Update on PI-RADS Version 2.1 Diagnostic Performance Benchmarks for Prostate MRI: Systematic Review and Meta-Analysis.

Background Prostate MRI for the detection of clinically significant prostate cancer (csPCa) is standardized by the Prostate Imaging Reporting and Data System (PI-RADS), currently in version 2.1. A systematic review and meta-analysis infrastructure with a 12-month update cycle was established to evaluate the diagnostic performance of PI-RADS over time. Purpose To provide estimates of diagnostic accuracy and cancer detection rates (CDRs) of PI-RADS version 2.1 categories for prostate MRI, which is required for further evidence-based patient management. Materials and Methods A systematic search of PubMed, Embase, Cochrane Library, and multiple trial registers (English-language studies published from March 1, 2019, to August 30, 2022) was performed. Studies that reported data on diagnostic accuracy or CDRs of PI-RADS version 2.1 with csPCa as the primary outcome were included. For the meta-analysis, pooled estimates for sensitivity, specificity, and CDRs were derived from extracted data at the lesion level and patient level. Sensitivity and specificity for PI-RADS greater than or equal to 3 and PI-RADS greater than or equal to 4 considered as test positive were investigated. In addition to individual PI-RADS categories 1-5, subgroup analyses of subcategories (ie, 2+1, 3+0) were performed. Results A total of 70 studies (11 686 lesions, 13 330 patients) were included. At the patient level, with PI-RADS greater than or equal to 3 considered positive, meta-analysis found a 96% summary sensitivity (95% CI: 95, 98) and 43% specificity (95% CI: 33, 54), with an area under the summary receiver operating characteristic (SROC) curve of 0.86 (95% CI: 0.75, 0.93). For PI-RADS greater than or equal to 4, meta-analysis found an 89% sensitivity (95% CI: 85, 92) and 66% specificity (95% CI: 58, 74), with an area under the SROC curve of 0.89 (95% CI: 0.85, 0.92). CDRs were as follows: PI-RADS 1, 6%; PI-RADS 2, 5%; PI-RADS 3, 19%; PI-RADS 4, 54%; and PI-RADS 5, 84%. The CDR was 12% (95% CI: 7, 19) for transition zone 2+1 lesions and 19% (95% CI: 12, 29) for 3+0 lesions (P = .12). Conclusion Estimates of diagnostic accuracy and CDRs for PI-RADS version 2.1 categories are provided for quality benchmarking and to guide further evidence-based patient management. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Tammisetti and Jacobs in this issue.

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.

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.

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.

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.

Degarelix for treating advanced hormone-sensitive prostate cancer.

