Conventional Meta-analysis Research Articles

Impact of Corticosteroids on Short- and Long-Term Mortality in Patients with Sepsis and Septic Shock: A Meta-Analysis with Trial Sequential Analysis

Background Findings on the benefits and harms of corticosteroids for sepsis and septic shock from published meta-analyses are conflicting. With new randomized evidence emerging, an updated analysis of best available evidence on the effects of corticosteroids in sepsis and septic shock is warranted. Methods We did a conventional and cumulative meta-analysis and trial sequential analysis. Ovid MEDLINE, Ovid Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and LILACS were searched until May 2, 2018. Two reviewers selected randomized controlled trials (RCTs) reporting benefits and harms of corticosteroids as compared to placebo, standard therapy or no steroids in patients with sepsis and septic shock and independently collected data of interest. Primary outcomes were short-term (14-day and 28-day) mortality and long-term (90-day, 180-day, 1-year) mortality. Secondary outcomes included intensive care unit (ICU)- and hospital mortality, shock reversal by day 7 and 28, length of ICU and hospital stay, sequential organ failure assessment (SOFA) score at day 7 and adverse events. Fixed-effect and random-effects models were used to provide pooled estimates on predefined outcomes. This study is registered with PROSPERO, number CRD 42018092849. Findings Thirty-four RCTs including 9,942 participants were included in this meta-analysis. Results showed that long course of low-dose corticosteroids could improve 28-day mortality (relative ratio (RR), 0.91; 95% confidence interval (CI), 0.86 to 0.97; I2=0%; high-quality evidence), ICU mortality (RR, 0.87; 95%CI, 0.79 to 0.95; I2=21%; moderate-quality evidence) and hospital mortality (RR, 0.89; 95%CI, 0.79 to 0.99; I2=40%; low-quality evidence). Meta-regression analyses confirmed the benefits of corticosteroids in14-day and 28-day mortality and indicated that the use of hydrocortisone at least 135mg per day for at least 87h was associated with significant benefits. However, this meta-analysis found no benefits for 90-day mortality from low-quality evidence (RR, 0.96; 95%CI, 0.85 to 1.09; I2=44%), 180-day mortality and 1-year mortality and about 38,340 participants were required for clarification of the effect of 90-day mortality. In terms of adverse events, long course of low-dose corticosteroids were associated with hyperglycaemia (RR, 1.20; 95%CI, 1. 09 to 1.32; I2=40%) and hypernatraemia (RR, 1.60; 95%CI, 1.26 to 2.02; I2=0%). Short course of high-dose corticosteroids showed no significant benefits in any of the predefined outcomes. Interpretation Long course (at least 87h) of low-dose (at least 135 mg per day) hydrocortisone could improve 28-day mortality of patients with sepsis and septic shock as well as ICU- and hospital mortality, with varied quality of evidence. However, it could not reduce long-term (90-day, 180-day and 1-year) mortality. Funding: None. Declaration of Interest: We declare no competing interests.

Comparative effectiveness of preoperative, postoperative and perioperative treatments for resectable gastric cancer: A network meta-analysis of the literature from the past 20 years

BackgroundDifferent preoperative, postoperative or perioperative treatment strategies, including chemotherapy or chemoradiotherapy, are available for patients with gastric cancer, but conventional meta-analyses that assess two alternative treatments are unable to compare differences in overall survival. Thus, we performed a network meta-analysis to identify the best treatment strategy. MethodsWe systematically searched and assessed studies for eligibility and extracted data. We then pooled the data and conducted a Bayesian network meta-analysis to combine direct comparisons with indirect evidence. The node-splitting method was used to assess the inconsistency. Rank probabilities were assessed by the probability of treatment rankings. ResultsThirty-three eligible randomized controlled trials were included in the network meta-analysis. Four treatments that had significantly improved prognoses when compared with surgery only were postoperative chemotherapy [HR = 0.80 with 95% CrI: (0.73, 0.88)], postoperative chemoradiotherapy [HR = 0.73 with 95% CrI: (0.61, 0.87)], preoperative chemoradiotherapy [HR = 0.77 with 95% CrI: (0.62, 0.98)] and perioperative chemotherapy [HR = 0.69 with 95% CrI: (0.55, 0.84)]. Preoperative chemotherapy, however, did not significantly improve survival when compared with surgery alone [HR = 0.94 with 95% CrI: (0.71, 1.2)]. There was no statistically significant difference between postoperative chemotherapy, postoperative chemoradiotherapy, preoperative chemoradiotherapy and perioperative chemotherapy in terms of overall survival. Chemoradiotherapy after D2 lymphadenectomy did not significantly improve OS when compared with postoperative chemotherapy [HR = 0.95 with 95% CrI: (0.73, 1.3)]. ConclusionAmong patients with operable gastric cancer, perioperative chemotherapy had the highest probability of being the best treatment. Further clinical resources may be required to assess the efficacy and safety of perioperative chemotherapy for patients with gastric cancer.

