To adjust or not to adjust in living systematic reviews? It's all about the context.

With each update of meta-analyses from living systematic reviews, treatment effects and their confidence intervals are recalculated. This often raises the question whether or not multiplicity is an issue and whether a method to adjust for multiplicity is needed. It seems that answering these questions is not that straightforward. We approach this matter by considering the context of systematic reviews and pointing out existing methods for handling multiplicity in meta-analysis. We conclude that multiplicity is not a relevant issue in living systematic reviews when they are planned with the aim to provide up-to-date evidence, without any direct control on the decision over future research. Multiplicity might be an issue, though, in living systematic reviews designed under a protocol involving a "stopping decision", which can be the case in living guideline development or in reimbursement decisions. Several appropriate methods exist for handling multiplicity in meta-analysis. Existing methods, however, are also associated with several technical and conceptual limitations, and could be improved in future methodological projects. To better decide whether an adjustment for multiplicity is necessary at all, authors and users of living systematic reviews should be aware of the context of the work and question whether there is a dependency between the effect estimates of the living systematic review and its stopping/updating or an influence on future research.

Efficacy of Physical Activity Promoting Interventions in Physical Therapy and Exercise Therapy for Persons with Noncommunicable Diseases: An Overview of Systematic Reviews.

OBJECTIVE: The objective of this study was to synthesize the evidence from systematic reviews on the efficacy of physical therapy and exercise therapy including interventional elements explicitly aiming at physical activity promotion (PAP) in patients with noncommunicable diseases (NCDs). METHODS: PubMed, Scopus, PsycINFO, and Cochrane Database of Systematic Reviews were searched from inception to February 28, 2023. Two independent reviewers screened the literature to identify systematic reviews that evaluated the effect of physical therapy and exercise therapy including PAP interventions. Patient-reported and device-based measures of physical activity outcomes were included. Qualitative and quantitative data from systematic reviews were extracted by 2 independent reviewers. Assessment of the methodological quality of included systematic reviews was performed using the AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews). We assessed primary study overlap by calculating the corrected covered area and conducted the evidence synthesis in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Fourteen systematic reviews were included in the present overview, including patients with a variety of NCDs. Most included systematic reviews had critically low (n = 5) to low (n = 7) methodological quality. Most meta-analysis (67%; 8/12) provided evidence supporting the short- and long-term efficacy of PAP interventions but not all pooled estimates were clinically relevant. Only 3 of the systematic reviews with meta-analysis included an assessment of the certainty of evidence. The evidence from systematic reviews without meta-analysis was inconclusive. CONCLUSIONS: The results of the present overview suggest that PAP interventions in physical therapy or exercise therapy may be effective to improve physical activity for patients with NCDs in the short term and long term. The results should be interpreted with caution due to the limited certainty of evidence and critically low to low methodological quality of included systematic reviews. Both high quality primary studies and systematic reviews are required to confirm these results. IMPACT: There is limited evidence that PAP interventions in physical therapy and exercise therapy may be effective to improve physical activity for patients with NCDs.

Needs and feasibility of living systematic reviews (LSRs): Experience from LSRs on COVID-19 vaccine effectiveness.

During 2021 and 2023, a team of researchers at the Robert Koch Institute (RKI) and partnering institutions conducted two living systematic reviews (LSRs) on the effectiveness of COVID-19 vaccines in different age groups to inform recommendations of the Standing Committee on Vaccination in Germany (Ständige Impfkommission, STIKO). Based on our experience from the realization of these LSRs, we developed certain criteria to assess the needs and feasibility of conducting LSRs. Combining these with previously established criteria, we developed the following set to inform future planning of LSRs for STIKO: Needs criterion (N)1: Relevance of the research question, N2: Certainty of evidence (CoE) at baseline; N3: Expected need for Population-Intervention-Comparator-Outcome (PICO) adaptations; N4: Expected new evidence over time; N5: Expected impact of new evidence on CoE; Feasibility criterion (F)1: Availability of sufficient human resources; F2: Feasibility of timely dissemination of the results to inform decision-making. For each criterion we suggest rating options which may support the decision to conduct an LSR or other forms of evidence synthesis when following the provided flowchart. The suggested criteria were developed on the basis of the experiences from exemplary reviews in a specific research field (i.e., COVID-19 vaccination), and did not follow a formal development or validation process. However, these criteria might also be useful to assess whether questions from other research fields can and should be answered using the LSR approach, or assist in determining whether the use of an LSR is sensible and feasible for specific questions in health policy and practice.