BACKGROUND: Degarelix is a gonadotropin-releasing hormone antagonist that leads to medical castration used to treat men with advanced or metastatic prostate cancer, or both. It is unclear how its effects compare to standard androgen suppression therapy. OBJECTIVES: To assess the effects of degree compared with standard androgen suppression therapy for men with advanced hormone-sensitive prostate cancer. SEARCH METHODS: We searched multiple databases (CENTRAL, MEDLINE, Embase, Scopus, Web of Science, LILACS until September 2020), trial registries (until October 2020), and conference proceedings (until December 2020). We identified other potentially eligible trials by reference checking, citation searching, and contacting study authors. SELECTION CRITERIA: We included randomized controlled trials comparing degarelix with standard androgen suppression therapy for men with advanced prostate cancer. DATA COLLECTION AND ANALYSIS: Three review authors independently classified studies and abstracted data from the included studies. The primary outcomes were overall survival and serious adverse events. Secondary outcomes were quality of life, cancer-specific survival, clinical progression, other adverse events, and biochemical progression. We used a random-effects model for meta-analyses and assessed the certainty of evidence for the main outcomes according to GRADE. MAIN RESULTS: We included 11 studies with a follow-up of between three and 14 months. We also identified five ongoing trials. Primary outcomes Data to evaluate overall survival were not available.  Degarelix may result in little to no difference in serious adverse events compared to standard androgen suppression therapy (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.62 to 1.05; low-certainty evidence; 2750 participants). Based on 114 serious adverse events in the standard androgen suppression group, this corresponds to 23 fewer serious adverse events per 1000 participants (43 fewer to 6 more). We downgraded the certainty of evidence for study limitations and imprecision. Secondary outcomes Degarelix likely results in little to no difference in quality of life assessed with a variety of validated questionnaires (standardized mean difference 0.06 higher, 95% CI 0.05 lower to 0.18 higher; moderate-certainty evidence; 2887 participants), with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. Data to evaluate cancer-specific survival were not available. The effects of degarelix on cardiovascular events are very uncertain (RR 0.15, 95% CI 0.04 to 0.61; very low-certainty evidence; 80 participants). We downgraded the certainty of evidence for study limitations, imprecision, and indirectness as this trial was conducted in a unique group of high-risk participants with pre-existing cardiovascular morbidities. Degarelix likely results in an increase in injection site pain (RR 15.68, 95% CI 7.41 to 33.17; moderate-certainty evidence; 2670 participants). Based on 30 participants per 1000 with injection site pain with standard androgen suppression therapy, this corresponds to 440 more injection site pains per 1000 participants (192 more to 965 more). We downgraded the certainty of evidence for study limitations. We did not identify any relevant subgroup differences for different degarelix maintenance doses. AUTHORS' CONCLUSIONS: We did not find trial evidence for overall survival or cancer-specific survival comparing degarelix to standard androgen suppression, but serious adverse events and quality of life may be similar between groups. The effects of degarelix on cardiovascular events are very uncertain as the only eligible study had limitations, was small with few events, and was conducted in a high-risk population. Degarelix likely results in an increase in injection site pain compared to standard androgen suppression therapy. Maximum follow-up of included studies was 14 months, which is short. There is a need for methodologically better designed and executed studies with long-term follow-up evaluating men with metastatic prostate cancer.

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

BACKGROUND: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. OBJECTIVES: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-6 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 standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 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 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes. AUTHORS' CONCLUSIONS: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).

Post-Neoadjuvant Surveillance and Surgery as Needed Compared with Post-Neoadjuvant Surgery on Principle in Multimodal Treatment for Esophageal Cancer: A Scoping Review.

BACKGROUND: A substantial fraction of patients with esophageal cancer show post-neoadjuvant pathological complete response (pCR). Principal esophagectomy after neoadjuvant treatment is the standard of care for all patients, although surveillance and surgery as needed in case of local recurrence may be a treatment alternative for patients with complete response (CR). METHODS: We performed a scoping review to describe key characteristics of relevant clinical studies including adults with non-metastatic esophageal cancer receiving multimodal treatment. Until September 2020, relevant studies were identified through systematic searches in the bibliographic databases Medline, Web of Science, Cochrane Library, Science Direct, ClinicalTrials, the German study register, and the WHO registry platform. RESULTS: In total, three completed randomized controlled trials (RCTs, with 468 participants), three planned/ongoing RCTs (with a planned sample size of 752 participants), one non-randomized controlled study (NRS, with 53 participants), ten retrospective cohort studies (with 2228 participants), and one survey on patients' preferences (with 100 participants) were identified. All studies applied neoadjuvant chemoradiation protocols. None of the studies examined neoadjuvant chemotherapeutic protocols. Studies investigated patient populations with esophageal squamous cell carcinoma, adenocarcinoma, and mixed cohorts. Important outcomes reported were overall, disease-free and local recurrence-free survival. Limitations of the currently available study pool include heterogeneous chemoradiation protocols, a lack of modern neoadjuvant treatment protocols in RCTs, short follow-up times, the use of heterogeneous diagnostic methods, and different definitions of clinical CR. CONCLUSION: Although post-neoadjuvant surveillance and surgery as needed compared with post-neoadjuvant surgery on principle has been investigated within different study designs, the currently available results are based on a wide variation of diagnostic tools to identify patients with pCR, short follow-up times, small sample sizes, and variations in therapeutic procedures. A thoroughly planned RCT considering the limitations in the currently available literature will be of great importance to provide patients with CR with the best and less harmful treatment.

