-density lipoprotein cholesterol levels. In this meta-analysis of randomised controlled trials, the stroke risk monotonically reduced with lowering of low-density lipoprotein cholesterol to very low levels.

Exercise for preventing falls in older people living in the community.

Exercise for preventing falls in older people living in the community.

The use of drug-eluting stents in infrapopliteal arteries: an updated systematic review and meta-analysis of randomized trials.

Endovascular treatment below-the-knee is safe and effective but limited by poor patency. Coronary drug-eluting stents (DES) may play a role in providing mechanical scaffolding and deliver anti-proliferative drug to the site of vascular barotrauma to reduce the incidence of restenosis. Our aim was to evaluate and compare the use of contemporary DES with standard endovascular-therapies for atherosclerotic disease of infrapopliteal arteries. We performed a meta-analysis of randomized controlled trials comparing DES with conventional treatment for symptomatic peripheral artery disease (search date 30 August 2017). The primary endpoint was primary patency. Secondary endpoints were freedom from target lesion revascularization (TLR), major amputation, sustained Rutherford class improvement and mortality. We identified 7 trials enrolling 801 randomly assigned patients (392 DES, 409 control). At the median follow-up of 12-months DES improved rates of primary patency (OR 3.49, 95%CI 2.38-5.12, I2=0%, P<0.00001), freedom from TLR (OR 2.19, 95%CI 1.30-3.69, I2=38%, P=0.003), major amputation (OR 0.56, 95%CI 0.31-0.99, I2=0%, P=0.049), and Rutherford class improvement (OR 1.62, 95%CI 1.01-2.59, I2=65%, P=0.046), but not mortality (OR 1.05, 95%CI 0.68-1.62; I2 =0%, P=0.91) compared to control. Subgroup analysis of primary patency favoured DES coated in sirolimus analogues compared to paclitaxel (Test for subgroup differences, Chi2=6.51, df=1, P=0.01, I2=84.6%). At midterm follow-up DES significantly improved rates of primary patency, re-intervention, Rutherford class improvement and major amputation for the treatment of atherosclerotic disease of infrapopliteal arteries compared to control therapy, with no effect on patient survival. Stents coated in sirolimus analogues were more effective than paclitaxel.

Informal and formal care preferences and expected willingness of providing elderly care in Germany: protocol for a mixed-methods study

IntroductionIn Germany, the number of elderly people in need of care is expected to increase from 2.4 million in 2015 to 3.2 million in 2030. The subsequent rise in demand...

Quality ratings of reviews in overviews: a comparison of reviews with and without dual (co-)authorship

BackgroundPrevious research shows that many authors of Cochrane overviews were also involved in some of the included systematic reviews (SRs). This type of dual (co-)authorship (DCA) may be a conflict of interest and a potential source of bias. Our objectives were to (1) additionally investigate DCA in non-Cochrane overviews; (2) investigate whether there is an association between DCA and quality assessments of SRs in Cochrane and non-Cochrane overviews.MethodsWe selected a sample of Cochrane (n = 20) and non-Cochrane (n = 78) overviews for analysis. We extracted data on the number of reviews affected by DCA and whether quality assessment of included reviews was conducted independently. Differences in mean quality scores between SRs with and without DCA were calculated in each overview. These differences were standardized (using the standardized mean difference (SMD)) and meta-analyzed using a random effects model.ResultsForty out of 78 non-Cochrane overviews (51%) and 18 out of 20 Cochrane overviews (90%) had included at least one SR with DCA. For Cochrane overviews, a median of 5 [interquartile range (IQR) 2.5 to 7] SRs were affected by DCA (median of included reviews 10). For non-Cochrane overviews a median of 1 [IQR 0 to 2] of the included SRs were affected (median of included reviews 14). The meta-analysis showed a SMD of 0.58 (95% confidence interval (CI) 0.27 to 0.90) indicating higher quality scores in reviews with overlapping authors. The test for subgroup differences shows no evidence of a difference between Cochrane (SMD 0.44; 95% CI 0.07 to 0.81) and non-Cochrane overviews (SMD 0.62; 95% CI 0.06 to 1.17).ConclusionsMany authors of overviews also often have an authorship on one or more of the underlying reviews. Our analysis shows that, on average, authors of overviews give higher quality ratings to SRs in which they were involved themselves than to other SRs. Conflict of interest is one explanation, but there are several others such as reviewer expertise. Independent and blinded reassessments of the reviews would provide more robust evidence on potential bias arising from DCA.

Alpha-blockers as medical expulsive therapy for ureteral stones.

