Informing pandemic management in Germany with trustworthy, living evidence syntheses and guideline development: Lessons learned from the COVID-19 evidence ecosystem (CEOsys).

OBJECTIVE: We present the 'COVID-19 evidence ecosystem' (CEOsys) as a German network to inform pandemic management and to support clinical and public health decision-making. We discuss challenges faced when organizing the ecosystem and derive lessons learned for similar networks acting during pandemics or health-related crises. STUDY DESIGN AND SETTING: Bringing together 18 university hospitals and additional institutions, CEOsys key activities included research prioritization, conducting living systematic reviews, supporting evidence-based (living) guidelines, knowledge translation, detecting research gaps and deriving recommendations, backed by technical infrastructure and capacity building. RESULTS: CEOsys rapidly produced 31 high-quality evidence syntheses and supported three living guidelines on COVID-19-related topics, while also developing methodological procedures. Challenges included CEOsys' late initiation in relation to the pandemic outbreak, the delayed prioritization of research questions, the continuously evolving COVID-19-related evidence, and establishing a technical infrastructure. Methodological-clinical tandems, the cooperation with national guideline groups and international collaborations were key for efficiency. CONCLUSION: CEOsys provided a proof-of-concept for a functioning evidence ecosystem at the national level. Lessons learned include that similar networks should, among others, involve methodological and clinical key stakeholders early on, aim for (inter-)national collaborations, and systematically evaluate their value. We particularly call for a sustainable network.

Clinical and methodological implications for research elements in systematic reviews on COVID-19 treatment were often unstructured and under-reported: a metaresearch study.

OBJECTIVES: Numerous systematic reviews (SRs) have been published in the first months of the COVID-19 pandemic and clinical trials were designed rapidly highlighting the importance of informative implications for research (IfRs) sections in SRs. IfR is one item of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 checklist and the Cochrane Handbook suggests considering population, intervention, control, outcome (PICO) and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) domains when developing IfR. We aimed (1) to assess whether SRs on COVID-19 treatments included any IfR statements and, for SRs with an IfR statement, (2) to examine which elements informed the IfR statement. STUDY DESIGN AND SETTING: We conducted a metaresearch study based on SRs on COVID-19 treatment identified in the Living OVerview of the Evidence COVID-19 database in May 2021 as part of another research project (CRD42021240423). We defined an IfR statement as at least one sentence that contained at least one bit of information that could be informative for planning future research. We extracted any IfR statements anywhere in the SRs on predefined IfR variables, in particular PICO elements, study design, and concepts underlying GRADE domains. Three authors extracted data independently after piloting the data extraction form. We resolved discrepancies in weekly discussions to ensure a high-quality data extraction. RESULTS: We included 326 SRs, of which 284 SRs (87.1%) stated IfR. Of these 284 SRs, 201 (70.8%) reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses and 66 (23.2%) using GRADE. IfR statements (n = 284) addressing PICO were unstructured and commonly reported 'population' (n = 195, 68.7%), 'intervention' (n = 242, 85.2%), and 'outcome' (n = 127, 44.7%) but not 'control' (n = 29, 10.2%). Concepts underlying GRADE domains were infrequently reported in IfR statements of SRs (n = 284): 'risk of bias' (n = 14, 4.9%), 'imprecision' (n = 8, 2.8%), 'inconsistency' (n = 7, 2.5%), 'publication bias' (n = 3, 1.1%), and 'indirectness' (n = 1, 0.4%). Additional IfR elements mentioned in IfR were 'better reporting' of future studies (n = 17, 6.0%) and 'standardization of procedures in clinical trials' (n = 12, 4.2%). CONCLUSION: Almost 90% of SRs on COVID-19 treatments reported IfR. IfR statements addressing PICO were unstructured across SRs and concepts underlying GRADE were rarely reported to inform IfR. Further work is needed to assess generalizability beyond COVID-19 and to define more precisely which IfR elements should be considered, and how they should be reported in SRs of interventions. Until then, considering PICO elements and concepts underlying GRADE to derive IfR seems to be a sensible starting point.

Computer-Assisted Visual Training in Children and Adolescents with Developmental Visual Disorders.