Major Congenital Malformations Associated With Exposure to Antiepileptic Drugs During Pregnancy.

Antiepileptic drugs (AEDs) are prescribed for approved and off-label indications that include epilepsy, bipolar disorder, and other neurologic and psychiatric disorders. The risk of major congenital malformations (MCMs) following gestational exposure to AEDs, particularly exposure at the time of conception and early trimester exposure, has been examined in many studies. This risk has been compared with the risk in unexposed general population controls as well as in untreated controls with the same treatment indication, and this risk has been compared pairwise among the AEDs. There is consistent evidence from conventional and network meta-analyses and from prospectively collected pregnancy registry data that early gestational exposure to valproate is associated with the highest risk of MCMs among the AEDs; the risk is around 10% and is dose-dependent. Furthermore, in pairwise comparisons that attenuate confounding by indication, valproate is significantly more teratogenic than most other AEDs. Phenobarbitone, phenytoin, carbamazepine, and topiramate are the other AEDs that are consistently associated with higher MCM risk relative to unexposed control groups and relative to certain other AEDs. Besides valproate (> 650 mg/d), phenobarbitone (> 80 mg/d) and carbamazepine (> 700 mg/d) are also associated with dose-dependent risks. In the AEDs associated with elevated risks, the extent to which the risks are due to confounding by indication is unknown. Importantly, confounding by indication notwithstanding, at conventional doses lamotrigine, levetiracetam, and oxcarbazepine, and possibly zonisamide and gabapentin, as well, are associated with absolute MCM risks that are no greater than the 2%-3% MCM risk in the general population.

Intralesional immunotherapy for the treatment of warts: A network meta-analysis

Without clear evidence, selecting among the existing immunotherapeutic options for warts remains challenging. Through network meta-analyses, we aimed to evaluate the comparative efficacy of different intralesional immunotherapeutic modalities. We included randomized controlled trials comparing intralesional immunotherapeutic modalities to cryotherapy, placebo, or imiquimod. All outcomes were presented as odds ratios (ORs) with 95% confidence intervals. Both conventional and network meta-analyses (with a frequentist approach) were conducted on R software. The P-score was used to rank different treatments. Network meta-analysis of 17 randomized controlled trials (1676 patients) showed that PPD (purified protein derivative vaccine, OR 39.56), MMR (measles, mumps, rubella vaccine, OR 17.46) and interferon β (OR 15.55) had the highest efficacy in terms of complete recovery at the primary site compared with placebo. Regarding complete recovery at the distant site, autoinoculation (OR 79.95), PPD (OR 42.95), and MMR (OR 15.39) were all statistically superior to placebo. According to the P-score, MMR was more effective than other modalities in reducing the recurrence rate at the same site. Relatively small sample size in some comparisons and variability in baseline characteristics. PPD and MMR were the most effective in achieving complete primary and distant recovery (along with autoinoculation for distant recovery) and reducing the recurrence rate at the same site compared with cryotherapy and other immunotherapeutic modalities.

Comparative Efficacy and Safety of Antiulcer Drugs for Stress Ulcer Prophylaxis (SUP) in Critically Ill Patients: A Systematic Review and Network Meta-Analysis