Ureteral colic is a common reason for patients to seek medical care. Alpha-blockers are commonly used to improve stone passage through so-called medical expulsive therapy (MET), but their effectiveness remains controversial. This is an update of a 2014 Cochrane review; since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant. To assess effects of alpha-blockers compared with standard therapy for ureteral stones 1 cm or smaller confirmed by imaging in adult patients presenting with symptoms of ureteral stone disease. On 18 November 2017, we searched CENTRAL, MEDLINE Ovid, and Embase. We also searched ClinicalTrials.gov and the WHO Portal/ICTRP to identify all published/unpublished and ongoing trials. We checked all references of included and review articles and conference proceedings for articles relevant to this review. We sent letters to investigators to request information about unpublished or incomplete studies. We included RCTs of ureteral stone passage in adult patients that compared alpha-blockers versus standard therapy. Two review authors screened studies for inclusion and extracted data using standard methodological procedures. We performed meta-analysis using a random-effects model. Primary outcomes were stone clearance and major adverse events; secondary outcomes were stone expulsion time, number of pain episodes, use of diclofenac, hospitalisation, and surgical intervention. We assessed the quality of evidence on a per-outcome basis using the GRADE approach. 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).

The Neonatal Behavioral Assessment Scale (NBAS) and Newborn Behavioral Observations (NBO) system for supporting caregivers and improving outcomes in caregivers and their infants.

The first three years of a child's life are a key period of physical, physiological, cognitive and social development, and the caregiver-infant relationship in early infancy plays an important role in influencing these aspects of development. Specifically, caregiver attunement facilitates the move from coregulation to self-regulation; a parent's ability to understand their infant's behaviour as communication is a key part of this process. Early, brief interventions such as the Neonatal Behavioral Assessment Scale (NBAS) or Neonatal Behavioral Observation (NBO) system are potential methods of improving outcomes for both infant and caregiver. To assess the effects of the NBAS and NBO system for improving caregiver-infant interaction and related outcomes in caregivers and newborn babies. Secondary objectives were to determine whether the NBAS and NBO are more effective for particular groups of infants or parents, and to identify the factors associated with increased effectiveness (e.g. timing, duration, etc.). In September 2017 we searched CENTRAL, MEDLINE, Embase, PsycINFO, 12 other databases and four trials registers. We also handsearched reference lists of included studies and relevant systematic reviews, and we contacted the Brazelton Institute and searched its websites to identify any ongoing and unpublished studies. We included randomised controlled trials (RCTs) and quasi-RCTs that had used at least one standardised measure to assess the effects of the NBAS or NBO versus inactive control for improving outcomes for caregivers and their infants. Two reviewer authors independently assessed the records retrieved from the search. One reviewer extracted data, and a second checked them for accuracy. We presented the results for each outcome in each study as standardised mean differences (SMDs) or as risk ratios (RR) with 95% confidence intervals (CIs). When appropriate, we combined the results in a meta-analysis using standard methodological procedures expected by Cochrane. We used the GRADE approach to assess the overall quality of the body of evidence for each outcome. We identified and included 16 RCTs in this review: 13 assessing the NBAS and 3 the NBO for improving outcomes in 851 randomised participants, including parents and their premature or newborn (aged 4 to 12 weeks) infants. All studies took place in the USA, and we judged all of them to be at high risk of bias.Seven studies involving 304 participants contributed data to one meta-analysis of the impact of the NBAS or NBO for caregiver-infant interaction, and the results suggest a significant, medium-sized difference between intervention and control groups (SMD -0.53, 95% CI -0.90 to -0.17; very low-quality evidence), with moderate heterogeneity (I2 = 51%). Subgroup analysis comparing the two types of programmes (i.e. NBAS and NBO) found a medium but non-significant effect for the NBAS (-0.49, 95% CI -0.99 to 0.00, 5 studies), with high levels of heterogeneity (I2 = 61%), compared with a significant, large effect size for the NBO (-0.69, 95% CI -1.18 to -0.20, 2 studies), with no heterogeneity (I2 = 0.0%). A test for subgroup differences between the two models, however, was not significant. One study found a significant impact on the secondary outcome of caregiver knowledge (SMD -1.30, 95% CI -2.16 to -0.44; very low-quality evidence). There was no evidence of an impact on maternal depression. We did not identify any adverse effects. There is currently only very low-quality evidence for the effectiveness of the NBAS and NBO in terms of improving parent-infant interaction for mostly low-risk, first-time caregivers and their infants. Further research is underway regarding the effectiveness of the NBO and is necessary to corroborate these results.

Antifibrinolytic drugs for treating primary postpartum haemorrhage.

Antifibrinolytic drugs for treating primary postpartum haemorrhage.

Abiraterone or docetaxel in men with metastatic castration-sensitive prostate cancer: A pooled analysis of castration resistance-free survival and toxicity.

