Interleukin-1 blocking agents for treating COVID-19.

BACKGROUND: Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19. OBJECTIVES: To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021). SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-1 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 28; ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28; ≥ D60); all-cause mortality (D28; ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab. Effectiveness of anakinra for people with COVID-19 Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence. The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence).  The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence). Safety of anakinra for people with COVID-19 Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence).  The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence). Effectiveness of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence).  The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence).  The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence). Safety of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence). The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence). AUTHORS' CONCLUSIONS: Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com).

Quality improvement strategies to prevent falls in older adults: a systematic review and network meta-analysis.

BACKGROUND: Falls are a common occurrence and the most effective quality improvement (QI) strategies remain unclear. METHODS: We conducted a systematic review and network meta-analysis (NMA) to elucidate effective quality improvement (QI) strategies for falls prevention. Multiple databases were searched (inception-April 2017). We included randomised controlled trials (RCTs) of falls prevention QI strategies for participants aged ≥65 years. Two investigators screened titles and abstracts, full-text articles, conducted data abstraction and appraised risk of bias independently. RESULTS: A total of 126 RCTs including 84,307 participants were included after screening 10,650 titles and abstracts and 1210 full-text articles. NMA including 29 RCTs and 26,326 patients found that team changes was statistically superior in reducing the risk of injurious falls relative to usual care (odds ratio [OR] 0.57 [0.33 to 0.99]; absolute risk difference [ARD] -0.11 [95% CI, -0.18 to -0.002]). NMA for the outcome of number of fallers including 61 RCTs and 40 128 patients found that combined case management, patient reminders and staff education (OR 0.18 [0.07 to 0.47]; ARD -0.27 [95% CI, -0.33 to -0.15]) and combined case management and patient reminders (OR, 0.36 [0.13 to 0.97]; ARD -0.19 [95% CI, -0.30 to -0.01]) were both statistically superior compared to usual care. CONCLUSIONS: Team changes may reduce risk of injurious falls and a combination of case management, patient reminders, and staff education, as well as case management and patient reminders may reduce risk of falls. Our results can be tailored to decision-maker preferences and availability of resources. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42013004151).

Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes.

BACKGROUND: Pregnant women with epilepsy frequently experience seizures related to pregnancy complications and are often prescribed anti-epileptic drugs (AEDs) to manage their symptoms. However, less is known about the comparative safety of AED exposure in utero. We aimed to compare the risk of congenital malformations (CMs) and prenatal outcomes of AEDs in infants/children who were exposed to AEDs in utero through a systematic review and Bayesian random-effects network meta-analysis. METHODS: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to December 15, 2015. Two reviewers independently screened titles/abstracts and full-text papers for experimental and observational studies comparing mono- or poly-therapy AEDs versus control (no AED exposure) or other AEDs, then abstracted data and appraised the risk of bias. The primary outcome was incidence of major CMs, overall and by specific type (cardiac malformations, hypospadias, cleft lip and/or palate, club foot, inguinal hernia, and undescended testes). RESULTS: After screening 5305 titles and abstracts, 642 potentially relevant full-text articles, and 17 studies from scanning reference lists, 96 studies were eligible (n = 58,461 patients). Across all major CMs, many AEDs were associated with higher risk compared to control. For major CMs, ethosuximide (OR, 3.04; 95% CrI, 1.23-7.07), valproate (OR, 2.93; 95% CrI, 2.36-3.69), topiramate (OR, 1.90; 95% CrI, 1.17-2.97), phenobarbital (OR, 1.83; 95% CrI, 1.35-2.47), phenytoin (OR, 1.67; 95% CrI, 1.30-2.17), carbamazepine (OR, 1.37; 95% CrI, 1.10-1.71), and 11 polytherapies were significantly more harmful than control, but lamotrigine (OR, 0.96; 95% CrI, 0.72-1.25) and levetiracetam (OR, 0.72; 95% CrI, 0.43-1.16) were not. CONCLUSION: The newer generation AEDs, lamotrigine and levetiracetam, were not associated with significant increased risks of CMs compared to control, and were significantly less likely to be associated with children experiencing cardiac malformations than control. However, this does not mean that these agents are not harmful to infants/children exposed in utero. Counselling is advised concerning teratogenic risks when the prescription is written for a woman of childbearing age and before women continue with these agents when considering pregnancy, such as switching from polytherapy to monotherapy with evidence of lower risk and avoiding AEDs, such as valproate, that are consistently associated with CMs. These decisions must be balanced against the need for seizure control. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014008925.