Background: Stress ulcers can affect the prognosis of critically ill patients. However, is stress ulcer prophylaxis (SUP) necessary for critically ill patients? What is the best choice of SUP? There are no specific answers to these two questions. The aim of our study was to conduct a conventional pairwise meta-analysis to assess the effects of SUP versus no prophylaxis and to perform a network meta-analysis to evaluate the efficacy and safety of antiulcer drugs for SUP in adult critically ill patients. Methods: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library, EMBASE, MEDLINE, CINAHL, and the Web of Science using a combination of MeSH and text words relevant to SUP, critically ill patients, adults, proton pump inhibitors (PPIs), histamine-2-receptor antagonists (H2RAs), sucralfate, and antacids, together with randomized controlled trials from the date of database inception to July 5, 2017. We extracted relevant information using a predefined data extraction form and assessed the risk of bias using the Cochrane risk of bias tool. Our primary outcome was the incidence of gastrointestinal (GI) bleeding. The secondary outcome was all-cause mortality and the risk of pneumonia. Findings: A total of 73 randomized controlled trials, with a total of 10,509 adult critically ill patients, were identified in our study. In the pairwise meta-analysis, we found a statistically significant difference between SUP and no prophylaxis for GI bleeding (RR 0·45, 95% CI 0·38 to 0·53) but no statistically significant differences in mortality (RR 0·96, 95% CI 0·84 to 1·10) or the risk of pneumonia (RR 1·15, 95% CI 0·91 to 1·46). In a 5-node network meta-analysis, pooled effect sizes suggested that, compared to no prophylaxis, all interventions were associated with reduced GI bleeding. Additionally, compared to PPIs (RR 0·60, 95% CI 0·47 to 0·76) and H2RAs (RR 0·77, 95% CI 0·67 to 0·88), sucralfate was associated with a reduction in pneumonia. In an 11-node network meta-analysis, omeprazole was significantly more effective than cimetidine, ranitidine, and sucralfate in preventing GI bleeding, while compared to omeprazole, pantoprazole and ranitidine, sucralfate was associated with a decreased risk of pneumonia. In terms of mortality, the combined results showed no statistically significant differences in any comparisons. Interpretation: SUP is necessary for preventing GI bleeding in adult critically ill patients. We recommend sucralfate as a better choice for SUP in adult critically ill patients. Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 81402462, 81571871 and 81770276) and the Yuweihan Fund for Distinguished Young Scholars. Declaration of interests: We declare no competing interests.

The impact of telehealth remote patient monitoring on glycemic control in type 2 diabetes: a systematic review and meta-analysis of systematic reviews of randomised controlled trials

BackgroundThere is a growing body of evidence to support the use of telehealth in monitoring HbA1c levels in people living with type 2 diabetes. However, the overall magnitude of effect is yet unclear due to variable results reported in existing systematic reviews. The objective of this study is to conduct a systematic review and meta-analysis of systematic reviews of randomised controlled trials to create an evidence-base for the effectiveness of telehealth interventions on glycemic control in adults with type 2 diabetes.MethodsElectronic databases including The Cochrane Library, MEDLINE, EMBASE, HMIC, and PsychINFO were searched to identify relevant systematic reviews published between 1990 and April 2016, supplemented by references search from the relevant reviews. Two independent reviewers selected and reviewed the eligible studies. Of the 3279 references retrieved, 4 systematic reviews reporting in total 29 unique studies relevant to our review were included. Both conventional pairwise meta-analyses and network meta-analyses were performed.ResultsEvidence from pooling four systematic reviews found that telehealth interventions produced a small but significant improvement in HbA1c levels compared with usual care (MD: -0.55, 95% CI: -0.73 to − 0.36). The greatest effect was seen in telephone-delivered interventions, followed by Internet blood glucose monitoring system interventions and lastly interventions involving automatic transmission of SMBG using a mobile phone or a telehealth unit.ConclusionCurrent evidence suggests that telehealth is effective in controlling HbA1c levels in people living with type 2 diabetes. However there is need for better quality primary studies as well as systematic reviews of RCTs in order to confidently conclude on the impact of telehealth on glycemic control in type 2 diabetes.

Visual and radiographic caries detection: a tailored meta-analysis for two different settings, Egypt and Germany

BackgroundDiagnostic meta-analyses on caries detection methods should assist practitioners in their daily practice. However, conventional meta-analysis estimates may be inapplicable due to differences in test conduct, applied thresholds and assessed population between settings. Our aim was to demonstrate the impact of tailored meta-analysis of visual and radiographic caries detection to different settings using setting-specific routine data.MethodsPublished systematic reviews and meta-analyses on the accuracy of visual and radiographic caries detection were used. In two settings (a private practice in Germany and a public health clinic in Egypt), routine data of a total of 100 (n = 50/practice) consecutive 12–14 year-olds were collected. Test-positive rates of visual and radiographic detection for initial and advanced carious lesions on occlusal or proximal surfaces of molars were used to tailor meta-analyses. If prevalence data were available, these were also used for tailoring.ResultsFrom the original reviews, 210 and 100 heterogeneous studies on visual and radiographic caries detection were included in our meta-analyses. For radiographic detection, sensitivity and specificity estimates derived from conventional and tailored meta-analysis were similar. For visual detection of advanced occlusal carious lesions, the conventional meta-analysis yielded a sensitivity and specificity (95% CI) of 64.6% (57–71) and 90.9% (88–93), whereas the tailored estimates for Egypt were 75.1% (70–81) and 84.9% (82–89), respectively, and 43.7% (37–51) and 96.5% (95–97) for Germany, respectively.ConclusionConventional test accuracy meta-analyses may yield aggregate estimates which are inapplicable to specific settings. Routine data may be used to produce a meta-analysis estimate which is tailored to the setting and thereby improving its applicability.