354 Background: Recent meta-analyses suggested an improvement in overall survival (OS) with the addition of Abiraterone (A) vs Docetaxel (D) to androgen deprivation therapy (ADT) in the treatment of men with metastatic castration-sensitive prostate cancer. However, none have reported castration resistance-free survival (CFS) and toxicity data; two clinically relevant outcomes for physicians and patients. Methods: We conducted a systematic review and meta-analysis to assess CFS and toxicity of adding A or D to ADT in men with castration-sensitive prostate cancer. The electronic databases Ovid MEDLINE, Cochrane Central Register of Controlled Trials and EMBASE, were searched for randomized controlled trials. Pooled hazard ratios (HR) for CFS, and pooled risk ratios (RR) for grade 3 or higher toxicity were analyzed using the Mantel-Haenszel method and generic inverse variance. To account for between-studies heterogeneity, random-effect models were used to compute pooled estimates. Subgroup analyses compared patients on A and D in terms of CFS. Results: Five studies were included. The addition of A or D to ADT decreased the risk of development of castration-resistance by 53% (5 studies, 4,462 participants, HR = 0.47, 95% CI 0.33-0.67). In a subgroup analysis, the addition of A seemed to be better than D for the outcome CFS (5 studies, HR = 0.31, 95% CI 0.27-0.34 versus HR = 0.62, 95% CI 0.56-0.69, test for subgroup difference, p&lt; 0.001). Different profiles of toxicity were seen with A and D. While A increased the risk of hypokalemia (3,107 participants, HR = 6.63, 95% CI 3.5-12.5) and cardiac toxicity (3,107 participants, HR = 2.4, 95% CI 1.7-3.3), D increased the risk of neutropenia (2,151 participants, HR = 13, 95% CI 8.9-18.8) and neuropathy (2,151 participants, HR = 2.25, 95% CI 1.18-4.3). Conclusions: The addition of A and D to ADT increases CFS in men with castration-sensitive prostate cancer, with a longer CFS noted for A compared to D. Considering CFS and OS, A may be preferred to D as initial therapy. Toxicity profiles differed between A and D. Quality of life and cost differences between A and D are other important factors and were not considered in this analysis.

Probiotics for preventing acute otitis media in children

Background Acute otitis media (AOM), or acute middle ear infection, is one of the most frequently occurring childhood diseases, and the most common reason given for prescribing antibiotics in this age group. Guidelines often recommend antibiotics as first-line treatment for severe AOM. However, antibiotics also lead to antibiotic resistance, so preventing episodes of AOM is an urgent priority. Objectives To assess the effects of probiotics to prevent the occurrence and reduce the severity of acute otitis media in children. Search methods We searched CENTRAL, PubMed, Embase, and three other databases (October 2018), two trial registers (October 2018), and conducted a backwards and forwards citation analysis (August 2018). We did not apply any language, publication date, or publication status restrictions. Selection criteria Randomised controlled trials (RCTs) of children (aged up to 18 years), comparing probiotics with placebo, usual care, or no probiotic. Data collection and analysis Two review authors independently assessed the eligibility of trials for inclusion and risk of bias of the included trials, and extracted data using pre-piloted data extraction forms. We analysed dichotomous data as either risk ratio (RR) or odds ratios (OR) and continuous data as mean differences (MD). Main results We included 17 RCTs involving 3488 children, of which 16 RCTs were included in the meta-analyses. Of the 16 RCTs that reported the mean age of children, mean age overall was 2.4 years; in 4 RCTs the mean age of children participating in the trial was less than 1 year old; in 2 RCTs the mean age was between 1 and 2 years old; and in 10 RCTs the mean age was older than 2 years. Probiotic strains evaluated by the trials varied, with 11 of the included RCTs evaluating Lactobacillus-containing probiotics, and six RCTs evaluating Streptococcus-containing probiotics.The proportion of children (i.e. the number of children in each group) experiencing one or more episodes of AOM during the treatment was lower for those taking probiotics (RR 0.77, 95% confidence interval (CI) 0.63 to 0.93; 16 trials; 2961 participants; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-certainty evidence).Post hoc subgroup analysis found that among children not prone to otitis media, a lower proportion of children receiving probiotics experienced AOM (RR 0.64, 95% CI 0.49 to 0.84; 11 trials; 2227 participants; NNTB = 9; moderate-certainty evidence). However, among children who were otitis prone, there was no difference between probiotic and comparator groups (RR 0.97, 95% CI 0.85 to 1.11; 5 trials; 734 participants; high-certainty evidence). The test for subgroup differences was significant (P = 0.007).None of the included trials reported on the severity of AOM.The proportion of children experiencing adverse events did not differ between the probiotic and comparator groups (OR 1.54, 95% CI 0.60 to 3.94; 4 trials; 395 participants; low-certainty evidence).Probiotics decreased the proportion of children taking antibiotics for any infection (RR 0.66, 95% CI 0.51 to 0.86; 8 trials; 1768 participants; NNTB = 8; moderate-certainty evidence). Test for subgroup differences (use of antibiotic specifically for AOM, use of antibiotic for infections other than AOM) was not significant.There was no difference in the mean number of school days lost (MD -0.95, 95% CI -2.47 to 0.57; 5 trials; 1280 participants; moderate-certainty evidence). There was no difference between groups in the level of compliance in taking the intervention (RR 1.02, 95% CI 0.99 to 1.05; 5 trials; 990 participants).Probiotics decreased the proportion of children having other infections (RR 0.75, 95% CI 0.65 to 0.87; 11 trials; 3610 participants; NNTB = 12; moderate-certainty evidence). Test for subgroup differences (acute respiratory infections, gastrointestinal infections) was not significant.Probiotic strains trialled and their dose, frequency, and duration of administration varied considerably across studies, which likely contributed to the substantial levels of heterogeneity. Sensitivity testing of funnel plots did not reveal publication bias. Authors' conclusions Probiotics may prevent AOM in children not prone to AOM, but the inconsistency of the subgroup analyses suggests caution in interpreting these results. Probiotics decreased the proportion of children taking antibiotics for any infection. The proportion of children experiencing adverse events did not differ between the probiotic and comparator groups. The optimal strain, duration, frequency, and timing of probiotic administration still needs to be established.