Comparisons of Interventions for Preventing Falls in Older Adults: A Systematic Review and Meta-analysis.

Importance: Falls result in substantial burden for patients and health care systems, and given the aging of the population worldwide, the incidence of falls continues to rise. Objective: To assess the potential effectiveness of interventions for preventing falls. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Ageline databases from inception until April 2017. Reference lists of included studies were scanned. Study Selection: Randomized clinical trials (RCTs) of fall-prevention interventions for participants aged 65 years and older. Data Extraction and Synthesis: Pairs of reviewers independently screened the studies, abstracted data, and appraised risk of bias. Pairwise meta-analysis and network meta-analysis were conducted. Main Outcomes and Measures: Injurious falls and fall-related hospitalizations. Results: A total of 283 RCTs (159 910 participants; mean age, 78.1 years; 74% women) were included after screening of 10 650 titles and abstracts and 1210 full-text articles. Network meta-analysis (including 54 RCTs, 41 596 participants, 39 interventions plus usual care) suggested that the following interventions, when compared with usual care, were associated with reductions in injurious falls: exercise (odds ratio [OR], 0.51 [95% CI, 0.33 to 0.79]; absolute risk difference [ARD], -0.67 [95% CI, -1.10 to -0.24]); combined exercise and vision assessment and treatment (OR, 0.17 [95% CI, 0.07 to 0.38]; ARD, -1.79 [95% CI, -2.63 to -0.96]); combined exercise, vision assessment and treatment, and environmental assessment and modification (OR, 0.30 [95% CI, 0.13 to 0.70]; ARD, -1.19 [95% CI, -2.04 to -0.35]); and combined clinic-level quality improvement strategies (eg, case management), multifactorial assessment and treatment (eg, comprehensive geriatric assessment), calcium supplementation, and vitamin D supplementation (OR, 0.12 [95% CI, 0.03 to 0.55]; ARD, -2.08 [95% CI, -3.56 to -0.60]). Pairwise meta-analyses for fall-related hospitalizations (2 RCTs; 516 participants) showed no significant association between combined clinic- and patient-level quality improvement strategies and multifactorial assessment and treatment relative to usual care (OR, 0.78 [95% CI, 0.33 to 1.81]). Conclusions and Relevance: Exercise alone and various combinations of interventions were associated with lower risk of injurious falls compared with usual care. Choice of fall-prevention intervention may depend on patient and caregiver values and preferences.

Seeking effective interventions to treat complex wounds: an overview of systematic reviews.

BACKGROUND: Numerous, often multi-faceted regimens are available for treating complex wounds, yet the evidence of these interventions is recondite across the literature. We aimed to identify effective interventions to treat complex wounds through an overview of systematic reviews. METHODS: MEDLINE (OVID interface, 1946 until October 26, 2012), EMBASE (OVID interface, 1947 until October 26, 2012), and the Cochrane Database of Systematic Reviews (Issue 10 of 12, 2012) were searched on October 26, 2012. Systematic reviews that examined adults receiving care for their complex wounds were included. Two reviewers independently screened the literature, abstracted data, and assessed study quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. RESULTS: Overall, 99 systematic reviews were included after screening 6,200 titles and abstracts and 422 full-texts; 54 were systematic reviews with a meta-analysis (including data on over 54,000 patients) and 45 were systematic reviews without a meta-analysis. Overall, 44% of included reviews were rated as being of high quality (AMSTAR score ≥ 8). Based on data from systematic reviews including a meta-analysis with an AMSTAR score ≥ 8, promising interventions for complex wounds were identified. These included bandages or stockings (multi-layer, high compression) and wound cleansing for venous leg ulcers; four-layer bandages for mixed arterial/venous leg ulcers; biologics, ultrasound, and hydrogel dressings for diabetic leg/foot ulcers; hydrocolloid dressings, electrotherapy, air-fluidized beds, and alternate foam mattresses for pressure ulcers; and silver dressings and ultrasound for unspecified mixed complex wounds. For surgical wound infections, topical negative pressure and vacuum-assisted closure were promising interventions, but this was based on evidence from moderate to low quality systematic reviews. CONCLUSIONS: Numerous interventions can be utilized for patients with varying types of complex wounds, yet few treatments were consistently effective across all outcomes throughout the literature. Clinicians and patients can use our results to tailor effective treatment according to type of complex wound. Network meta-analysis will be of benefit to decision-makers, as it will permit multiple treatment comparisons and ranking of the effectiveness of all interventions. Please see related article: http://dx.doi.org/10.1186/s12916-015-0326-3.