BACKGROUND: In this systematic review, we address the question whether children and adolescents with developmental visual disorders benefit from computer-assisted visual training. METHODS: Systematic literature searches were carried out in three bibliographic databases (initial search in October 2021) and trial registries. Included were randomized controlled trials that evaluated the efficacy of computer-assisted visual training in children and adolescents with developmental visual disorders in comparison to no training, sham training, or conservative treatment. RESULTS: The inclusion criteria were met by 17 trials (with a total of 1323 children and adolescents) focusing on binocular or monocular computer-assisted visual training for the treatment of amblyopia. In these trials, visual training was carried out for 2 to 24 weeks, either as "stand alone" therapy or in addition to occlusion therapy. Six trials showed a statistically significant difference in favor of the visual training for the outcome "best corrected visual acuity of the amblyopic eye." However, this difference was small and mostly below the threshold of clinical relevance of -0.05 logMAR (equivalent to an improvement of 0.5 lines on the eye chart, or 2.5 letters per line). Only few data were available for the outcomes "binocular vision" and "adverse events"; the differences between the groups were similarly small. CONCLUSION: The currently available data do not permit any firm conclusions regarding the efficacy of visual training in children and adolescents with amblyopia. Moreover, treatment adherence was often insufficient and the treatment durations in the trials was relatively short. No results from randomized trials have yet been published with respect to other developmental visual disorders (refractive errors, strabismus).

A Machine Learning Framework Reduces the Manual Workload for Systematic Reviews of the Diagnostic Performance of Prostate Magnetic Resonance Imaging.

Prostate magnetic resonance imaging has become the imaging standard for prostate cancer in various clinical settings, with interpretation standardized according to the Prostate Imaging Reporting and Data System (PI-RADS). Each year, hundreds of scientific studies that report on the diagnostic performance of PI-RADS are published. To keep up with this ever-increasing evidence base, systematic reviews and meta-analyses are essential. As systematic reviews are highly resource-intensive, we investigated whether a machine learning framework can reduce the manual workload and speed up the screening process (title and abstract). We used search results from a living systematic review of the diagnostic performance of PI-RADS (1585 studies, of which 482 were potentially eligible after screening). A naïve Bayesian classifier was implemented in an active learning environment for classification of the titles and abstracts. Our outcome variable was the percentage of studies that can be excluded after 95% of relevant studies have been identified by the classifier (work saved over sampling: WSS@95%). In simulation runs of the entire screening process (controlling for classifier initiation and the frequency of classifier updating), we obtained a WSS@95% value of 28% (standard error of the mean ±0.1%). Applied prospectively, our classification framework would translate into a significant reduction in manual screening effort. Patient summary: Systematic reviews of scientific evidence are labor-intensive and take a lot of time. For example, many studies on prostate cancer diagnosis via MRI (magnetic resonance imaging) are published every year. We describe the use of machine learning to reduce the manual workload in screening search results. For a review of MRI for prostate cancer diagnosis, this approach reduced the screening workload by about 28%.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

Acupuncture in management of acute dental pain - A systematic review and meta-analysis.

Acute dental pain is a common issue leading to dental consultation. Besides causal therapy, patients are treated with acupuncture, but efficacy in acute dental pain is still not clarified. We aimed to evaluate results of recent research to estimate the efficacy of acupuncture compared to pain-relieving approaches in treatment of acute dental pain. A systematic review of controlled trials being published between database inception and 2020 were conducted to evaluate the efficacy of acupuncture (alone or as complementary therapy) compared to local anesthesia or conventional analgesic medications in acute dental pain (intraoperatively and postoperatively) and to clarify whether acupuncture reduces the use of postoperative analgesic medications. Of 1672 publications, 23 publications met the inclusion criteria. From these, 11 randomized controlled trials (n = 668) reported on the efficacy of acupuncture on postoperative acute dental pain. Patients, who received acupuncture, showed lower pain scores postoperatively compared to sham acupuncture (Relative Risk -0.77, 95% Confidence interval -1.52 to -0.03). Overall, the results suggest a potential role of acupuncture in improving acute dental pain intraoperatively and postoperatively as well as improving the efficacy of local anesthesia, but the results are limited due to methodological shortcomings emphasizing the necessity for future high-quality research.

Self-management in adults after solid-organ transplantation: a scoping review protocol.

INTRODUCTION: After solid-organ transplantation (SOTx), recipients must adhere to a lifelong medical regimen, change their lifestyle and cope with physiological and psychosocial challenges. This requires active participation in their care and self-management abilities. The concept of self-management after SOTx has only been described regarding specific organs and focused on adherence to medical treatment. A comprehensive conceptualisation of self-management entailing all solid organs and beyond medical aspects does not exist. This might lead to unmet self-management support needs of SOTx recipients and hinder a more holistic and integrative approach in self-management support. Therefore, a better understanding of the concept of self-management after SOTx is needed to facilitate a comprehensive evidence base for healthcare providers and researchers. The purpose of this scoping review is to explore existing evidence on self-management in adults after SOTx. METHODS AND ANALYSIS: To identify relevant evidence, six electronic databases and three study registers will be searched, supplemented by handsearches, reference checking and expert recommendations. Screening and selection of available evidence will be carried out in a two-step process by two independent reviewers. International evidence published in English or German reporting on adults after heart, lung, liver, pancreas, kidney or small bowel transplantation will be considered. To meet inclusion criteria, articles have to focus on either: self-management, self-management support or recipients' or healthcare providers' perspectives of challenges and needs potentially addressable by self-management. Data extraction will be performed by two reviewers independently using a structured form. Data will be analysed descriptively and using content analysis procedures. Findings will be summarised narratively and presented in tabular format. ETHICS AND DISSEMINATION: The consultation and approval of an ethics committee is not required for this scoping review. Findings of the scoping review will be published in a peer-reviewed open-access journal and presented at conferences.