Anti-IL5 therapies for asthma.

This review is the first update of a previously published review in The Cochrane Library (Issue 7, 2015). Interleukin-5 (IL-5) is the main cytokine involved in the activation of eosinophils, which cause airway inflammation and are a classic feature of asthma. Monoclonal antibodies targeting IL-5 or its receptor (IL-5R) have been developed, with recent studies suggesting that they reduce asthma exacerbations, improve health-related quality of life (HRQoL) and lung function. These are being incorporated into asthma guidelines. To compare the effects of therapies targeting IL-5 signalling (anti-IL-5 or anti-IL-5Rα) with placebo on exacerbations, health-related qualify of life (HRQoL) measures, and lung function in adults and children with chronic asthma, and specifically in those with eosinophilic asthma refractory to existing treatments. We searched the Cochrane Airways Trials Register, clinical trials registries, manufacturers' websites, and reference lists of included studies. The most recent search was March 2017. We included randomised controlled trials comparing mepolizumab, reslizumab and benralizumab versus placebo in adults and children with asthma. Two authors independently extracted data and analysed outcomes using a random-effects model. We used standard methods expected by Cochrane. Thirteen studies on 6000 participants met the inclusion criteria. Four used mepolizumab, four used reslizumab, and five used benralizumab. One study in benralizumab was terminated early due to sponsor decision and contributed no data. The studies were predominantly on people with severe eosinophilic asthma, which was similarly but variably defined. Eight included children over 12 years but these results were not reported separately. We deemed the risk of bias to be low, with all studies contributing data being of robust methodology. We considered the quality of the evidence for all comparisons to be high overall using the GRADE scheme, with the exception of intravenous mepolizumab because this is not currently a licensed delivery route.All of the anti-IL-5 treatments assessed reduced rates of 'clinically significant' asthma exacerbation (defined by treatment with systemic corticosteroids for three days or more) by approximately half in participants with severe eosinophilic asthma on standard of care (at least medium-dose inhaled corticosteroids (ICS)) with poorly controlled disease (either two or more exacerbations in the preceding year or Asthma Control Questionnaire (ACQ) 1.5 or more). Non-eosinophilic participants treated with benralizumab also showed a significant reduction in exacerbation rates, but no data were available for non-eosinophilic participants, and mepolizumab or reslizumab.We saw modest improvements in validated HRQoL scores with all anti-IL-5 agents in severe eosinophilic asthma. However these did not exceed the minimum clinically important difference for ACQ and Asthma Quality of Life Questionnaire (AQLQ), with St. George's Respiratory Questionnaire (SGRQ) only assessed in two studies. The improvement in HRQoL scores in non-eosinophilic participants treated with benralizumab, the only intervention for which data were available in this subset, was not statistically significant, but the test for subgroup difference was negative.All anti-IL-5 treatments produced a small but statistically significant improvement in mean pre-bronchodilator forced expiratory flow in one second (FEV1) of between 0.08 L and 0.11 L.There were no excess serious adverse events with any anti-IL-5 treatment, and indeed a reduction in favour of mepolizumab that could be due to a beneficial effect on asthma-related serious adverse events. There was no difference compared to placebo in adverse events leading to discontinuation with mepolizumab or reslizumab, but significantly more discontinued benralizumab than placebo, although the absolute numbers were small (36/1599 benralizumab versus 9/998 placebo).Mepolizumab, reslizumab and benralizumab all markedly reduced blood eosinophils, but benralizumab resulted in almost complete depletion, whereas a small number remained with mepolizumab and reslizumab. The implications for efficacy and/or adverse events are unclear. Overall our study supports the use of anti-IL-5 treatments as an adjunct to standard of care in people with severe eosinophilic asthma and poor control. These treatments roughly halve the rate of asthma exacerbations in this population. There is limited evidence for improved HRQoL scores and lung function, which may not meet clinically detectable levels. There were no safety concerns regarding mepolizumab or reslizumab, and no excess serious adverse events with benralizumab, although there remains a question over adverse events significant enough to prompt discontinuation.Further research is needed on biomarkers for assessing treatment response, optimal duration and long-term effects of treatment, risk of relapse on withdrawal, non-eosinophilic patients, children (particularly under 12 years), and comparing anti-IL-5 treatments to each other and, in people eligible for both, to anti-immunoglobulin E. For benralizumab, future studies should closely monitor rates of adverse events prompting discontinuation.