Experience report of two living systematic Cochrane reviews on COVID-19.

INTRODUCTION: Up-to-date systematic reviews (SRs) are essential for making evidence-based decisions. During the 2019 coronavirus (COVID-19) pandemic, there was a particular need for up-to-date evidence, making the living systematic review (LSR) approach an appropriate review type. However, this approach poses certain challenges. OBJECTIVE AND OUTLINE: We aim to provide practice insights and report challenges that we faced while conducting two Cochrane LSRs on COVID-19 treatments with (i) convalescent plasma and (ii) systemic corticosteroids. We address our objective with an experience report and share challenges of the following components based on Iannizzi et al. (2022): study design, publication types, intervention/comparator, outcomes, search strategy, review updates and transparent reporting of differences between review updates. RESULTS: Regarding the study design, the plasma LSR included different study designs because RCT data were not available at the beginning of the pandemic, whereas for the corticosteroids LSR, which started several months later, RCT data were already available. The challenges in both LSRs included the publication types (preprints were included with caution) and the intervention/comparator, for instance the unavailability of standard of care for either LSR, or SARS-CoV-2 variants occurrence. Further challenges in both LSRs occurred in the components "outcome sets" (which had to be adjusted) and "literature search". The decision criteria for updating were based on important studies and available resources in both LSRs and policy relevance in the plasma LSR. Transparent reporting of the differences between the various update versions were discussed for both LSRs. DISCUSSION AND CONCLUSION: In summary, there are similarities and differences regarding challenges of review components for both LSRs. It is important to keep in mind that the two LSR examples presented here were conducted in the wake of the COVID-19 pandemic. Therefore, many of the challenges are attributable to the pandemic and are not specific to LSRs, such as constant adjustments of the outcome sets or changes in the database search. Nevertheless, we believe that some of these aspects are helpful for LSR authors and are applicable to other LSRs outside the pandemic context, particularly in areas where new evidence is rapidly emerging.

[Development of criteria for the prospective assessment of the need for updating guideline recommendations: The AGIL criteria]. / Entwicklung von Kriterien für die prospektive Einschätzung des Aktualisierungsbedarfs von Leitlinienempfehlungen: AGIL-Kriterien.

BACKGROUND: Evidence-based guideline and vaccination recommendations should continuously be updated to appropriately support health care decisions. However, resources for updating guidelines are often limited. The aim of this project was to develop a list of criteria for the prospective assessment of the need for updating individual guideline or vaccination recommendations, which can be applied from the time a guideline or guideline update is finalised. METHODS: In this article we describe the development of the AGIL criteria (Assessment of Guidelines for Updating Recommendations). The AGIL criteria were developed by experienced scientists and experts in the field of guideline development in a multi-step process. The five steps included: 1) development of an initial list of criteria by the project team; 2) online survey of guideline experts on the initial version of the criteria list; 3) revision of the criteria list based on the results of the online survey; 4) workshop on the criteria list at the EbM Congress 2023; 5) creation of version 1.0 of the AGIL criteria based on the workshop results. RESULTS: The initial list included the following three criteria: 1) relevance of the question 2) availability of new relevant evidence, and 3) impact of potentially new evidence. The response rate of the online survey for fully completed questionnaires was 31.0% (N=195; 630 guideline experts were contacted by email). For 90.3% (n=176) of the respondents, the criteria list included all essential aspects for assessing the need for updating guideline recommendations. More than three quarters of respondents rated the importance of the three criteria as "very important" or "important" (criteria 1-3: 75.3%, 86.1%, 85.2%) and - with the exception of criterion 1 - comprehensibility as "very comprehensible" or "comprehensible" (criteria 1-3: 58.4%, 75.9%, 78.5%). The results of the online survey and the workshop generally confirmed the three criteria with their two sub-questions. The incorporation of all feedback resulted in the AGIL criteria (version 1.0), recapping: 1) relevance of the question regarding a) PICO components and b) other factors, e.g. epidemiological aspects; 2) availability of new evidence a) on health-related benefits and harms and b) on other decision factors, e.g. feasibility, acceptability; 3) impact of new evidence a) on the certainty of evidence on which the recommendation is based and b) on the present recommendation, e.g. DISCUSSION: The moderate response rate of the online survey may have limited its representativeness. Nevertheless, we consider the response rate to be satisfactory in this research context. The inclusion of many experts in the online survey and the EbM Congress workshop is a strength of the project and supports the quality of the results. CONCLUSIONS: The AGIL criteria provide a structured guidance for the prospective assessment of the need for updating individual guideline recommendations and other evidence-based recommendations. The implementation and evaluation of the AGIL criteria 1.0 in a field test is planned.