A systematic review of cost-effectiveness analyses of complex wound interventions reveals optimal treatments for specific wound types.

BACKGROUND: Complex wounds present a substantial economic burden on healthcare systems, costing billions of dollars annually in North America alone. The prevalence of complex wounds is a significant patient and societal healthcare concern and cost-effective wound care management remains unclear. This article summarizes the cost-effectiveness of interventions for complex wound care through a systematic review of the evidence base. METHODS: We searched multiple databases (MEDLINE, EMBASE, Cochrane Library) for cost-effectiveness studies that examined adults treated for complex wounds. Two reviewers independently screened the literature, abstracted data from full-text articles, and assessed methodological quality using the Drummond 10-item methodological quality tool. Incremental cost-effectiveness ratios were reported, or, if not reported, calculated and converted to United States Dollars for the year 2013. RESULTS: Overall, 59 cost-effectiveness analyses were included; 71% (42 out of 59) of the included studies scored 8 or more points on the Drummond 10-item checklist tool. Based on these, 22 interventions were found to be more effective and less costly (i.e., dominant) compared to the study comparators: 9 for diabetic ulcers, 8 for venous ulcers, 3 for pressure ulcers, 1 for mixed venous and venous/arterial ulcers, and 1 for mixed complex wound types. CONCLUSIONS: Our results can be used by decision-makers in maximizing the deployment of clinically effective and resource efficient wound care interventions. Our analysis also highlights specific treatments that are not cost-effective, thereby indicating areas of resource savings. Please see related article: http://dx.doi.org/10.1186/s12916-015-0288-5.

Mistletoe Extracts during the Oncological Perioperative Period: A Systematic Review and Meta-Analysis of Human Randomized Controlled Trials.

BACKGROUND: We aim to evaluate the safety and efficacy of mistletoe extract (ME) use during the oncological perioperative period. METHODS: Details registered a priori on PROSPERO (CRD42018086168). RESULTS: Seven RCTs (comprising 663 participants in nine reports) and three nonrandomized studies were included. In five RCTs, ME was evaluated as adjunctive care and the control group had no additional intervention, whereas in two RCTs, ME was compared head-to-head against common cancer treatments (i.e., etoposide or bacillus Calmette-Guérin) with the intervention groups not receiving standard care. Meta-analyses found no evidence for a difference between ME and no added therapy for mortality and recurrence (RR, 95% CI: 1.00, 0.79-1.27; and 1.03, 0.79-1.33, respectively). Two RCTs reported beneficial effects of ME on immune cells, specifically natural killer cells, in colorectal cancer, and one RCT reported quality of life improvement. Two RCTs reported ME discontinuations due to adverse events and grade 3/4 toxicities. Nevertheless, no safety signals were detected from these 10 studies. Quality appraisal revealed a substantial risk of bias. CONCLUSIONS: Preliminary data are encouraging for mistletoe extracts, particularly in the context of colorectal cancer. However, the evidence is limited by the number of studies, an evaluation of different outcomes, and methodological limitations. Further high-quality research is warranted.

What is the most appropriate knowledge synthesis method to conduct a review? Protocol for a scoping review.