Women's attitudes towards a human papillomavirus-based cervical cancer screening strategy: a systematic review.

OBJECTIVE: To provide insights into women's attitudes towards a human papillomavirus (HPV)-based cervical cancer screening strategy. DATA SOURCES: Medline, Web of Science Core Collection, Cochrane Library, PsycINFO, CINAHL and ClinicalTrials.gov were systematically searched for published and ongoing studies (last search conducted in August 2021). METHODS OF STUDY SELECTION: The search identified 3162 references. Qualitative and quantitative studies dealing with women's attitudes towards, and acceptance of, an HPV-based cervical cancer screening strategy in Western healthcare systems were included. For data analysis, thematic analysis was used and synthesised findings were presented descriptively. TABULATION, INTEGRATION, AND RESULTS: Twelve studies (including 9928 women) from USA, Canada, UK and Australia met the inclusion criteria. Women's attitudes towards HPV-based screening strategies were mainly affected by the understanding of (i) the personal risk of an HPV infection, (ii) the implication of a positive finding and (iii) the overall screening purpose. Women who considered their personal risk of HPV to be low and women who feared negative implications of a positive finding were more likely to express negative attitudes, whereas positive attitudes were particularly expressed by women understanding the screening purpose. Overall acceptance of an HPV-based screening strategy ranged between 13% and 84%. CONCLUSION: This systematic review provides insights into the attitudes towards HPV-based cervical cancer screening and its acceptability based on studies conducted with women from USA, Canada, UK and Australia. This knowledge is essential for the development of education and information strategies to support the implementation of HPV-based cervical cancer screening. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42020178957).

Living systematic review and meta-analysis of the prostate MRI diagnostic test with Prostate Imaging Reporting and Data System (PI-RADS) assessment for the detection of prostate cancer: study protocol.

INTRODUCTION: The Prostate Imaging Reporting and Data System (PI-RADS) standardises reporting of prostate MRI for the detection of clinically significant prostate cancer. We provide the protocol of a planned living systematic review and meta-analysis for (1) diagnostic accuracy (sensitivity and specificity), (2) cancer detection rates of assessment categories and (3) inter-reader agreement. METHODS AND ANALYSIS: Retrospective and prospective studies reporting on at least one of the outcomes of interest are included. Each step that requires literature evaluation and data extraction is performed by two independent reviewers. Since PI-RADS is intended as a living document itself, a 12-month update cycle of the systematic review and meta-analysis is planned.This protocol is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocols statement. The search strategies including databases, study eligibility criteria, index and reference test definitions, outcome definitions and data analysis processes are detailed. A full list of extracted data items is provided.Summary estimates of sensitivity and specificity (for PI-RADS ≥3 and PI-RADS ≥4 considered positive) are derived with bivariate binomial models. Summary estimates of cancer detection rates are calculated with random intercept logistic regression models for single proportions. Summary estimates of inter-reader agreement are derived with random effects models. ETHICS AND DISSEMINATION: No original patient data are collected, ethical review board approval, therefore, is not necessary. Results are published in peer-reviewed, open-access scientific journals. We make the collected data accessible as supplemental material to guarantee transparency of results. PROSPERO REGISTRATION NUMBER: CRD42022343931.

Three out of four published systematic reviews on COVID-19 treatments were not registered and one-third of those registered were published: a meta-research study.

OBJECTIVES: The aim of this study is to describe (1) registered and (2) published systematic reviews (SRs) on COVID-19 treatments, and to analyze (3) the proportion of publications among registered SRs and (4) the proportion of registrations among published SRs. STUDY DESIGN AND SETTING: This meta-research study (CRD42021240423) is part of CEOsys (http://www.covid-evidenz.de/). Two reviewers identified protocols in PROSPERO (registered January 2020 to September 2020) and SRs published as preprint or peer-reviewed article in L·OVE (Living OVerview of the Evidence) COVID-19 (by May 2021). SRs of all types assessing COVID-19 treatments in humans were included. RESULTS: We included 239 PROSPERO protocols and 346 SRs published in L·OVE. In both samples, the affiliation of the corresponding author with an Asian institution, standard SR as review type, and meta-analysis as synthesis method were the most frequent characteristics. Living SRs made up ≤10%. A total of 71 of 239 (29.7%) PROSPERO protocols were published as SR by February 2022, that is, after at least 17 months of follow-up (25 of 71 as preprints, 35.2%). In L·OVE, 261 of 346 (75.4%) SRs published by May 2021 were not registered in PROSPERO. CONCLUSION: Overall, one-third PROSPERO protocols were published and three-fourth published SRs were not registered. We strongly encourage authors to register and publish their SRs promptly to reduce research waste and to allocate resources efficiently during the pandemic and beyond.