Postneoadjuvant surveillance and surgery as needed compared with postneoadjuvant surgery on principle in multimodal treatment for oesophageal cancer: a scoping review protocol.

INTRODUCTION: In current medical practice of curative treatment for non-metastatic oesophageal cancer, surgery on principle is carried out by oesophagectomy after neoadjuvant treatment. However, oesophagectomy is often associated with postoperative morbidity and mortality. Taking into account that modern neoadjuvant therapy is effective and many of patients show no vital tumour cells in the operative specimens, we aim to perform a scoping review as part of the development phase for a prospectively planned multicentre randomised controlled trial investigating 'surgery as needed vs surgery on principle in patients with postneoadjuvant complete response of oesophageal cancer' (Prospective trial registration number DRKS00022801). This scoping approach will allow us to finally define and/or adapt the research question including the design and methodology of the randomised controlled trial taking into account the findings for example, research gaps and/or pitfalls in the currently available study pool addressing this or very similar questions. METHODS AND ANALYSIS: To identify relevant research, we will conduct searches in the electronic databases Medline, Web of Science Core Collection, Cochrane Library and Science Direct. We will also check references of relevant studies and perform a cited reference research (forward citation tracking). Titles and abstracts of the records identified by the searches will be screened and full texts of all potentially relevant articles will be obtained. We will consider randomised trials and non-randomised controlled studies. Data extraction tables will be set up, including study and patients' characteristics, aim of study and reported outcomes. We will summarise the data using tables and figures (eg, bubble plots) to present the research landscape and to describe potential clusters and/or gaps to support the planning of a randomised trial in this patient population. ETHICS AND DISSEMINATION: Ethical approval is not required for this scoping review. Study findings will be shared by publication in a peer-reviewed journal and by presentation to key stakeholders on scientific meetings.

Surgical and Non-Surgical Interventions in Complete Rotator Cuff Tears.

BACKGROUND: This systematic review compares the efficacy and safety of surgical and non-surgical interventions for full- thickness rotator cuff tears. METHODS: A systematic literature search was conducted in five databases. Randomized (RCTs) and non-randomized controlled trials of interventions (non-RCTs) for the surgical or non-surgical treatment of patients with traumatic or atraumatic full-thickness rotator cuff tears were included. The review protocol was published in the PROSPERO registry (CRD42018100343). RESULTS: Ten studies (three RCTs with 332 participants; seven non-RCTs with 650 participants) met the inclusion criteria. One year after treatment, shoulder function, measured with the 100-point Constant score, had improved by 6.7 points (95% confidence interval [2.3; 11.0]) and pain, measured with the 10-cm visual analog scale, by 1.1 cm (0.5; 1.7] in the full-thickness rotator cuff tears treated surgically compared with non-surgical treatment. In one study the difference in favor of surgery persisted after 10 years' follow-up. For other outcomes, such as range of motion, muscle strength, quality of life, and adverse events, the data were sparse and the group differences were similar. The findings of the non-RCTs were comparable with those of the RCTs. CONCLUSION: With regard to functional improvement and pain reduction, surgical treatment of full-thickness rotator cuff tears was superior to non-surgical treatment in the short and the long term. Whether the differences between the groups are relevant for individual cases is uncertain, as the measured results were distributed below and above the threshold of clinical relevance. The conclusions may not be applicable to rotator cuff tears over 3 cm in size or to young persons.

Experiencing the risk of overutilising opioids among patients with chronic non-cancer pain in ambulatory care (ERONA): the protocol of an exploratory, randomised controlled trial.