BACKGROUND: A knowledge synthesis attempts to summarize all pertinent studies on a specific question, can improve the understanding of inconsistencies in diverse evidence, and can identify gaps in research evidence to define future research agendas. Knowledge synthesis activities in healthcare have largely focused on systematic reviews of interventions. However, a wider range of synthesis methods has emerged in the last decade addressing different types of questions (e.g., realist synthesis to explore mediating mechanisms and moderators of interventions). Many different knowledge synthesis methods exist in the literature across multiple disciplines, but locating these, particularly for qualitative research, present challenges. There is a need for a comprehensive manual for synthesis methods (quantitative/qualitative or mixed), outlining how these methods are related, and how to match the most appropriate knowledge synthesis method to answer a research question. The objectives of this scoping review are to: 1) conduct a systematic search of the literature for knowledge synthesis methods across multi-disciplinary fields; 2) compare and contrast the different knowledge synthesis methods; and, 3) map out the specific steps to conducting the knowledge syntheses to inform the development of a knowledge synthesis methods manual/tool. METHODS: We will search relevant electronic databases (e.g., MEDLINE, CINAHL), grey literature, and discipline-based listservs. The scoping review will consider all study designs including qualitative and quantitative methodologies (excluding economic analysis or clinical practice guideline development), and identify knowledge synthesis methods across the disciplines of health, education, sociology, and philosophy. Two reviewers will pilot-test the screening criteria and data abstraction forms, and will independently screen the literature and abstract the data. A three-step synthesis process will be used to map the literature to our objectives. DISCUSSION: This project represents the first attempt to broadly and systematically identify, define and classify knowledge synthesis methods (i.e., less traditional knowledge synthesis methods). We anticipate that our results will lead to an accepted taxonomy for less traditional knowledge synthesis methods, and to the development and implementation of a methods manual for these reviews which will be relevant to a wide range of knowledge users, including researchers, funders, and journal editors.

Suicide rates and suicidal behaviour in displaced people: A systematic review.

BACKGROUND: Refugees, and other forcibly displaced people, face mental distress and may be disproportionately affected by risk factors for suicide. Little is known about suicidal behaviour in these highly mobile populations because collecting timely, relevant, and reliable data is challenging. METHODS AND FINDINGS: A systematic review was performed to identify studies of any design reporting on suicide, suicide attempts, or suicidal ideation among populations of displaced people. A sensitive electronic database search was performed in August 2020, and all retrieved studies were screened for relevance by two authors. Studies were categorised by the population being evaluated: refugees granted asylum, refugees living in temporary camps, asylum seekers, or internally displaced people. We distinguished between whether the sampling procedure in the studies was likely to be representative, or the sample examined a specific non-representative subgroup of displaced people (such as those already diagnosed with mental illness). Data on the rates of suicide or the prevalence of suicide attempts or suicidal ideation were extracted by one reviewer and verified by a second reviewer from each study and converted to common metrics. After screening 4347 articles, 87 reports of 77 unique studies were included. Of these, 53 were studies in representative samples, and 24 were based on samples of specific target populations. Most studies were conducted in high-income countries, and the most studied population subgroup was refugees granted asylum. There was substantial heterogeneity across data sources and measurement instruments utilised. Sample sizes of displaced people ranged from 33 to 196,941 in studies using general samples. Suicide rates varied considerably, from 4 to 290 per 100,000 person-years across studies. Only 8 studies were identified that compared suicide rates with the host population. The prevalence of suicide attempts ranged from 0.14% to 15.1% across all studies and varied according to the prevalence period evaluated. Suicidal ideation prevalence varied from 0.17% to 70.6% across studies. Among refugees granted asylum, there was evidence of a lower risk of suicide compared with the host population in 4 of 5 studies. In contrast, in asylum seekers there was evidence of a higher suicide risk in 2 of 3 studies, and of a higher risk of suicidal ideation among refugees living in camps in 2 of 3 studies compared to host populations. CONCLUSION: While multiple studies overall have been published in the literature on this topic, the evidence base is still sparse for refugees in camps, asylum seekers, and internally displaced people. Less than half of the included studies reported on suicide or suicide attempt outcomes, with most reporting on suicidal ideation. International research networks could usefully define criteria, definitions, and study designs to help standardise and facilitate more research in this important area. REGISTRATION: PROSPERO CRD42019137242.

Searching for controlled trials of complementary and alternative medicine: a comparison of 15 databases.