Alcohol intake and gastric cancer: Meta-analyses of published data versus individual participant data pooled analyses (StoP Project)

BackgroundIndividual participant data pooled analyses allow access to non-published data and statistical reanalyses based on more homogeneous criteria than meta-analyses based on systematic reviews. We quantified the impact of publication-related biases and heterogeneity in data analysis and presentation in summary estimates of the association between alcohol drinking and gastric cancer. MethodsWe compared estimates obtained from conventional meta-analyses, using only data available in published reports from studies that take part in the Stomach Cancer Pooling (StoP) Project, with individual participant data pooled analyses including the same studies. ResultsA total of 22 studies from the StoP Project assessed the relation between alcohol intake and gastric cancer, 19 had specific data for levels of consumption and 18 according to cancer location; published reports addressing these associations were available from 18, 5 and 5 studies, respectively. The summary odds ratios [OR, (95%CI)] estimate obtained with published data for drinkers vs. non-drinkers was 10% higher than the one obtained with individual StoP data [18 vs. 22 studies: 1.21 (1.07–1.36) vs. 1.10 (0.99–1.23)] and more heterogeneous (I2: 63.6% vs 54.4%). In general, published data yielded less precise summary estimates (standard errors up to 2.6 times higher). Funnel plot analysis suggested publication bias. ConclusionMeta-analyses of the association between alcohol drinking and gastric cancer tended to overestimate the magnitude of the effects, possibly due to publication bias. Additionally, individual participant data pooled analyses yielded more precise estimates for different levels of exposure or cancer subtypes.

Comparative Efficacy and Safety of Different Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis

Over the past 25 years, several randomized controlled trials have investigated the efficacy of different antiviral agents for cytomegalovirus (CMV) prophylaxis in allogeneic hematopoietic cell transplantation. We performed a systematic literature review, conventional meta-analysis, and network meta-analysis using a random-effects model and risk ratios (RRs) with corresponding 95% confidence intervals (CIs) as effect estimates. Fifteen randomized controlled trials were identified, including 7 different antiviral agents: acyclovir, ganciclovir, maribavir, brincidofovir, letermovir, valacyclovir, and vaccine. Twelve trials used placebo as comparator while 3 trials compared different antiviral agents. We found evidence for CMV disease and infection being significantly reduced by antiviral prophylaxis, with an RR of .66 (95% CI, .48 to .90) and .63 (95% CI, .50 to .79). Across the network, ganciclovir showed the best relative efficacy for CMV disease while letermovir provided first rank of being the best option for CMV infection. The risk for death was not significantly influenced by antiviral prophylaxis in the meta-analysis, with an RR of .92 (95% CI, .78 to 1.08), as well as in the network meta-analysis. In terms of safety, letermovir was at least similar in comparison with placebo and most agents while both letermovir and acyclovir showed significantly reduced risk for serious adverse events compared with ganciclovir, with RRs of .55 (95% CI, .30 to 1.00) for letermovir and .63 (95% CI, .42 to .93) for acyclovir. With a probability of 81%, letermovir appears to be the best option in terms of safety. Future randomized head-to-head comparisons are needed to evaluate the definite efficacy and safety of different prophylactic strategies.

Comparative effectiveness of adjuvant treatments for resected gastric cancer: a network meta-analysis.

Different adjuvant treatments are available for patients with gastric cancer, but conventional meta-analyses performing direct comparisons between two alternative treatments did not have enough power to compare all the adjuvant treatments. Thus, we did a network meta-analysis summarizing the direct and indirect comparisons to identify the optimum treatment. We systematically searched for RCTs of adjuvant treatments for gastric cancer comparing two or more of the following treatments: surgery alone, radiotherapy with fluoropyrimidine, S-1-based regimens, andXELOX. The treatments offering available indirect evidence to investigate the comparative effectiveness of adjuvant treatments mentioned above were also included. Then we performed a Bayesian network meta-analysis to summarize the direct and indirect comparisons. We estimated hazard ratios with 95% credible intervals (CrI) for OS and DFS. 11 eligible RCTs (5620 patients) were included in the network meta-analysis. Radiotherapy with fluorouracil (5-FU/RT), S-1-based regimens, and XELOX significantly improved OS as compared with surgery alone [(HR = 0.75 with 95% CrI: 0.63-0.89), (HR = 0.63 with 95% CrI: 0.52-0.76), and (HR = 0.66 with 95% CrI: 0.51-0.85), respectively]. No treatment was clearly superior to others; however, S-1-based regimes and XELOX showed a statistically non-significant trend to better survival as compared with 5-FU/RT. S-1-based chemotherapy and XELOX are likely to be the most effective adjuvant treatments for patients with resected gastric cancer. 5-FU alone provided little survival benefits as compared with surgery alone. Further clinical trials may be required to investigate S-1-based and XELOX-based adjuvant treatment strategies.