Self-management interventions including action plans for exacerbations versus usual care in patients with chronic obstructive pulmonary disease.

Self-management interventions including action plans for exacerbations versus usual care in patients with chronic obstructive pulmonary disease.

The Association Between Borna Disease Virus and Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis

Context: Several studies have controversial results regarding the association between Borna disease virus (BDV) and chronic fatigue syndrome (CFS). The present systematic review and meta-analysis investigated the association between CFS and BDV. Evidence Acquisition: The present study was conducted based on the PRISMA guidelines for systematic review and meta-analysis studies. To avoid bias, all procedures of the study were performed by two researchers independently. A comprehensive search was performed using online databases, including PubMed, Scopus, Embase, PsycINFO, science Direct, Cochrane Library, web of science, and Google scholar using the MeSH keywords until December 12th, 2016. Heterogeneity among studies was evaluated using Cochran's Q test I2 Index. Finally, the random effect model was used for combined Odds Ratio (OR) using Review Manger software version 5.3.5. Results: Among 9 eligible studies comprising 610 cases and 2176 controls, the total OR for association between BDV and CFS was estimated to be 10.41 (95% confidence interval [CI]: 4.24 - 25.55, P < 0.0001). For subgroup analysis by the diagnostic methods (ELISA, RT-PCR, and Western blot), OR was 2.47 (95% CI: 0.77 - 7.96, P=0.13), 12.20 (95% CI: 1.66 - 89.57, P=0.01), and 28.36 (95% CI: 3.76-213.85, P=0.001), respectively (test for subgroup differences: P=0.08; I2=59.5). Subgroup analysis for BDV and CFS association by antigens and antibodies had an OR of 12.20 (1.66, 89.57) and 8.20 (3.32, 20.22), respectively (test for subgroup differences: P=0.72; I2=0). Conclusions: This study supports the association between BDV and CFS and shows the role of viral agents in etiology of CFS. Therefore, viral agents may play a role in the etiology of neuropsychiatric disorders.

Piezoelectric versus conventional techniques for orthognathic surgery: Systematic review and meta-analysis

PurposeThe purpose of this study was to perform a systematic review and meta-analysis of complications after orthognathic surgery comparing piezo-surgery with conventional osteotomy. MethodsWe conducted this study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed a systematic search of PubMed, Scopus, Science Direct, Lilacs, Cochrane Central Register of Controlled Trials, Google Scholar, and OpenThesis to identify randomized and nonrandomized controlled trials (RCTs and nRCTs, respectively) comparing patient outcomes (operative time, intraoperative blood loss, postoperative swelling, pain, neurosensitivity) after orthognathic surgery by piezoelectric or conventional osteotomy. We pooled individual results of continuous and dichotomous outcome data using the mean difference (MD) and risk difference (RD) with the 95% confidence interval, respectively. ResultsThree RCTs and five nRCTs were selected. No difference in operative time was observed between piezo-surgery and conventional osteotomies. We found a decrease of intraoperative blood loss with piezo-surgery (MD −128 mL; P < 0.001) and a pooled difference in severe blood loss of 35% (P = 0.008) favouring piezo-surgery. Based on pooled individual results of studies evaluating neurosensitivity by clinical neurosensory testing, our meta-analysis showed a pooled difference in severe nerve disturbance of 25% (P < 0.0001) favouring piezo-surgery. Test for subgroup differences (I2 = 26.6%) indicated that follow-up time may have an effect on neurosensory disturbance. We found differences between piezo-surgery and conventional osteotomy at 3 months (RD 28%; P < 0.001) and 6 months (RD 15%; P = 0.001) after surgery. Meta-analyses for pain and swelling were not performed because of a lack of sufficient studies. ConclusionCurrently available evidence suggests that piezo-surgery has favorable effects on complications associated with orthognathic surgery, including reductions in intraoperative blood loss and severe nerve disturbance.

Effect of cocoa on blood pressure.

Effect of cocoa on blood pressure.

European real world trans-catheter aortic valve implantation: systematic review and meta-analysis of European national registries.