INTRODUCTION: The US opioid crisis and increasing prescription rates in Europe suggest inappropriate risk perceptions and behaviours of people who prescribe, take or advise on opioids: physicians, patients and pharmacists. Findings from cognitive and decision science in areas other than drug safety suggest that people's risk perception and behaviour can differ depending on whether they learnt about a risk through personal experience or description. Experiencing the risk of overutilising opioids among patients with chronic non-cancer pain in ambulatory care (ERONA) is the first-ever conducted trial that aims at investigating the effects of these two modes of learning on individuals' risk perception and behaviour in the long-term administration of WHO-III opioids in chronic non-cancer pain. METHODS AND ANALYSIS: ERONA-an exploratory, randomised controlled online survey intervention trial with two parallel arms-will examine the opioid-associated risk perception and behaviour of four groups involved in the long-term administration of WHO-III opioids: (1) family physicians, (2) physicians specialised in pain therapy, (3) patients with chronic (≥3 months) non-cancer pain and (4) pharmacists who regularly dispense narcotic substances. Participants will be randomly assigned to one of two online risk education interventions, description based or experiencebased. Both interventions will present the best medical evidence available. Participants will be queried at baseline and after intervention on their risk perception of opioids' benefit-harm ratio, their medical risk literacy and their current/intended risk behaviour (in terms of prescribing, taking or counselling, depending on study group). A follow-up will occur after 9 months, when participants will be queried on their actual risk behaviour. The study was developed by the authors and will be conducted by the market research institution IPSOS Health. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board of the Max Planck Institute for Human Development. Results will be disseminated through peer-reviewed journals, conference presentations and social media. TRIAL REGISTRATION NUMBER: DRKS00020358.

Impact of different types of olive oil on cardiovascular risk factors: A systematic review and network meta-analysis.

BACKGROUND AND AIM: This network meta-analysis (NMA) compares the effects of different types of olive oil (OO) on cardiovascular risk factors. METHODS AND RESULTS: Literature search was conducted on three electronic databases (Medline, Web of Science, and Cochrane Central). INCLUSION CRITERIA: Randomized controlled trials (RCTs) (≥3 weeks duration of intervention) comparing at least two of the following types of OO: refined OO (ROO), mixed OO (MOO), low phenolic (extra) virgin OO (LP(E)VOO), and high phenolic (extra) virgin OO (HP(E)VOO). Random-effects NMA was performed for seven outcomes; and surface under the cumulative ranking curve (SUCRA) was estimated, using an analytical approach (P-score). Thirteen RCTs (16 reports) with 611 mainly healthy participants (mean age: 26-70 years) were identified. No differences for total cholesterol, HDL-cholesterol, triacylglycerols, and diastolic blood pressure were observed comparing ROO, MOO, LP(E)VOO and HP(E)VOO. HP(E)VOO slightly reduce LDL-cholesterol (LDL-C) compared to LP(E)VOO (mean difference [MD]: -0.14 mmol/L, 95%-CI: -0.28, -0.01). Both, HP(E)VOO and LP(E)VOO reduces SBP compared to ROO (range of MD: -2.99 to -2.87 mmHg), and HP(E)VOO may improve oxidized LDL-cholesterol (oxLDL-C) compared to ROO (standardized MD: -0.68, 95%-CI: -1.31, -0.04). In secondary analyses, EVOO may reduce oxLDL-C compared to ROO, and a dose-response relationship between higher intakes of phenolic compounds from OO and lower SBP and oxLDL-C values was detected. HP(E)VOO was ranked as best treatment for LDL-C (P-score: 0.83), oxLDL-C (0.88), and SBP (0.75). CONCLUSIONS: HP(E)VOO may improve some cardiovascular risk factors, however, public health implications are limited by overall low or moderate certainty of evidence.

Evaluating the Diagnostic Accuracy of the Head-Impulse Test: A Scoping Review.