This project aims to assess the utility of bibliographic databases beyond the three major ones (MEDLINE, EMBASE and Cochrane CENTRAL) for finding controlled trials of complementary and alternative medicine (CAM). Fifteen databases were searched to identify controlled clinical trials (CCTs) of CAM not also indexed in MEDLINE. Searches were conducted in May 2006 using the revised Cochrane highly sensitive search strategy (HSSS) and the PubMed CAM Subset. Yield of CAM trials per 100 records was determined, and databases were compared over a standardized period (2005). The Acudoc2 RCT, Acubriefs, Index to Chiropractic Literature (ICL) and Hom-Inform databases had the highest concentrations of non-MEDLINE records, with more than 100 non-MEDLINE records per 500. Other productive databases had ratios between 500 and 1500 records to 100 non-MEDLINE records-these were AMED, MANTIS, PsycINFO, CINAHL, Global Health and Alt HealthWatch. Five databases were found to be unproductive: AGRICOLA, CAIRSS, Datadiwan, Herb Research Foundation and IBIDS. Acudoc2 RCT yielded 100 CAM trials in the most recent 100 records screened. Acubriefs, AMED, Hom-Inform, MANTIS, PsycINFO and CINAHL had more than 25 CAM trials per 100 records screened. Global Health, ICL and Alt HealthWatch were below 25 in yield. There were 255 non-MEDLINE trials from eight databases in 2005, with only 10% indexed in more than one database. Yield varied greatly between databases; the most productive databases from both sampling methods were Acubriefs, Acudoc2 RCT, AMED and CINAHL. Low overlap between databases indicates comprehensive CAM literature searches will require multiple databases.

Probiotics Evaluation in Oncological Surgery: A Systematic Review of 36 Randomized Controlled Trials Assessing 21 Diverse Formulations.

BACKGROUND: Objectives were to evaluate probiotics safety and efficacy in oncological surgery. METHODS: Systematic review methodology guided by Cochrane, PRISMA, SWiM, and CIOMS. Protocol registered on PROSPERO (CRD42018086168). RESULTS: 36 RCTs (on 3305 participants) and 6 nonrandomized/observational studies were included, mainly on digestive system cancers. There was evidence of a beneficial effect on preventing infections, with 70% of RCTs' (21/30) direction of effect favoring probiotics. However, five RCTs (17%) favored controls for infections, including one trial with RR 1.57 (95% CI: 0.79, 3.12). One RCT that changed (balanced) its antibiotics protocol after enrolling some participants had mortality risk RR 3.55 (95% CI: 0.77, 16.47; 7/64 vs. 2/65 deaths). The RCT identified with the most promising results overall administered an oral formulation of Lactobacillus acidophilus LA-5 + Lactobacillus plantarum + Bifidobacterium lactis BB-12 + Saccharomyces boulardii. Methodological quality appraisals revealed an overall substantial risk-of-bias, with only five RCTs judged as low risk-of-bias. CONCLUSIONS: This large evidence synthesis found encouraging results from most formulations, though this was contrasted by potential harms from a few others, thus validating the literature that "probiotics" are not homogeneous microorganisms. Given microbiome developments and infections morbidity, further high-quality research is warranted using those promising probiotics identified herein.

Are Supplemental Branched-Chain Amino Acids Beneficial During the Oncological Peri-Operative Period: A Systematic Review and Meta-Analysis.