Fluvoxamine for the treatment of COVID-19.

BACKGROUND: Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has been approved for the treatment of depression, obsessive-compulsive disorder, and a variety of anxiety disorders; it is available as an oral preparation. Fluvoxamine has not been approved for the treatment of infections, but has been used in the early treatment of people with mild to moderate COVID-19. As there are only a few effective therapies for people with COVID-19 in the community, a thorough understanding of the current evidence regarding the efficacy and safety of fluvoxamine as an anti-inflammatory and possible anti-viral treatment for COVID-19, based on randomised controlled trials (RCTs), is needed. OBJECTIVES: To assess the efficacy and safety of fluvoxamine in addition to standard care, compared to standard care (alone or with placebo), or any other active pharmacological comparator with proven efficacy for the treatment of COVID-19 outpatients and inpatients. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (including Cochrane Central Register of Controlled Trials, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv), Web of Science and WHO COVID-19 Global literature on COVID-19 to identify completed and ongoing studies up to 1 February 2022. SELECTION CRITERIA: We included RCTs that compared fluvoxamine in addition to standard care (also including no intervention), with standard care (alone or with placebo), or any other active pharmacological comparator with proven efficacy in clinical trials for the treatment of people with confirmed COVID-19, irrespective of disease severity, in both inpatients and outpatients. Co-interventions needed to be the same in both study arms. We excluded studies comparing fluvoxamine to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed risk of bias of primary outcomes using the Cochrane Risk of Bias 2 tool for RCTs. We used GRADE to rate the certainty of evidence to treat people with asymptomatic to severe COVID-19 for the primary outcomes including mortality, clinical deterioration, clinical improvement, quality of life, serious adverse events, adverse events of any grade, and suicide or suicide attempt. MAIN RESULTS: We identified two completed studies with a total of 1649 symptomatic participants. One study was conducted in the USA (study with 152 participants, 80 and 72 participants per study arm) and the other study in Brazil (study with 1497 high-risk participants for progression to severe disease, 741 and 756 participants per study arm) among outpatients with mild COVID-19. Both studies were double-blind, placebo-controlled trials in which participants were prescribed 100 mg fluvoxamine two or three times daily for a maximum of 15 days. We identified five ongoing studies and two studies awaiting classification (due to translation issues, and due to missing published data). We found no published studies comparing fluvoxamine to other pharmacological interventions of proven efficacy. We assessed both included studies to have an overall high risk of bias. Fluvoxamine for the treatment of COVID-19 in inpatients We did not identify any completed studies of inpatients. Fluvoxamine for the treatment of COVID-19 in outpatients Fluvoxamine in addition to standard care may slightly reduce all-cause mortality at day 28 (RR 0.69, 95% CI 0.38 to 1.27; risk difference (RD) 9 per 1000; 2 studies, 1649 participants; low-certainty evidence), and may reduce clinical deterioration defined as all-cause hospital admission or death before hospital admission (RR 0.55, 95% CI 0.16 to 1.89; RD 57 per 1000; 2 studies, 1649 participants; low-certainty evidence). We are very uncertain regarding the effect of fluvoxamine on serious adverse events (RR 0.56, 95% CI 0.15 to 2.03; RD 54 per 1000; 2 studies, 1649 participants; very low-certainty evidence) or adverse events of any grade (RR 1.06, 95% CI 0.82 to 1.37; RD 7 per 1000; 2 studies, 1649 participants; very low-certainty evidence). Neither of the studies reported on symptom resolution (clinical improvement), quality of life or suicide/suicide attempt. AUTHORS' CONCLUSIONS: Based on a low-certainty evidence, fluvoxamine may slightly reduce all-cause mortality at day 28, and may reduce the risk of admission to hospital or death in outpatients with mild COVID-19. However, we are very uncertain regarding the effect of fluvoxamine on serious adverse events, or any adverse events. In accordance with the living approach of this review, we will continually update our search and include eligible trials as they arise, to complete any gaps in the evidence.

Characteristics of registered and published systematic reviews focusing on the prevention of COVID-19: a meta-research study.