Optimal reconstruction methods after distal gastrectomy for gastric cancer

Background:The choice of anastomosis methods including Billroth I, Billroth II, and Roux-en-Y after a distal gastrectomy is still controversial. The conventional meta-analyses assessing 2 alternative treatments were not powered to compare differences in clinical outcomes. To guide treatment decisions in patients with gastric cancer (GC) after distal gastrectomy, we did a systematic review and network meta-analysis to identify the best reconstruction method.Methods:We systematically searched PubMed, EMBASE, the Cochrane Library for randomized controlled trials comparing the outcomes of Billroth I, Billroth II, or Roux-en-Y reconstruction after distal subtotal gastrectomy for patients with GC, then we performed a direct meta-analysis and Bayesian network meta-analysis to pooled odds ratios (OR) or weighted mean differences (WMD) with 95% credible intervals (CrI) with random effects model. The node-splitting method was used to assess the inconsistency. We estimated the potential ranking probability of treatments by calculating the surface under the cumulative ranking curve for each intervention.Results:Nine studies involving 1161 patient were included in the network meta-analysis. Statistical significance was reached for the comparisons of Roux-en-Y versus Billroth I reconstruction (WMD 37, 95% Crl: 22–51) and Billroth II versus Billroth I reconstruction (WMD 25, 95% Crl: 5.8–43) for operation time; and Roux-en-Y versus Billroth I reconstruction (WMD 26, 95% Crl: 2.1–68) for intraoperative blood loss; and Roux-en-Y versus Billroth I reconstruction (OR 3.4, 95% Crl: 1.1–13) for delayed gastric emptying. Roux-en-Y reconstruction was superior to Billroth I and Billroth II reconstruction in terms of frequency of bile reflux (OR 0.095, 95% Crl: 0.010–0.63; OR 0.064, 95% Crl: 0.0037–0.84, respectively) and the incidence of remnant gastritis (OR 0.33, 95% Crl: 0.16–0.58; OR 0.40, 95% Crl: 0.17–0.92, respectively).Conclusion:Roux-en-Y reconstruction is superior to Billroth I and Billroth II reconstruction in terms of preventing bile reflux and remnant gastritis, Billroth I and Billroth II anastomosis could be considered as the substitute in consideration of technical simplicity. As for postoperative morbidity and the advantage of physiological food passage, Billroth I method is the choice.

Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted patients.