BACKGROUND: Branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) are essential amino acids involved in immune responses, and may have roles in protein malnutrition and sarcopenia. Furthermore, certain liver diseases have been associated with a decreased Fischer's ratio (BCAAs to aromatic amino acids; phenylalanine, tyrosine, and tryptophan). We aimed to evaluate the safety and efficacy of BCAAs use in patients with cancer undergoing surgery. METHODS: MEDLINE, Embase, and CENTRAL were searched (inception to July 24, 2020) for randomized controlled trials (RCTs) and comparative observational studies in English evaluating BCAAs (alone or in combinations) during the oncological peri-operative period. Study selection, data extraction, and quality appraisal were done in duplicate. RCT risk-of-bias was appraised using Cochrane Risk-of-Bias tool, and observational studies' quality assessment was conducted with Newcastle-Ottawa Scale. Meta-analyses were conducted when appropriate. RESULTS: 20 articles were included comprising 13 RCTs and 6 observational cohort studies in 7 reports and 2019 total participants overall. Among 13 RCTs, 77% involved liver cancer. Methodological study quality scored substantial risk-of-bias across most RCTs. Meta-analysis of RCTs found a 38% decreased risk of post-operative infections in BCAAs group compared to controls (RR = 0.62; 95% CI = 0.44 to 0.87; P = .006; number of RCTs, k = 6; total sample size, N = 389; I2 = 0%). BCAAs were also found to be beneficial for ascites (RR = 0.55; 95% CI = 0.35 to 0.86; P = .008; k = 4; N = 296; I2 = 0%), body weight (MD = 3.24 kg; 95% CI = 0.44 to 6.04; P = .02; k = 3; N = 196; I2 = 24%), and hospitalization length (MD = -2.07 days; 95% CI = -3.97 to -0.17; P = .03; k = 5; N = 362; I2 = 59%). No differences were found between BCAAs and controls for mortality, recurrence, other post-operative complications (liver failure, edema, pleural effusion), blood loss, quality of life, ammonia level, and prothrombin time. No serious adverse events were related to BCAAs; however, serious adverse events were reported due to intravenous catheters. No safety concerns from observational studies were identified. CONCLUSIONS: Branched-chain amino acids during the oncological surgical period demonstrated promise in reducing important post-operative morbidity from infections and ascites compared to controls. Blinded, placebo-controlled confirmatory trials of higher methodological quality are warranted, especially using oral, short-term BCAAs-enriched supplements within the context of recent ERAS programs. PROSPERO REGISTRATION: CRD42018086168.

Comparative effectiveness of exercise interventions for preventing falls in older adults: A secondary analysis of a systematic review with network meta-analysis.

BACKGROUND: Systematic reviews have established that exercise reduces falls in older adults, however the most effective types of exercise are not known. This secondary analysis determined the comparative effectiveness of fall prevention exercise approaches. METHOD: All fall prevention exercise interventions for older adults were identified from an existing search from inception until April 2017. Interventions were coded using a framework of 25 exercise types. Two reviewers independently screened studies, extracted data, and appraised risk of bias. Pairwise meta-analysis and network meta-analysis (NMA) were conducted. P-scores were used to rank exercise combinations. RESULTS: One hundred and sixty-nine studies were included. NMA was conducted on 73 studies (30,697 participants) for the outcome of number of fallers. The exercise combination ranked with the greatest likelihood of being most effective relative to no exercise was: anticipatory control, dynamic stability, functional stability limits, reactive control and flexibility (p-score = 0.95). This exercise combination also significantly reduced number of fallers compared to 16 other combinations. No exercise combination had a significantly greater effect on reducing number of fallers more than this combination. CONCLUSION: This analysis identified components of effective fall prevention exercise. The results can inform evidence-informed exercise recommendations and be used to design effective programs.

A rapid evidence-based service by librarians provided information to answer primary care clinical questions.

BACKGROUND: A librarian consultation service was offered to 88 primary care clinicians during office hours. This included a streamlined evidence-based process to answer questions in fewer than 20 min. This included a contact centre accessed through a Web-based platform and using hand-held devices and computers with Web access. Librarians were given technical training in evidence-based medicine, including how to summarise evidence. OBJECTIVES: To describe the process and lessons learned from developing and operating a rapid response librarian consultation service for primary care clinicians. METHODS: Evaluation included librarian interviews and a clinician exit satisfaction survey. RESULTS: Clinicians were positive about its impact on their clinical practice and decision making. The project revealed some important 'lessons learned' in the clinical use of hand-held devices, knowledge translation and training for clinicians and librarians. CONCLUSIONS: The Just-in-Time Librarian Consultation Service showed that it was possible to provide evidence-based answers to clinical questions in 15 min or less. The project overcame a number of barriers using innovative solutions. There are many opportunities to build on this experience for future joint projects of librarians and healthcare providers.

No consensus exists on search reporting methods for systematic reviews.