OBJECTIVE: We investigated characteristics of systematic reviews (SRs) assessing measures to prevent COVID-19 by (1) identifying SR registrations in Prospective Register of Systematic Reviews (PROSPERO), (2) identifying published SRs in COVID-19 Living Overview of the Evidence (L-OVE) and (3) estimating the proportion of PROSPERO registrations published as full SR between 8 and 16 months after registration. STUDY DESIGN: This meta-research study is part of the German CEOsys project, www.covid-evidenz.de. We searched PROSPERO entries registered between 1 January 2020 and 31 August 2020, and we searched COVID-19 L-OVE for published SRs (search date: 5 May 2021) focusing on measures to prevent COVID-19 and SARS-CoV-2 transmission. The two samples were screened for eligibility and key characteristics were extracted and summarised. RESULTS: Of 612 PROSPERO registrations, 47 focused on prevention and were included. The preventive measures included public health interventions (20), followed by personal protective equipment (10), vaccinations (9) and others (8). In total, 13 of 47 (28%) PROSPERO registrations had been published as full SR (as preprint only (6), as peer-reviewed article only (6), as preprint and peer-reviewed article (1)). Median time between PROSPERO registration and publication was 5 months for peer-reviewed SRs and 2 months for preprints.Of the 2182 entries identified in COVID-19 L-OVE, 51 published SRs focused on prevention and were included. Similar to the PROSPERO sample, most published SRs focused on public health interventions (21). The number of included primary studies ranged between 0 and 64 (median: 7). Nine published SRs did not include any studies because of a lack of primary studies. CONCLUSION: Considering the urgent information needs of policymakers and the public, our findings reveal the high-speed publication of preprints and lack of primary studies in the beginning of the COVID-19 crisis. Further meta-research on COVID-19 SRs is important to improve research efficiency among researchers across the world. PROSPERO REGISTRATION NUMBER: CRD42021240423.

Assessing severe acute respiratory syndrome coronavirus 2 infectivity by reverse-transcription polymerase chain reaction: A systematic review and meta-analysis.

The cornerstone of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is reverse-transcription polymerase chain reaction (RT-PCR) of viral RNA. As a surrogate assay SARS-CoV-2 RNA detection does not necessarily imply infectivity. Only virus isolation in permissive cell culture systems can indicate infectivity. Here, we review the evidence on RT-PCR performance in detecting infectious SARS-CoV-2. We searched for any studies that used RT-PCR and cell culture to determine infectious SARS-CoV-2 in respiratory samples. We assessed (i) diagnostic accuracy of RT-PCR compared to cell culture as reference test, (ii) performed meta-analysis of positive predictive values (PPV) and (iii) determined the virus isolation probabilities depending on cycle threshold (Ct) or log10 genome copies/ml using logistic regression. We included 55 studies. There is substantial statistical and clinical heterogeneity. Seven studies were included for diagnostic accuracy. Sensitivity ranged from 90% to 99% and specificity from 29% to 92%. In meta-analysis, the PPVs varied across subgroups with different sampling times after symptom onset, with 1% (95% confidence interval [CI], 0%-7%) in sampling beyond 10 days and 27% (CI, 19%-36%) to 46% (CI, 33%-60%) in subgroups that also included earlier samples. Estimates of virus isolation probability varied between 6% (CI, 0%-100%) and 50% (CI, 0%-100%) at a Ct value of 30 and between 0% (CI, 0%-22%) and 63% (CI, 0%-100%) at 5 log10 genome copies/ml. Evidence on RT-PCR performance in detecting infectious SARS-CoV-2 in respiratory samples was limited. Major limitations were heterogeneity and poor reporting. RT-PCR and cell culture protocols need further standardisation.

Effects of a gluten-reduced or gluten-free diet for the primary prevention of cardiovascular disease.