ObjectiveTranscatheter aortic valve implantation (TAVI) has been adopted rapidly in Europe. TAVI national registries can augment understanding of technologies and represent real-world experience, providing further clinical insights. We undertook a meta-analysis of published European national TAVI registries to assess current results following TAVI in Europe.MethodsElectronic databases were searched. The review focused on the comparison of the following TAVI strategies: transfemoral (TF) and transapical (TA) SAPIEN and CoreValve implantation. Individual event rates for outcomes of interest were pooled using a mixed effect model.ResultsSeven European national TAVI registries (UK, Swiss, Belgium, Italy, Spain, France, Germany) were identified, including a total of 9786 patients who received TF-SAPIEN (n = 2885), TA-SAPIEN (n = 2252) and CoreValve (n = 4649) implantation. Pooled incidence of 30-day mortality was 0.08% [95% Confidence Interval (CI): 0.05–0.11], 0.12% [95% CI: 0.07–0.19] and 0.06% [95% CI: 0.03–0.11] for TF-SAPIEN, TA-SAPIEN and CoreValve respectively (test for subgroup difference P = 0.18); there was high heterogeneity across European countries. Pooled incidence of stroke was comparable among the TAVI strategies (test for subgroup difference P = 0.79); the incidence of post-procedural moderate paravalvular leak ≥ 2 (P = 0.9) was similar across groups. CoreValve implantation was associated with an increased risk of pacemaker implantation (0.22 [95% CI: 0.19–0.26]; test for subgroup difference P < 0.0001). The lowest 30-day mortality was associated with TAVI performed in Spain (b coefficient −4.3; P = 0.03), in Italy (b coefficient −2.1; P < 0.0001), in UK (b coefficient −1.95; P = 0.01) and in France (b coefficient −2.8; P = 0.03). The German registry has the highest mortality for every TAVI strategy amongst all other European registries and especially for the TA-SAPIEN group.ConclusionsTransarterial TAVI approaches were associated with a low early mortality regardless of the type of device used. There was marked heterogeneity among European countries for early mortality.

Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction

Despite modern antimicrobials and supportive therapy bacterial and fungal infections are still major complications in people with prolonged disease-related or treatment-related neutropenia. Transfusions of granulocytes have a long history of usage in clinical practice to support and treat severe infection in high-risk groups of patients with neutropenia or neutrophil dysfunction. However, there is considerable current variability in therapeutic granulocyte transfusion practice, and uncertainty about the beneficial effect of transfusions given as an adjunct to antibiotics on mortality. This is an update of a Cochrane review first published in 2005.To determine the effectiveness and safety of granulocyte transfusions compared to no granulocyte transfusions as adjuncts to antimicrobials for treating infections in people with neutropenia or disorders of neutrophil function aimed at reducing mortality and other adverse outcomes related to infection.We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 2). MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1980) and ongoing trial databases to 11 February 2016.RCTs comparing people with neutropenia or disorders of neutrophil dysfunction receiving granulocyte transfusions to treat infection with a control group receiving no granulocyte transfusions. Neonates are the subject of another Cochrane review and were excluded from this review. There was no restriction by outcomes examined, language or publication status.We used standard methodological procedures expected by the Cochrane Collaboration.We identified 10 trials that met the inclusion criteria with a total of 587 participants. We also identified another ongoing trial. These trials were conducted between 1975 and 2015. None of the studies included people with neutrophil dysfunction. The studies differed in the type of infections they included. Six studies included both children and adults, however data were not reported separately for children and adults. The two newest studies gave granulocyte colony stimulating factor (G-CSF) to donors; both were stopped early due to lack of recruitment. Three studies re-randomised participants and therefore quantitative analysis was unable to be performed.Overall the quality of the evidence was very low to low across different outcomes according to GRADE methodology. This was due to many of the studies being at high risk of bias, and many of the outcomes being imprecise.There may be no difference in all-cause mortality over 30 days between participants receiving therapeutic granulocyte transfusions and those that did not (six studies; 321 participants; RR 0.75, 95% CI 0.54 to 1.04; very low-quality evidence). There were no differences between the granulocyte dose subgroups (< 1 x 10(10) per day versus ≥ 1 x 10(10) per day) (test for subgroup differences P = 0.39). There was a difference in all-cause mortality between the studies based on the age of the study (published before 2000 versus published 2000 or later) (test for subgroup differences P = 0.03). There was no difference in all-cause mortality between participants receiving granulocyte transfusions and those that did not in the newest study (one study; 111 participants; RR 1.10, 95% CI 0.70 to 1.73, low-quality evidence). There may be a reduction in all-cause mortality in participants receiving granulocyte transfusions compared to those that did not in studies published before the year 2000 (five studies; 210 participants; RR 0.53, 95% CI 0.33 to 0.85; low-quality evidence).There may be no difference in clinical reversal of concurrent infection between participants receiving therapeutic granulocyte transfusions and those that did not (five studies; 286 participants; RR 0.98, 95% CI 0.81 to 1.19; low-quality evidence).There is insufficient evidence to determine whether there is a difference in pulmonary serious adverse events (1 study; 24 participants; RR 0.85, 95% CI 0.38 to 1.88; very low-quality evidence).None of the studies reported number of days on therapeutic antibiotics, number of adverse events requiring discontinuation of treatment, or quality of life.Six studies reported their funding sources and all were funded by governments or charities.In people who are neutropenic due to myelosuppressive chemotherapy or a haematopoietic stem cell transplant, there is insufficient evidence to determine whether granulocyte transfusions affect all-cause mortality. To be able to detect a decrease in all-cause mortality from 35% to 30% would require a study containing at least 2748 participants (80% power, 5% significance). There is low-grade evidence that therapeutic granulocyte transfusions may not increase the number of participants with clinical resolution of an infection.