OBJECTIVES: The reporting of the search methods used in systematic reviews has implications for how systematic reviews are critically appraised, their reproducibility and how easily they may be updated. The objective of this paper was to identify validated or evaluated search reporting instruments used in reporting systematic review searches and to compare reported and recommended searching practices. STUDY DESIGN AND SETTING: This cohort study was a systematic review. The search strategy to identify instruments addressing the reporting of search strategies was developed first in the Library & Information Science Abstracts (LISAs) database and then adapted for MEDLINE and five additional databases. Additional instruments were identified through experts. Current reporting practice data were analyzed from a cohort of 297 recent systematic reviews. RESULTS: Of the 11 instruments examined, 7 cited supporting evidence but only 4 were validated. Eighteen different reporting items were identified but only one item, "databases used," appeared in all instruments. There was a trend toward including more items in more recent instruments (r=0.41). Current search reporting practices ranged from a high of 98.7% for databases used to a low of 11.4% for qualifications of the searcher. CONCLUSIONS: There is no clear consensus regarding optimum reporting of systematic review search methods and commonly recommended items show suboptimal reporting.

Few systematic reviews exist documenting the extent of bias: a systematic review.

OBJECTIVE: To summarize the evidence concerning bias and confounding in conducting systematic reviews (SRs). STUDY DESIGN AND SETTING: Literature was identified through searching the Cochrane Library, MEDLINE, PsycINFO until November 2006, and the authors' files. Studies were included if they were SRs of bias that can occur while conducting a SR. Risk of bias in the SRs was appraised using the Oxman and Guyatt index. RESULTS: Ten SRs were included. All examined biases related to searching for evidence (e.g., publication bias). One also reported bias associated with obtaining data from included studies (e.g., outcome reporting bias). To minimize bias, data suggest including unpublished material, hand searching for additional material, searching multiple databases, assessing for publication bias, and periodically updating SRs. No SRs were found examining biases related to choosing studies for inclusion or combining studies. CONCLUSIONS: There is little evidence from SRs to support commonly practiced methods for conducting SRs. No SRs summarized studies with prospective designs and most had moderate or minimal risk of bias. Future research should examine bias that can occur during the selection of studies for inclusion and the synthesis of studies, as well as systematically review the existing empirical evidence.

Scoping review identifies significant number of knowledge translation theories, models, and frameworks with limited use.

OBJECTIVES: To conduct a scoping review of knowledge translation (KT) theories, models, and frameworks that have been used to guide dissemination or implementation of evidence-based interventions targeted to prevention and/or management of cancer or other chronic diseases. STUDY DESIGN AND SETTING: We used a comprehensive multistage search process from 2000 to 2016, which included traditional bibliographic database searching, searching using names of theories, models and frameworks, and cited reference searching. Two reviewers independently screened the literature and abstracted the data. RESULTS: We found 596 studies reporting on the use of 159 KT theories, models, or frameworks. A majority (87%) of the identified theories, models, or frameworks were used in five or fewer studies, with 60% used once. The theories, models, and frameworks were most commonly used to inform planning/design, implementation and evaluation activities, and least commonly used to inform dissemination and sustainability/scalability activities. Twenty-six were used across the full implementation spectrum (from planning/design to sustainability/scalability) either within or across studies. All were used for at least individual-level behavior change, whereas 48% were used for organization-level, 33% for community-level, and 17% for system-level change. CONCLUSION: We found a significant number of KT theories, models, and frameworks with a limited evidence base describing their use.

Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis.

OBJECTIVES: Compare the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding. DESIGN AND SETTING: Systematic review and Bayesian random-effects network meta-analysis (NMA). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched until 27 April 2017. Screening, data abstraction and quality appraisal were completed in duplicate by independent reviewers. PARTICIPANTS: 29 cohort studies including 5100 infants/children. INTERVENTIONS: Monotherapy and polytherapy AEDs including first-generation (carbamazepine, clobazam, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproate) and newer-generation (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin) AEDs. Epileptic women who did not receive AEDs during pregnancy or breast feeding served as the control group. PRIMARY AND SECONDARY OUTCOME MEASURES: Cognitive developmental delay and autism/dyspraxia were primary outcomes. Attention-deficit hyperactivity disorder, language delay, neonatal seizures, psychomotor developmental delay and social impairment were secondary outcomes. RESULTS: The NMA on cognitive developmental delay (11 cohort studies, 933 children, 18 treatments) suggested that among all AEDs only valproate was statistically significantly associated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46). The NMA on autism (5 cohort studies, 2551 children, 12 treatments) suggested that oxcarbazepine (OR 13.51, CrI 1.28 to 221.40), valproate (OR 17.29, 95% CrI 2.40 to 217.60), lamotrigine (OR 8.88, CrI 1.28 to 112.00) and lamotrigine+valproate (OR 132.70, CrI 7.41 to 3851.00) were associated with significantly greater odds of developing autism compared with control. The NMA on psychomotor developmental delay (11 cohort studies, 1145 children, 18 treatments) found that valproate (OR 4.16, CrI 2.04 to 8.75) and carbamazepine+phenobarbital+valproate (OR 19.12, CrI 1.49 to 337.50) were associated with significantly greater odds of psychomotor delay compared with control. CONCLUSIONS: Valproate alone or combined with another AED is associated with the greatest odds of adverse neurodevelopmental outcomes compared with control. Oxcarbazepine and lamotrigine were associated with increased occurrence of autism. Counselling is advised for women considering pregnancy to tailor the safest regimen. TRIAL REGISTRATION NUMBER: PROSPERO database (CRD42014008925).