BACKGROUND: Cardiovascular diseases (CVD) are a major cause of disability and the leading cause of death worldwide. To reduce mortality and morbidity, prevention strategies such as following an optimal diet are crucial. In recent years, low-gluten and gluten-free diets have gained strong popularity in the general population. However, study results on the benefits of a gluten-reduced or gluten-free diet are conflicting, and it is unclear whether a gluten-reduced diet has an effect on the primary prevention of CVD. OBJECTIVES: To determine the effects of a gluten-reduced or gluten-free diet for the primary prevention of CVD in the general population. SEARCH METHODS: We systematically searched CENTRAL, MEDLINE, Embase, CINAHL and Web of Science up to June 2021 without language restrictions or restrictions regarding publication status. Additionally, we searched ClinicalTrials.gov for ongoing or unpublished trials and checked reference lists of included studies as well as relevant systematic reviews for additional studies. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs), such as prospective cohort studies, comparing a low-gluten or gluten-free diet or providing advice to decrease gluten consumption with no intervention, diet as usual, or a reference gluten-intake category. The population of interest comprised adults from the general population, including those at increased risk for CVD (primary prevention). We excluded cluster-RCTs, case-control studies, studies focusing on participants with a previous myocardial infarction and/or stroke, participants who have undergone a revascularisation procedure as well as participants with angina or angiographically-defined coronary heart disease, with a confirmed diagnosis of coeliac disease or with type 1 diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility of studies in a two-step procedure following Cochrane methods. Risk of bias (RoB) was assessed using the Cochrane risk of bias tool (RoB2) and the 'Risk Of Bias In Non-randomised Studies - of Interventions' (ROBINS-I) tool, and the certainty of evidence was rated using the GRADE approach. MAIN RESULTS: One RCT and three NRSIs (with an observational design reporting data on four cohorts: Health Professionals Follow-up Study (HPFS), Nurses' Health Study (NHS-I), NHS-II, UK Biobank) met the inclusion criteria. The RCT was conducted in Italy (60 participants, mean age 41 ± 12.1 years), two NRSIs (three cohorts, HPFS, NHS-I, NHS II) were conducted across the USA (269,282 health professionals aged 24 to 75 years) and one NRSI (Biobank cohort) was conducted across the UK (159,265 participants aged 49 to 62 years). Two NRSIs reported that the lowest gluten intake ranged between 0.0 g/day and 3.4 g/day and the highest gluten intake between 6.2 g/day and 38.4 g/day. The NRSI reporting data from the UK Biobank referred to a median gluten intake of 8.5 g/day with an interquartile range from 5.1 g/day to 12.4 g/day without providing low- and high-intake categories. Cardiovascular mortality From a total of 269,282 participants, 3364 (1.3%) died due to cardiovascular events during 26 years of follow-up. Low-certainty evidence may show no association between gluten intake and cardiovascular mortality (adjusted hazard ratio (HR) for low- versus high-gluten intake 1.00, 95% confidence interval (CI) 0.95 to 1.06; 2 NRSIs (3 cohorts)). All-cause mortality From a total of 159,265 participants, 6259 (3.9%) died during 11.1 years of follow-up. Very low-certainty evidence suggested that it is unclear whether gluten intake is associated with all-cause mortality (adjusted HR for low vs high gluten intake 1.00, 95% CI 0.99 to 1.01; 1 NRSI (1 cohort)). Myocardial infarction  From a total of 110,017 participants, 4243 (3.9%) participants developed non-fatal myocardial infarction within 26 years. Low-certainty evidence suggested that gluten intake may not be associated with the development of non-fatal myocardial infarction (adjusted HR for low versus high gluten intake 0.99, 95% CI 0.89 to 1.10; 1 NRSI (2 cohorts)). Lowering gluten intake by 5 g/day also showed no association on the primary prevention of non-fatal and fatal myocardial infarction (composite endpoint) in linear dose-response meta-analyses (adjusted HR 1.02, 95% CI 0.98 to 1.06; 1 NRSI (2 cohorts)). Coronary risk factors  Type 2 diabetes From a total of 202,114 participants, 15,947 (8.0%) developed type 2 diabetes after a follow-up between 22 and 28 years. There was low-certainty evidence that a lower compared with a higher gluten intake may be associated with a slightly increased risk to develop type 2 diabetes (adjusted HR 1.14, 95% CI 1.07 to 1.22; 1 NRSI (3 cohorts)). Furthermore, lowering gluten intake by 5 g/day may be associated with a slightly increased risk to develop type 2 diabetes in linear dose-response meta-analyses (adjusted HR 1.12, 95% CI 1.08 to 1.16; 1 NRSI (3 cohorts)). Blood pressure, low-density lipoprotein level, body mass index (BMI) After six months of follow-up, very low-certainty evidence suggested that it is unclear whether gluten intake affects systolic blood pressure (mean difference (MD) -6.9, 95% CI -17.1 to 3.3 mmHg). There was also no difference between the interventions for diastolic blood pressure (MD -0.8, 95% CI -5.9 to 4.3 mmHg), low-density lipoprotein levels (MD -0.1, 95% CI -0.5 to 0.3 mmol/L) and BMI (MD -0.1, 95% CI -3.3 to 3.1 kg/m²).  No study reported data on adverse events or on other outcomes. Funding sources did not appear to have distorted the results in any of the studies. AUTHORS' CONCLUSIONS: Very low-certainty evidence suggested that it is unclear whether gluten intake is associated with all-cause mortality. Our findings also indicate that low-certainty evidence may show little or no association between gluten intake and cardiovascular mortality and non-fatal myocardial infarction. Low-certainty evidence suggested that a lower compared with a higher gluten intake may be associated with a slightly increased risk to develop type 2 diabetes - a major cardiovascular risk factor. For other cardiovascular risk factors it is unclear whether there is a difference between a gluten-free and normal diet. Given the limited findings from this review predominantly based on observational studies, no recommendations for practice can be made.

HPA axis activity in patients with chronic insomnia: A systematic review and meta-analysis of case-control studies.