Enteral versus parenteral nutrition in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials.

BackgroundEnteral nutrition (EN) is recommended as the preferred route for early nutrition therapy in critically ill adults over parenteral nutrition (PN). A recent large randomized controlled trial (RCT) showed no outcome differences between the two routes. The objective of this systematic review was to evaluate the effect of the route of nutrition (EN versus PN) on clinical outcomes of critically ill patients.MethodsAn electronic search from 1980 to 2016 was performed identifying relevant RCTs. Individual trial data were abstracted and methodological quality of included trials scored independently by two reviewers. The primary outcome was overall mortality and secondary outcomes included infectious complications, length of stay (LOS) and mechanical ventilation. Subgroup analyses were performed to examine the treatment effect by dissimilar caloric intakes, year of publication and trial methodology. We performed a test of asymmetry to assess for the presence of publication bias.ResultsA total of 18 RCTs studying 3347 patients met inclusion criteria. Median methodological score was 7 (range, 2–12). No effect on overall mortality was found (1.04, 95 % CI 0.82, 1.33, P = 0.75, heterogeneity I2 = 11 %). EN compared to PN was associated with a significant reduction in infectious complications (RR 0.64, 95 % CI 0.48, 0.87, P = 0.004, I2 = 47 %). This was more pronounced in the subgroup of RCTs where the PN group received significantly more calories (RR 0.55, 95 % CI 0.37, 0.82, P = 0.003, I2 = 0 %), while no effect was seen in trials where EN and PN groups had a similar caloric intake (RR 0.94, 95 % CI 0.80, 1.10, P = 0.44, I2 = 0 %; test for subgroup differences, P = 0.003). Year of publication and methodological quality did not influence these findings; however, a publication bias may be present as the test of asymmetry was significant (P = 0.003). EN was associated with significant reduction in ICU LOS (weighted mean difference [WMD] -0.80, 95 % CI −1.23, −0.37, P = 0.0003, I2 = 0 %) while no significant differences in hospital LOS and mechanical ventilation were observed.ConclusionsIn critically ill patients, the use of EN as compared to PN has no effect on overall mortality but decreases infectious complications and ICU LOS. This may be explained by the benefit of reduced macronutrient intake rather than the enteral route itself.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1298-1) contains supplementary material, which is available to authorized users.

Incomparable Subsequent Effects between Study and Control Fluids Might Cause Questionable Results in Randomized Controlled Trials

Dr. Wiedermann commented on our systematic review and meta-regression for the sources of heterogeneity in trials reporting HES 130/0.4 or 0.42 associated excess mortality in septic patients[1] that the pooled analysis of mortality, which showed neither benefit nor harm, might be influenced by trials of low-quality. Statistically, we agree with this conclusion if two of the recruited trials judged as the intermediate risk of bias are precluded. Sensitivity tests in a meta-analysis are important. But an issue need for further discussing is that whether the results from a sensitivity analysis should be considered as the confirmatory or just exploratory. The fundamental thought of meta-analysis is to synthesis all the evidence current available. The article search strategy and the study inclusion/exclusion criteria had both been prespecified without any knowledge of the pooled analysis of mortality. The overall results should be taken as primary analysis because all the studies were fulfilled the prespecified principle. Over-interpretation of any subgroup analysis may have raised potential risk even if only focus on the trials with low risk of bias, the reasons were followed below. (1) Quality of the reporting of a study does not equal to the quality of the study itself. A well conduct study may have a very low-quality on reporting.[2] In addition, the process for risk of bias assessment is a sort of subjective even two independent reviewers assessing separately. It is hard to demonstrate any solid result from sensitivity analysis unless the consensus on the risk of bias assessment focus on study conducting could be achieved. (2) The multiplicity issue is not very common mentioned in the meta-analysis. However, the false-positive rate does significantly increased accompany with the raised number of tests. Currently, the meta-analysis includes 11 trials in total.[1] If we assume 6 of them are a low risk of bias, but the question is they are not easy to identify. Theoretically, there will be 462 possible combinations (randomly choose 6 trials from 11) under this scenario. The corresponding type I error rate (at least to observe one false-positive subgroup result) would be almost 100% (=1-0.95^462). By this reason, it should use a more restricted significant level for each subgroup result. Further, the test for subgroup difference between trials with low versus high risk of bias is a kind of interaction test. It also has to face the multiplicity issue. More importantly, the uncertainty of chosen the threshold for the significant level for interaction test is still controversial. Thus, the significant results of subgroup should be interpreted with cautions.[3] There are many reasons for the heterogeneity of mortality as primary outcome under the same intervention in randomized controlled trials (RCTs).[4] Most importantly, bias associated with execution factors such as intervention or its subsequent effects may cause questionable results in RCTs.[5] The efficiency of fluid therapy as a subsequent effect was found incomparable between HES and control group in some of the recruited RCTs in this meta-regression. Interestedly, all of 3 out of 11 RCTs, which were calculated with more positive fluid balance in HES group (a colloid with more efficiency on plasma volume expansion than crystalloids in general) than in control group, similarly reported a high risk of HES on excess mortality in septic patients and with significance in Perner's trial.[6] Our analysis further suggested daily delta fluid balance being likely associated with mortality in septic patients receiving HES 130/130/0.4* (P = 0.079). Whereas, we failed to determine a dose-effect relationship of HES 130/0.4 or 0.42 with mortality (P = 0.298). These results indicated that fluid balance was an important factor confounding the results of these RCTs. This was the main finding of this meta-regression. In conclusion, information from bedside (such as incomparable subsequent effects in fluid therapy) should be considered with priority over statistics in interpreting the results of available RCTs in evaluating the impact of any clinical intervention on mortality in critically ill patients.