Liver transplantation is an established treatment option for end-stage liver failure. Now that newer, more potent immunosuppressants have been developed, glucocorticosteroids may no longer be needed and their removal may prevent adverse effects. To assess the benefits and harms of glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) or withdrawal versus glucocorticosteroid-containing immunosuppression following liver transplantation. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, Literatura Americano e do Caribe em Ciencias da Saude (LILACS), World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and The Transplant Library until May 2017. Randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal versus glucocorticosteroid-containing immunosuppression for liver transplanted people. Our inclusion criteria stated that participants should have received the same co-interventions. We included trials that assessed complete glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids, as well as trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids. We used RevMan to conduct meta-analyses, calculating risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables, both with 95% confidence intervals (CIs). We used a random-effects model and a fixed-effect model and reported both results where a discrepancy existed; otherwise we reported only the results from the fixed-effect model. We assessed the risk of systematic errors using 'Risk of bias' domains. We controlled for random errors by performing Trial Sequential Analysis. We presented our results in a 'Summary of findings' table. We included 17 completed randomised clinical trials, but only 16 studies with 1347 participants provided data for the meta-analyses. Ten of the 16 trials assessed complete postoperative glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids (782 participants) and six trials assessed short-term glucocorticosteroids versus long-term glucocorticosteroids (565 participants). One additional study assessed complete post-operative glucocorticosteroid avoidance but could only be incorporated into qualitative analysis of the results due to limited data published in an abstract. All trials were at high risk of bias. Only eight trials reported on the type of donor used. Overall, we found no statistically significant difference for mortality (RR 1.15, 95% CI 0.93 to 1.44; low-quality evidence), graft loss including death (RR 1.15, 95% CI 0.90 to 1.46; low-quality evidence), or infection (RR 0.88, 95% CI 0.73 to 1.05; very low-quality evidence) when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression. Acute rejection and glucocorticosteroid-resistant rejection were statistically significantly more frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 1.33, 95% CI 1.08 to 1.64; low-quality evidence; and RR 2.14, 95% CI 1.13 to 4.02; very low-quality evidence). Diabetes mellitus and hypertension were statistically significantly less frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 0.81, 95% CI 0.66 to 0.99; low-quality evidence; and RR 0.76, 95% CI 0.65 to 0.90; low-quality evidence). We performed Trial Sequential Analysis for all outcomes. None of the outcomes crossed the monitoring boundaries or reached the required information size. Hence, we cannot exclude random errors from the results of the conventional meta-analyses. Many of the benefits and harms of glucocorticosteroid avoidance or withdrawal remain uncertain because of the limited number of published randomised clinical trials, limited numbers of participants and outcomes, and high risk of bias in the trials. Glucocorticosteroid avoidance or withdrawal appears to reduce diabetes mellitus and hypertension whilst increasing acute rejection, glucocorticosteroid-resistant rejection, and renal impairment. We could identify no other benefits or harms of glucocorticosteroid avoidance or withdrawal. Glucocorticosteroid avoidance or withdrawal may be of benefit in selected patients, especially those at low risk of rejection and high risk of hypertension or diabetes mellitus. The optimal duration of glucocorticosteroid administration remains unclear. More randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal are needed. These should be large, high-quality trials that minimise the risk of random and systematic error.

Management of recurrent pancreatic cancer after surgical resection: a protocol for systematic review, evidence mapping and meta-analysis

IntroductionAlthough recurrence rate among cases of resected pancreatic cancer are as high as 85%, an optimal treatment for recurrent pancreatic cancer (RePC) has not been established. Previous evidence regarding RePC...

F214. PSYCHOLOGICAL INTERVENTIONS FOR POSITIVE SYMPTOMS IN SCHIZOPHRENIA: A NETWORK META-ANALYSIS

BackgroundThere is rising awareness about the need of multi-disciplinary approaches integrating psychological treatments for schizophrenia, but a comprehensive evidence base on their relative efficacy is lacking. Conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, acceptability and tolerability of psychological interventions for schizophrenia.MethodsWe performed a network meta-analysis (which uses both direct and indirect comparisons) of randomized controlled trials on psychological treatments aimed at positive symptoms in the acute treatment of schizophrenia, compared with another psychological intervention or with a no treatment condition (waiting list, treatment as usual). We excluded trials done in patients with predominant negative symptoms, concomitant psychiatric disorders or medical illnesses, and those done in first episode or stable patients. Published and unpublished studies were sought through database searches, trial registries and websites. Study selection and data extraction were conducted by at least two independent reviewers. Our primary outcome is the change in positive symptoms on a validated rating scale. Secondary outcomes include number of dropouts, overall and negative symptoms of schizophrenia, response, relapse, adherence, depression, quality of life, functioning and adverse events. Analyses were conducted in R within a frequentist framework. The risk of bias in studies has been evaluated using the Cochrane Risk of Bias tool and the credibility of the evidence will be evaluated using an adaptation of the GRADE framework to NMA, recommended by the Cochrane guidance. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. The protocol of this review has been registered in Prospero (registration number: CRD42017067795).ResultsAfter screening 20196 references for title and abstract and 2555 full text articles, we identified 58 suitable trials, for a total of 3956 participants.Regarding primary outcome positive symptoms, only Cognitive Behavioural Therapy was significantly more effective than treatment as usual, with a standardised mean difference of -0.59 [95% credible interval -1.03; -0.16].The standardised mean differences with 95% credible intervals for other interventions were: Acceptance and Commitment Therapy -0.07 [-2.12; 1.98], Cognitive Therapy -0.18 [-1.92; 1.55], Hallucination Treatment -0.69 [-2.40; 1.01], Metacognitive Therapy -0.26 [-1.16; 0.64], Mindfulness -0.26 [-2.14; 1.62], with heterogeneity tau2 = 0.6942.Data analyses on other outcomes are ongoing.DiscussionWe are going to investigate the possible sources of heterogeneity with the pre-planned subgroup analyses: number of sessions, study duration, individual versus group setting, expertise of the therapist and baseline severity.A network meta-analysis is the only methodology that allows the production of hierarchies of interventions for treatment of schizophrenia. Such hierarchies, saying which treatment is likely to be the best, the second best and so on, are essential for guideline development. The results of this study are therefore likely to provide knowledge of great impact for treatment decisions.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 701717.