Insomnia is a highly prevalent disorder and a state of 24 h hyperarousal is considered as a key factor of this condition. Various physiological markers of hyperarousal have been investigated, including the activity of the HPA axis. However, these studies yielded heterogenous results. The aim of this study was to qualitatively and quantitatively evaluate whether there are differences in cortisol levels, the hormonal end product of the HPA axis, between patients with insomnia and good sleeper controls (GSC). The databases PubMed, Cinahl, PsycInfo, PsycArticles and Web of Science were searched for case-control studies comparing cortisol levels in patients with insomnia and GSC. Twenty studies (449 patients with insomnia, limited to ages 18-70 not taking any medications; 357 GSC) met the inclusion criteria. For each study, standardized mean differences (SMD) were calculated as a measure of effect size. Results suggest that patients with insomnia show moderately increased cortisol levels (SMD = 0.50, 95% CI: [0.21-0.80]). Higher effect sizes were found by including only studies using blood samples in the analysis (SMD = 0.67, 95% CI: [0.15-1.18]). Furthermore, a positive, but insignificant association was found between the extent of objective sleep loss in insomnia patients and group differences in cortisol levels.

A1- and A2 beta-casein on health-related outcomes: a scoping review of animal studies.

PURPOSE: Food-derived bioactive peptides may influence important physiological functions. An important example is beta-casomorphins, which are opioid peptides derived from A1 beta-casein in bovine milk and have been associated to be risk factors for non-communicable diseases in humans. A1 and A2 beta-casein are different with respect to the release of bioactive peptides, in particular BCM-7. However, evidence from human studies is limited and could be complemented with evidence derived from animal studies. We conducted a scoping review to identify animal studies investigating the effects of A1 beta-casein or BCM-7 compared to A2 beta-casein or any other intervention on health-related outcomes. METHODS: We systematically searched for relevant studies in two electronic databases (Medline, Embase; last search performed March 2020). Two reviewers independently undertook study selection and data extraction of included references. Results were summarized tabularly and narratively. RESULTS: We included 42 studies investigating various animal models, including rats, mice, rabbits, and dogs. Six studies investigated health-related outcomes of A1- vs. A2 milk, while most studies (n = 36) reported on physiological properties (e.g., analgesic effect) of BCM-7 as an opioid peptide. Included studies were extremely heterogeneous in terms of the study population, type of intervention and dose, and type of outcome measures. CONCLUSIONS: Only a few studies comparing the effects of A1- and A2 milk were identified. More studies addressing this research question in animal models are needed to provide essential information to inform research gaps. Results from future studies could eventually complement research for humans, particularly when the body of evidence remains uncertain as is the case in the A1- and A2 milk debate.

Efficacy and safety of strong opioids for chronic noncancer pain and chronic low back pain: a systematic review and meta-analyses.

ABSTRACT: In recent years, long-term prescribing and use of strong opioids for chronic noncancer pain (CNCP) has increased in high-income countries. Yet existing uncertainties, controversies, and differing recommendations make the rationale for prolonged opioid use in CNCP unclear. This systematic review and meta-analyses compared the efficacy, safety, and tolerability of strong opioids with placebo or nonopioid therapy in CNCP, with a special focus on chronic low back pain (CLBP). Systematic literature searches were performed in 4 electronic databases (MEDLINE, Web of Science, Cochrane Library, and CINAHL) in July 2019 and updated by regular alerts until December 2020. We included 16 placebo-controlled randomized controlled trials for CLBP and 5 studies (2 randomized controlled trials and 3 nonrandomized studies) of opioids vs nonopioids for CNCP in the quantitative and qualitative synthesis. Random effects pairwise meta-analyses were performed for efficacy, safety, and tolerability outcomes and subgroup analyses for treatment duration, study design, and opioid experience status. Very low to low certainty findings suggest that 4 to 15 weeks (short or intermediate term) opioid therapy in CLBP (compared with placebo) may cause clinically relevant reductions in pain but also more gastrointestinal and nervous system adverse events, with likely no effect on disability. By contrast, long-term opioid therapy (≥6 months) in CNCP may not be superior to nonopioids in improving pain or disability or pain-related function but seems to be associated with more adverse events, opioid abuse or dependence, and possibly an increase in all-cause mortality. Our findings also underline the importance and need for well-designed trials assessing long-term efficacy and safety of opioids for CNCP and CLBP.

A Systematic Review with Meta-Analysis Investigating the Impact of Targeted Perfusion Parameters during Extracorporeal Cardiopulmonary Resuscitation in Out-of-Hospital and Inhospital Cardiac Arrest.