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.

How the COVID-19 pandemic and related school closures reduce physical activity among children and adolescents in the WHO European Region: a systematic review and meta-analysis.

BACKGROUND: Emerging research suggests that physical activity among children and adolescents decreased during the COVID-19 pandemic. However, a differentiated overview of European youth is lacking. In particular, no systematic analysis has been conducted to date on the impact of heterogeneous pandemic restrictions and school closures within European countries, and with regard to potentially vulnerable groups. METHODS: We searched seven databases and included studies for children and adolescents (≤ 19 years) of the WHO European Region that compared physical activity during the COVID-19 pandemic with a pre-pandemic baseline using validated measurement instruments. We used the Oxford Stringency Index and School Closure Index as indicators of restriction stringency. Screening for eligibility, data extraction, assessment of the study risk of bias (using the 'Risk of Bias in Non-randomized Studies - of Exposure' [ROBINS-E]) and certainty grading of evidence (using the GRADE approach), were all done in duplicate. Unpublished data was requested from study authors. Data were pooled in random effects models. An a priori protocol was published, reporting is carried out in accordance with the 'Preferred Reporting Items for Systematic Review and Meta-Analyses' (PRISMA) statement. RESULTS: Of 14,897 non-duplicate records, 26 publications (n = 15,038 pre-pandemic, n = 13,041 during pandemic) met full inclusion criteria. Comparison before and during the COVID-19 pandemic revealed a significant reduction in total physical activity (standardized mean difference [SMD], -0.57 [95%CI, -0.95; -0.20]) and moderate-to-vigorous physical activity (SMD, -0.43 [95% CI, -0.75; -0.10]), corresponding to a decrease of 12 min per day (a 20% reduction of the WHO recommendation). A decrease in sporting activity was also recorded. Subgroup analyses suggested that middle childhood (aged 8-12) and adolescents were particularly affected by the decline. School closures were associated with a reduction in physical activity. The certainty of evidence for all outcomes was low. CONCLUSIONS: A sharp decline in all forms of physical activity was recorded among European children and adolescents during the COVID-19 pandemic. This decline was higher during periods of school closure and mainly affected younger schoolchildren and adolescents. Immediate action by policy-makers and practitioners, as well as evidence-based public health strategies, are imperative in reversing this trend. TRIAL REGISTRATION: PROSPERO: CRD42023395871.

Cognitive behavioural therapy (CBT) with and without exercise to reduce fear of falling in older people living in the community.