Stress ulcer prophylaxis in adult intensive care unit patients - a protocol for a systematic review.

In the intensive care unit (ICU), stress ulcer prophylaxis with proton pump inhibitors or histamine-2-receptor antagonists is standard of care although gastrointestinal bleeding remains uncommon. It remains unknown whether its use is associated with benefits or harms and the quality of evidence supporting the use of stress ulcer prophylaxis has been questioned. Accordingly, the objective of this systematic review was to critically assess the evidence from randomized clinical trials on the benefits and harms of stress ulcer prophylaxis vs. placebo or no prophylaxis in adult ICU patients. We will systematically search for randomized clinical trials in major international databases. Two authors will independently screen and select trials for inclusion, extract data and assess the methodological quality using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will perform conventional meta-analyses using Review Manager, and STATA 15, and we will assess the risk of random errors using Trial Sequential Analysis. Also, we will assess and report the overall quality of evidence for all outcomes according to GRADE. The evidence on the benefits and harms of stress ulcer prophylaxis in adult ICU patients is unclear and an updated systematic review is warranted as new trials have been published. To control risks of systematic and random errors, we will use Cochrane and GRADE methodology and Trial Sequential Analysis. Our ambition with this systematic review is to provide updated, reliable and precise data to better inform decision makers on the use of stress ulcer prophylaxis in adult ICU patients.

Molecular hydrogen upregulates heat shock response and collagen biosynthesis, and downregulates cell cycles: meta-analyses of gene expression profiles

Molecular hydrogen exerts its effect on multiple pathologies, including oxidative stress, inflammation, and apoptosis. However, its molecular mechanisms have not been fully elucidated. In order to explore the effects of molecular hydrogen, we meta-analysed gene expression profiles modulated by molecular hydrogen. We performed microarray analysis of the mouse liver with or without drinking hydrogen water. We also integrated two previously reported microarray datasets of the rat liver into meta-analyses. We used two categories of meta-analysis methods: the cross-platform method and the conventional meta-analysis method (Fisher’s method). For each method, hydrogen-modulated pathways were analysed by (i) the hypergeometric test (HGT) in the class of over-representation analysis (ORA), (ii) the gene set enrichment analysis (GSEA) in the class of functional class scoring (FCS), and (iii) the signalling pathway impact analysis (SPIA), pathway regulation score (PRS), and others in the class of pathway topology-based approach (PTA).Pathways in the collagen biosynthesis and the heat-shock response were up-regulated according to (a) HGT with the cross-platform method, (b) GSEA with the cross-platform method, and (c) PRS with the cross-platform method. Pathways in cell cycles were down-regulated according to (a) HGT with the cross-platform method, (b) GSEA with the cross-platform method, and (d) GSEA with the conventional meta-analysis method.Because the heat-shock response leads to up-regulation of collagen biosynthesis and a transient arrest of cell cycles, induction of the heat-shock response is likely to be a primary event induced by molecular hydrogen in the liver of wild-type rodents.

Empirical metronidazole for patients with severe bacterial infection: protocol for a systematic review.

Anaerobic bacteria are believed to be common pathogens in severe infections. Yet, they are difficult to culture and consequently often unrecognised in clinical infections. Metronidazole is often used empirically for potential anaerobic infections, as the resistance to metronidazole is low. However, disadvantages of metronidazole use exist, including drug interactions, side effects and economical expenses. Currently, the balance between the benefits and harms of empirical metronidazole for severe bacterial infections is unknown. We aim to assess patient-important benefits and harms of empirical metronidazole vs. placebo or no treatment in adult patients with severe bacterial infection of any origin in a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. This protocol provides details on the planned systematic review, which will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the Cochrane Handbook, and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. The primary outcome is all-cause mortality. Secondary outcomes include adverse events, secondary infections, use of life support, antibiotic resistance and hospital length of stay. We will conduct conventional meta-analyses, including predefined subgroup- and sensitivity analyses. Additionally, we will assess the risk of random errors by trial sequential analysis. Ethical approval is not needed, as the outlined review exclusively will include previously published data. We aim to publish in an international, peer-reviewed journal.