Evidence regarding perfusion conditions during extracorporeal cardiopulmonary resuscitation (ECPR) is rare. Therefore, we investigated the impact of perfusion parameters on neurologic outcome and survival in patients with in- or out-of-hospital cardiac arrest (IHCA; OHCA) treated with ECPR. We performed a systematic review with meta-analysis. The focus was set on perfusion parameters and their impact on survival and a goal neurological outcome using the cerebral performance category score of 1-2. We conducted random- and mixed-effects meta-analyses and computed pooled estimates and 95% confidence intervals (CI). We included a total of n = 1,282 ECPR (100%) patients from 20 ECPR studies. The target values of flow and mean arterial pressure (MAP) were frequently available. We transferred flow and MAP target values to high, medium, and low categories. The meta-analysis could not demonstrate a single effect of flow or MAP on outcome variables. In a second mixed-effects model, the combined occurrence of targeted flow and MAP as medium and high showed a significant effect on survival (OHCA: 52%, 95% CI: 29%, 74%; IHCA: 60%, 95% CI: 35%, 85%) and on neurological outcomes (OHCA: 53%, 95% CI: 27%, 78%; IHCA: 62%, 95% CI: 38%, 86%). Random-effects analysis showed also that IHCA led to a significant 11% (p = 0.006; 95% CI: 3%, 18%) improvement in survival and 12% (p = .005; 95% CI: 4%, 21%) improvement in neurological outcomes compared to OHCA. A combination of medium flow and high MAP showed advantages in survival and for neurological outcomes. We also identified improved outcomes for IHCA.

Educating Pharmacists on the Risks of Strong Opioids With Descriptive and Simulated Experience Risk Formats: A Randomized Controlled Trial.

Objectives. High opioid prescription rates in the United States and Europe suggest miscalibrated risk perceptions among those who prescribe, dispense, and take opioids. Findings from cognitive decision science suggest that risk perceptions and behaviors can differ depending on whether people learn about risks by experience or description. This study investigated effects of a descriptive versus an experience-based risk education format on pharmacists' risk perceptions and counseling behavior in the long-term administration of strong opioids to patients with chronic noncancer pain. Methods. In an exploratory, randomized controlled online trial, 300 German pharmacists were randomly assigned to either a descriptive format (fact box) or a simulated experience format (interactive simulation). Primary Outcome Measures. 1) Objective risk perception, 2) subjective risk perception, and 3) intended and 4) actual counseling behavior. Results. Both risk formats significantly improved pharmacists' objective risk perception, but pharmacists exposed to the fact box estimated the benefit-harm ratio more accurately than those exposed to the simulation. Both formats proved equally effective in adjusting pharmacists' subjective risk perception toward a better recognition of opioids' harms; however, pharmacists receiving the simulation showed a greater change in their actual counseling behavior and higher consistency between their intended and actual counseling than pharmacists receiving the fact box. Conclusion. The simulated experience format was less effective than the descriptive format in improving pharmacists' objective risk perception, equally effective in motivating pharmacists to counsel patients on less risky treatment alternatives and more effective in changing the reported actual counseling behavior. Implications. These exploratory findings provide important insights into the relevance of the description-experience gap for drug safety and raise questions for future research regarding the specific mechanisms at work.

Treatment Regimens for Immunocompetent Elderly Patients with Primary Central Nervous System Lymphoma: A Scoping Review.

BACKGROUND: Most patients diagnosed with primary central nervous system lymphoma (PCNSL) are older than 60 years. Despite promising treatment options for younger patients, prognosis for the elderly remains poor and efficacy of available treatment options is limited. MATERIALS AND METHODS: We conducted a scoping review to identify and summarize the current study pool available evaluating different types and combinations of (immuno) chemotherapy with a special focus on HCT-ASCT in elderly PCNSL. Relevant studies were identified through systematic searches in the bibliographic databases Medline, Web of Science, Cochrane Library and ScienceDirect (last search conducted in September 2020). For ongoing studies, we searched ClinicalTrials.gov, the German study register and the WHO registry. RESULTS: In total, we identified six randomized controlled trials (RCT) with 1.346 patients, 26 prospective (with 1.366 patients) and 24 retrospective studies (with 2.629 patients). Of these, only six studies (one completed and one ongoing RCT (with 447 patients), one completed and one ongoing prospective single arm study (with 65 patients), and two retrospective single arm studies (with 122 patients)) evaluated HCT-ASCT. Patient relevant outcomes such as progression-free and overall survival and (neuro-)toxicity were adequately considered across almost all studies. The current study pool is, however, not conclusive in terms of the most effective treatment options for elderly. Main limitations were (very) small sample sizes and heterogeneous patient populations in terms of age ranges (particularly in RCTs) limiting the applicability of the results to the target population (elderly). CONCLUSIONS: Although it has been shown that HCT-ASCT is probably a feasible and effective treatment option, this approach has never been investigated within a RCT including a wide range of elderly patients. A RCT comparing conventional (immuno) chemotherapy with HCT-ASCT is crucial to evaluate benefit and harms in an un-biased manner to eventually provide older PCNSL patients with the most effective treatment.