Importance: Vestibular symptoms rank among the most common complaints in medicine worldwide. Underlying disorders manifested by these symptoms are generally associated with an impairment of the vestibular-ocular reflex and can be assessed with different diagnostic procedures. In recent years, an increasing number of diagnostic test accuracy studies comparing various head-impulse test (HIT) methods with other diagnostic procedures have been published but not systematically reviewed. Objective: To conduct a scoping review and describe key characteristics of the growing number of diagnostic studies in patients presenting with vestibular symptoms. Evidence Review: In April 2017, published studies were identified through searches of 4 bibliographic databases: Medline, Science Citation Index Expanded, the Cochrane Library, and ScienceDirect. Studies were included if they provided diagnostic accuracy data (sensitivity and specificity) for any HIT method with reference to any other vestibular test or clinical diagnosis in patients with vestibular symptoms. Study key characteristics were extracted, and the current literature was described narratively. All analysis took place between June 2017 and July 2018. Findings: We identified a total of 27 diagnostic studies (including 3821 participants). There were disagreements between diagnostic test accuracy data both within and between studies when different HIT methods were compared with other diagnostic procedures. The proportion of correctly identified people having the disease (sensitivity) ranged between 0% and 100% (median, 41%), whereas the proportion of correctly identified people without the disease (specificity) was higher and ranged between 56% and 100% (median, 94%). Conclusions and Relevance: Based on the studies included in this review, sensitivity, specificity, and, more importantly, the risk of misdiagnosis and associated undertreatment or overtreatment cannot be reliably estimated by HIT methods for patients with vestibular symptoms. We recommend that further diagnostic studies consider (1) multiple possible underlying causes of vestibular symptoms and multiple test thresholds, (2) a representative sample of patients with and without the disease, and (3) reporting guidelines for diagnostic test accuracy studies.

The prevalence of hearing loss and use of hearing aids among adults in Germany: a systematic review.

BACKGROUND: Worldwide approximately 360 million people suffer from hearing impairment, 328 million of whom are adults. Up to now there has been no systematic evaluation of any representative epidemiological data on the prevalence of hearing loss among adults in Germany. The present paper is intended to investigate this within the framework of a systematic review. METHODS: A systematic literature search was carried out in electronic databases as well as by means of hand-searching. Studies published after 1975 and indicating the prevalence or incidence of hearing impairment among German adults were included. Study selection, data extraction and additional quality assessments were made by two independent reviewers. RESULTS: By means of a systematic literature search it was possible to identify 6 sources, which provided solely cross-sectional data, whereby the reported data are based on a study population of between some hundred and 10 million people living in Germany. The prevalences ascertained showed a broad range of between 16% and 25% and varied according to age, study setting, definition of hearing loss and method of data capture. At present there are no utilizable data on the extent of the use of hearing aids. DISCUSSION: The present review demonstrates clearly that evidence-based information relating to Germany can only be made on the basis of a clear definition of hearing loss within the framework of an up-to-date and representative epidemiological study carried out with appropriate methodology. In view of the high prevalence of illnesses causing hearing impairment and of the risks to health associated with untreated hearing impairment as well as of socio-economic costs, such an epidemiological study is of great social significance.

Naturopathic Treatment and Complementary Medicine in Surgical Practice.

BACKGROUND: Many patients in Germany use naturopathic treatments and complementary medicine. Surveys have shown that many also use them as a concomitant treatment to surgery. METHODS: Multiple databases were systematically searched for systematic reviews, controlled trials, and experimental studies concerning the use of naturopathic treatments and complementary medicine in the management of typical post-operative problems (PROSPERO CRD42018095330). RESULTS: Of the 387 publications identified by the search, 76 fulfilled the inclusion criteria. In patients with abnormal gastrointestinal activity, acupuncture can improve motility, ease the passing of flatus, and lead to earlier defecation. Acupuncture and acupressure can reduce postoperative nausea and vomiting, as well as pain. More-over,aromatherapy and music therapy seem to reduce pain, stress and anxiety and to improve sleep. Further studies are needed to determine whether phytotherapeutic treatments are effective for the improvement of gastrointestinal function or the reduction of stress. It also remains unclear whether surgical patients can benefit from the methods of mind body medicine. CONCLUSION: Certain naturopathic treatments and complementary medical methods may be useful in postoperative care and deserve more intensive study. In the publications consulted for this review, no serious side effects were reported.