Intakes of citrus fruit and risk of esophageal cancer: A meta-analysis.

Esophageal cancer (EC) is the eighth most common cancer and the sixth most frequent cause of cancer death in the whole world. Many studies have investigated the association between citrus fruit intake and the risk of EC, but the results are inconsistent and not analyzed by category. We aimed to perform a meta-analysis of studies to evaluate the incidence between citrus fruit consumption and subtypes of esophageal cancer and derive a more precise estimation.Through searches of PubMed, OVID, and Web of Science we updated 1988 systematic review up to April 2016. Based on an inclusion and exclusion criteria, conventional meta-analysis according to DerSimonian and Laird method was used for the pooling of the results. Random-effect models were used to calculate subgroups.Twenty-five English articles (20 case-control studies and 5 cohort studies) comprising totally 5730 patients of esophageal cancer would be suitable for use in this study. The result indicated the inverse associations between intakes of citrus fruit and EC (relative risk [RR] = 0.65, 95% confidence interval [CI] 0.56−0.75, I2 = 51.1%, P = .001), Esophageal squamous cell carcinoma (ESCC) (RR = 0.59, 95% CI 0.47–0.76, I2 = 60.7%, P = .002), no significant relationship between citrus fruit and esophageal adenocarcinoma (EAC) (RR = 0.86, 95% CI 0.74–1.01, I2 = 0.0%, P = .598).This meta-analysis indicates that intakes of citrus fruit significantly reduce the risk of ESCC and is no obvious relationship with EAC. Further studies about constituents in citrus fruit and its mechanism are warranted.

Use of sunscreen and risk of melanoma and non-melanoma skin cancer: a systematic review and meta-analysis.

The use of sunscreen is a key component of public health campaigns for skin cancer prevention, but epidemiological studies have raised doubts on its effectiveness in the general population. This systematic review and meta-analysis aimed to assess the association between risk of skin cancer and sunscreen use. We searched PubMed, BIREME and Google Scholar from inception to May 17, 2017, to identify observational studies and controlled trials. We used a random-effects model for conventional and cumulative meta-analyses. We included 29 studies (25 case-control, two cohort, one cross-sectional, and one controlled trial) involving 313,717 participants (10,670 cases). The overall meta-analysis did not show a significant association between skin cancer and sunscreen use (odds ratio (OR)=1.08; 95%CI: 0.91-1.28, I2=89.4%). Neither melanoma (25 studies; 9,813 cases) nor non-melanoma skin cancer (five studies; 857 cases) were associated with sunscreen use, with a pooled OR (95%CI) of 1.10 (0.92-1.33) and 0.99 (0.62-1.57), respectively. The cumulative evidence before the 1980s showed a relatively strong positive association between melanoma and sunscreen use (cumulative OR: 2.35; 95%CI: 1.66-3.33). The strength of the association between risk of skin cancer and sunscreen use has constantly decreased since the early 1980s, and the association was no longer statistically significant from the early 1990s. While the current evidence suggests no increased risk of skin cancer related to sunscreen use, this systematic review does not confirm the expected protective benefits of sunscreen against skin cancer in the general population.

Long-term safety of bioresorbable scaffolds: insights from a network meta-analysis including 91 trials.

The aim of this study was to investigate the long-term safety and efficacy of biodegradable scaffolds and metallic stents. We analysed a total of 91 randomised controlled trials with a mean follow-up of 3.7 years in 105,842 patients which compared two or more coronary metallic stents or biodegradable scaffolds and reported the long-term clinical outcomes (≥2 years). Network meta-analysis showed that patients treated with the Absorb bioresorbable vascular scaffold (BVS) had a significantly higher risk of definite or probable scaffold thrombosis (ScT) compared to those treated with metallic DES. The risk of very late ScT was highest with the Absorb BVS among comparators. Pairwise conventional meta-analysis demonstrated that the elevated risk of ScT with Absorb BVS compared to cobalt-chromium everolimus-eluting stents was consistent across the time points of ≤30 days (early), 31 days - 1 year (late) and >1 year (very late) ScT. In addition, target lesion failure rates were significantly higher in the Absorb BVS cohort, driven by both increased risk of target vessel myocardial infarction and ischaemia-driven target lesion revascularisation. Absorb BVS implantation was associated with increased risk of long-term and very late ScT compared to current-generation metallic DES. The risk of ScT occurred with a rising trend beyond one year.