National programmes for validating physician competence and fitness for practice: a scoping review.

OBJECTIVE: To explore and categorise the state of existing literature for national programmes designed to affirm or establish the continuing competence of physicians. DESIGN: Scoping review. DATA SOURCES: MEDLINE, ERIC, Sociological Abstracts, web/grey literature (2000-2014). SELECTION: Included when a record described a (1) national-level physician validation system, (2) recognised as a system for affirming competence and (3) reported relevant data. DATA EXTRACTION: Using bibliographic software, title and abstracts were reviewed using an assessment matrix to ensure duplicate, paired screening. Dyads included both a methodologist and content expert on each assessment, reflective of evidence-informed best practices to decrease errors. RESULTS: 45 reports were included. Publication dates ranged from 2002 to 2014 with the majority of publications occurring in the previous six years (n=35). Country of origin--defined as that of the primary author--included the USA (N=32), the UK (N=8), Canada (N=3), Kuwait (N=1) and Australia (N=1). Three broad themes emerged from this heterogeneous data set: contemporary national programmes, contextual factors and terminological consistency. Four national physician validation systems emerged from the data: the American Board of Medical Specialties Maintenance of Certification Program, the Federation of State Medical Boards Maintenance of Licensure Program, the Canadian Revalidation Program and the UK Revalidation Program. Three contextual factors emerged as stimuli for the implementation of national validation systems: medical regulation, quality of care and professional competence. Finally, great variation among the definitions of key terms was identified. CONCLUSIONS: There is an emerging literature focusing on national physician validation systems. Four major systems have been implemented in recent years and it is anticipated that more will follow. Much of this work is descriptive, and gaps exist for the extent to which systems build on current evidence or theory. Terminology is highly variable across programmes for validating physician competence and fitness for practice.

PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement.

OBJECTIVE: To develop an evidence-based guideline for Peer Review of Electronic Search Strategies (PRESS) for systematic reviews (SRs), health technology assessments, and other evidence syntheses. STUDY DESIGN AND SETTING: An SR, Web-based survey of experts, and consensus development forum were undertaken to identify checklists that evaluated or validated electronic literature search strategies and to determine which of their elements related to search quality or errors. RESULTS: Systematic review: No new search elements were identified for addition to the existing (2008-2010) PRESS 2015 Evidence-Based Checklist, and there was no evidence refuting any of its elements. Results suggested that structured PRESS could identify search errors and improve the selection of search terms. Web-based survey of experts: Most respondents felt that peer review should be undertaken after the MEDLINE search had been prepared but before it had been translated to other databases. Consensus development forum: Of the seven original PRESS elements, six were retained: translation of the research question; Boolean and proximity operators; subject headings; text word search; spelling, syntax and line numbers; and limits and filters. The seventh (skilled translation of the search strategy to additional databases) was removed, as there was consensus that this should be left to the discretion of searchers. An updated PRESS 2015 Guideline Statement was developed, which includes the following four documents: PRESS 2015 Evidence-Based Checklist, PRESS 2015 Recommendations for Librarian Practice, PRESS 2015 Implementation Strategies, and PRESS 2015 Guideline Assessment Form. CONCLUSION: The PRESS 2015 Guideline Statement should help to guide and improve the peer review of electronic literature search strategies.