BACKGROUND: Fear of falling (FoF) is a lasting concern about falling that leads to an individual avoiding activities that he/she remains capable of performing. It is a common condition amongst older adults and may occur independently of previous falls. Cognitive behavioural therapy (CBT), a talking therapy that helps change dysfunctional thoughts and behaviour, with and without exercise, may reduce FoF, for example, by reducing catastrophic thoughts related to falls, and modifying dysfunctional behaviour. OBJECTIVES: To assess the benefits and harms of CBT for reducing FoF in older people living in the community, and to assess the effects of interventions where CBT is used in combination with exercise. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2023), MEDLINE Ovid (from 1946 to 11 January 2023), Embase Ovid (from 1980 to 11 January 2023), CINAHL Plus (Cumulative Index to Nursing and Allied Health Literature) (from 1982 to 11 January 2023), PsycINFO (from 1967 to 11 January 2023), and AMED (Allied and Complementary Medicine from 1985 to 11 January 2023). We handsearched reference lists and consulted experts for identifying additional studies. SELECTION CRITERIA: This review included randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs assessing CBT with and without exercise interventions compared to control groups with sham-treatment, or treatment as usual. We defined CBT as a collaborative, time-limited, goal-oriented, and structured form of speaking therapy. Included studies recruited community-dwelling older adults, with a mean population age of at least 60 years minus one standard deviation, and not defined by a specific medical condition. DATA COLLECTION AND ANALYSIS: Two review authors used standard methodological procedures expected by Cochrane. For continuous data, as assessed by single- or multiple-item questionnaires, we report the mean difference (MD) with 95% confidence interval (CI) when studies used the same outcome measures, and standardised mean difference (SMD) when studies used different measures for the same clinical outcome. For dichotomous outcomes, we reported the treatment effects as risk ratios (RR) with 95% CIs. We measured the primary outcome, FoF, immediately, up to, and more than six months after the intervention. We analysed secondary outcomes of activity avoidance, occurrence of falls, depression, and quality of life when measured immediately after the intervention. We assessed risk of bias for each included study, using the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We selected 12 studies for this review, with 11 studies included for quantitative synthesis. One study could not be included due to missing information. Of the 11 individual studies, two studies provided two comparisons, which resulted in 13 comparisons. Eight studies were RCTs, and four studies were cluster-RCTs. Two studies had multiple arms (CBT only and CBT with exercise) that fulfilled the inclusion criteria. The primary aim of 10 studies was to reduce FoF. The 11 included studies for quantitative synthesis involved 2357 participants, with mean ages between 73 and 83 years. Study total sample sizes varied from 42 to 540 participants. Of the 13 comparisons, three investigated CBT-only interventions while 10 investigated CBT with exercise. Intervention duration varied between six and 156 hours, at a frequency between three times a week and monthly over an eight- to 48-week period. Most interventions were delivered in groups of between five and 10 participants, and, in one study, up to 25 participants. Included studies had considerable heterogeneity, used different questionnaires, and had high risks of bias. CBT interventions with and without exercise probably improve FoF immediately after the intervention (SMD -0.23, 95% CI -0.36 to -0.11; 11 studies, 2357 participants; moderate-certainty evidence). The sensitivity analyses did not change the intervention effect significantly. Effects of CBT with or without exercise on FoF may be sustained up to six months after the intervention (SMD -0.24, 95% CI -0.41 to -0.07; 8 studies, 1784 participants; very low-certainty evidence). CBT with or without exercise interventions for FoF probably sustains improvements beyond six months (SMD -0.28, 95% CI -0.40 to -0.15; 5 studies, 1185 participants; moderate-certainty of evidence). CBT interventions for reducing FoF may reduce activity avoidance (MD -2.57, 95% CI -4.67 to -0.47; 1 study, 312 participants; low-certainty evidence), and level of depression (SMD -0.41, 95% CI -0.60 to -0.21; 2 studies, 404 participants; low-certainty evidence). We are uncertain whether CBT interventions reduce the occurrence of falls (RR 0.96, 95% CI 0.66 to 1.39; 5 studies, 1119 participants; very low-certainty evidence). All studies had a serious risk of bias, due to performance bias, and at least an unclear risk of detection bias, as participants and assessors could not be blinded due to the nature of the intervention. Downgrading of certainty of evidence also occurred due to heterogeneity between studies, and imprecision, owing to limited sample size of some studies. There was no reporting bias suspected for any article. No studies reported adverse effects due to their interventions. AUTHORS' CONCLUSIONS: CBT with and without exercise interventions probably reduces FoF in older people living in the community immediately after the intervention (moderate-certainty evidence). The improvements may be sustained during the period up to six months after intervention (low-certainty evidence), and probably are sustained beyond six months (moderate-certainty evidence). Further studies are needed to improve the certainty of evidence for sustainability of FoF effects up to six months. Of the secondary outcomes, we are uncertain whether CBT interventions for FoF reduce the occurrence of falls (very low-certainty evidence). However, CBT interventions for reducing FoF may reduce the level of activity avoidance, and may reduce depression (low-certainty evidence). No studies reported adverse effects. Future studies could investigate different populations (e.g. nursing home residents or people with comorbidities), intervention characteristics (e.g. duration), or comparisons (e.g. CBT versus exercise), investigate adverse effects of the interventions, and add outcomes (e.g. gait analysis). Future systematic reviews could search specifically for secondary outcomes.

Physical activity and physical fitness among children and adolescents after the onset of the COVID-19 pandemic in the WHO European Region: a systematic review protocol.