Mitomycin C versus 5-Fluorouracil for wound healing in glaucoma surgery.

Raised intraocular pressure is a risk factor for glaucoma. One treatment option is glaucoma drainage surgery (trabeculectomy). Antimetabolites are used during surgery to reduce postoperative scarring during wound healing. Two agents in common use are mitomycin C (MMC) and 5-Fluorouracil (5-FU). To assess the effects of MMC compared to 5-FU as an antimetabolite adjunct in trabeculectomy surgery. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015 Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2015), EMBASE (January 1980 to October 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 2 October 2015. We included randomised controlled trials where wound healing had been modified with MMC compared to 5-FU. Two review authors independently selected trials and collected data. The primary outcome was failure of a functioning trabeculectomy one year after surgery. Secondary outcomes included mean intraocular pressure at one year. We considered three subgroups: high risk of trabeculectomy failure (people with previous glaucoma surgery, extracapsular cataract surgery, African origin and people with secondary glaucoma or congenital glaucoma); medium risk of trabeculectomy failure (people undergoing trabeculectomy with extracapsular cataract surgery) and low risk of trabeculectomy failure (people who have received no previous surgical eye intervention). We identified 11 trials that enrolled 687 eyes of 679 participants. The studies were conducted in the United States, Europe, Asia and Africa. Five studies enrolled participants at low risk of trabeculectomy failure, five studies enrolled participants at high risk of failure, and one study enrolled people with both high and low risk of failure. None of the included trials enrolled participants with combined trabeculectomy/cataract surgery.We considered one study to be at low risk of bias in all domains, six studies to be at high risk of bias in one or more domains, and the remaining four studies to be at an unclear risk of bias in all domains.The risk of failure of trabeculectomy at one year after surgery was less in those participants who received MMC compared to those who received 5-FU, however the confidence intervals were wide and are compatible with no effect (risk ratio (RR) 0.54, 95% confidence interval (CI) 0.30 to 1.00; studies = 11; I(2) = 40%). There was no evidence for any difference between groups at high and low risk of failure (test for subgroup differences P = 0.69).On average, people treated with MMC had lower intraocular pressure at one year (mean difference (MD) -3.05 mmHg, 95% CI -4.60 to -1.50), but the studies were inconsistent (I(2) = 52%). The size of the effect was greater in the high-risk group (MD -4.18 mmHg, 95% CI -6.73 to -1.64) compared to the low-risk group (MD -1.72 mmHg, 95% CI -3.28 to -0.16), but again the test for interaction was not statistically significant (P = 0.11).Similar proportions of eyes treated with MMC lost 2 or more lines of visual acuity one year after surgery compared to 5-FU, but the confidence intervals were wide (RR 1.05, 95% CI 0.54 to 2.06).Adverse events occurred relatively rarely, and estimates of effect were generally imprecise. There was some evidence for less epitheliopathy in the MMC group (RR 0.23, 95% CI 0.11 to 0.47) and less hyphaema in the MMC group (RR 0.62, 95% CI 0.42 to 0.91).None of the studies reported quality of life.Overall, we graded the quality of the evidence as low largely because of risk of bias in the included studies and imprecision in the estimate of effect. We found low-quality evidence that MMC may be more effective in achieving long-term lower intraocular pressure than 5-FU. Further comparative research on MMC and 5-FU is needed to enhance reliability and validity of the results shown in this review. Furthermore, the development of new agents that control postoperative scar tissue formation without side effects would be valuable and is justified by the results of this review.