Gonadotropin-releasing hormone antagonists versus standard androgen suppression therapy for advanced prostate cancer A systematic review with meta-analysis.

OBJECTIVES: To evaluate efficacy and safety of gonadotropin-releasing hormone (GnRH) antagonists compared to standard androgen suppression therapy for advanced prostate cancer. SETTING: The international review team included methodologists of the German Cochrane Centre and clinical experts. PARTICIPANTS: We searched CENTRAL, MEDLINE, Web of Science, EMBASE, trial registries and conference books for randomised controlled trials (RCT) for effectiveness data analysis, and randomised or non-randomised controlled studies (non-RCT) for safety data analysis (March 2015). Two authors independently screened identified articles, extracted data, evaluated risk of bias and rated quality of evidence according to GRADE. RESULTS: 13 studies (10 RCTs, 3 non-RCTs) were included. No study reported cancer-specific survival or clinical progression. There were no differences in overall mortality (RR 1.35, 95% CI 0.63 to 2.93), treatment failure (RR 0.91, 95% CI 0.70 to 1.17) or prostate-specific antigen progression (RR 0.83, 95% CI 0.64 to 1.06). While there was no difference in quality of life related to urinary symptoms, improved quality of life regarding prostate symptoms, measured with the International Prostate Symptom Score (IPSS), with the use of GnRH antagonists compared with the use of standard androgen suppression therapy (mean score difference -0.40, 95% CI -0.94 to 0.14, and -1.84, 95% CI -3.00 to -0.69, respectively) was found. Quality of evidence for all assessed outcomes was rated low according to GRADE. The risk for injection-site events was increased, but cardiovascular events may occur less often by using GnRH antagonist. Available evidence is hampered by risk of bias, selective reporting and limited follow-up. CONCLUSIONS: There is currently insufficient evidence to make firm conclusive statements on the efficacy of GnRH antagonist compared to standard androgen suppression therapy for advanced prostate cancer. There is need for further high-quality research on GnRH antagonists with long-term follow-up. TRIAL REGISTRATION NUMBER: CRD42012002751.

Treatment as Required versus Regular Monthly Treatment in the Management of Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

BACKGROUND: To investigate whether treatment as required 'pro re nata' (PRN) versus regular monthly treatment regimens lead to differences in outcomes in neovascular age-related macular degeneration (nAMD). Regular monthly administration of vascular endothelial growth factor (VEGF) inhibitors is an established gold standard treatment, but this approach is costly. Replacement of monthly by PRN treatment can only be justified if there is no difference in patient relevant outcomes. METHODS: Systematic review and meta-analysis. The intervention was PRN treatment and the comparator was monthly treatment with VEGF-inhibitors. Four bibliographic databases were searched for randomised controlled trials comparing both treatment regimens directly (head-to-head studies). The last literature search was conducted in December 2014. Risk of bias assessment was performed after the Cochrane Handbook for Systematic Reviews of Interventions. FINDINGS: We included 3 head-to-head studies (6 reports) involving more than 2000 patients. After 2 years, the weighted mean difference in best corrected visual acuity (BCVA) was 1.9 (95% CI 0.5 to 3.3) ETDRS letters in favour of monthly treatment. Systemic adverse events were higher in PRN treated patients, but these differences were not statistically significant. After 2 years, the total number of intravitreal injections required by the patients in the PRN arms were 8.4 (95% CI 7.9 to 8.9) fewer than those having monthly treatment. The studies were considered to have a moderate risk of bias. CONCLUSIONS: PRN treatment resulted in minor but statistically significant decrease in mean BCVA which may not be clinically meaningful. There is a small increase in risk of systemic adverse events for PRN treated patients. Overall, the results indicate that an individualized treatment approach with anti-VEGF using visual acuity and OCT-guided re-treatment criteria may be appropriate for most patients with nAMD.