INTRODUCTION: The implementation of COVID-19 pandemic-related restrictions resulted in limitations for physical activity (PA) opportunities, which may have initiated a longer-term behavioural change. The protocol describes the methodology for a planned systematic review that aims to summarise changes in PA and physical fitness (PF) in children and adolescents in the WHO European Region after the onset of the COVID-19 pandemic. METHODS AND ANALYSIS: The protocol adheres to the 'Preferred Reporting Items for Systematic Review and Meta-Analysis for Protocols' (PRISMA-P) statement. Using a peer-reviewed search strategy according to the evidence-based checklist 'Peer Review of Electronic Search Strategies' (PRESS), we will perform a systematic literature search in seven databases. Inclusion criteria are all primary studies that gathered data on children and adolescents ≤19 years living in the WHO European Region and made a comparison to pre-pandemic data. Primary outcomes are PA and PF. We will assess the risk of bias with the 'Risk of Bias Instrument for Non-Randomized Studies of Exposures' (ROBINS-E). The 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) approach will be used for the evaluation of the certainty of evidence. Also, subgroup analyses will be performed (eg, for gender, age, stringency of pandemic restrictions). ETHICS AND DISSEMINATION: Ethical approval is not required, as primary data will not be collected in this study. The results will be presented in a peer-reviewed publication and at congresses relevant to the research field. PROSPERO REGISTRATION NUMBER: CRD42023395871.

Safety and effectiveness of vaccines against COVID-19 in children aged 5-11 years: a systematic review and meta-analysis.

BACKGROUND: To date, more than 761 million confirmed SARS-CoV-2 infections have been recorded globally, and more than half of all children are estimated to be seropositive. Despite high SARS-CoV-2 infection incidences, the rate of severe COVID-19 in children is low. We aimed to assess the safety and efficacy or effectiveness of COVID-19 vaccines approved in the EU for children aged 5-11 years. METHODS: In this systematic review and meta-analysis, we included studies of any design identified through searching the COVID-19 L·OVE (living overview of evidence) platform up to Jan 23, 2023. We included studies with participants aged 5-11 years, with any COVID-19 vaccine approved by the European Medicines Agency-ie, mRNA vaccines BNT162b2 (Pfizer-BioNTech), BNT162b2 Bivalent (against original strain and omicron [BA.4 or BA.5]), mRNA-1273 (Moderna), or mRNA-1273.214 (against original strain and omicron BA.1). Efficacy and effectiveness outcomes were SARS-CoV-2 infection (PCR-confirmed or antigen-test confirmed), symptomatic COVID-19, hospital admission due to COVID-19, COVID-19-related mortality, multisystem inflammatory syndrome in children (MIS-C), and long-term effects of COVID-19 (long COVID or post-COVID-19 condition as defined by study investigators or per WHO definition). Safety outcomes of interest were serious adverse events, adverse events of special interest (eg, myocarditis), solicited local and systemic events, and unsolicited adverse events. We assessed risk of bias and rated the certainty of evidence (CoE) using the Grading of Recommendations Assessment, Development and Evaluation approach. This study was prospectively registered with PROSPERO, CRD42022306822. FINDINGS: Of 5272 screened records, we included 51 (1·0%) studies (n=17 [33%] in quantitative synthesis). Vaccine effectiveness after two doses against omicron infections was 41·6% (95% CI 28·1-52·6; eight non-randomised studies of interventions [NRSIs]; CoE low), 36·2% (21·5-48·2; six NRSIs; CoE low) against symptomatic COVID-19, 75·3% (68·0-81·0; six NRSIs; CoE moderate) against COVID-19-related hospitalisations, and 78% (48-90, one NRSI; CoE very low) against MIS-C. Vaccine effectiveness against COVID-19-related mortality was not estimable. Crude event rates for deaths in unvaccinated children were less than one case per 100 000 children, and no events were reported for vaccinated children (four NRSIs; CoE low). No study on vaccine effectiveness against long-term effects was identified. Vaccine effectiveness after three doses was 55% (50-60; one NRSI; CoE moderate) against omicron infections, and 61% (55-67; one NRSI; CoE moderate) against symptomatic COVID-19. No study reported vaccine efficacy or effectiveness against hospitalisation following a third dose. Safety data suggested no increased risk of serious adverse events (risk ratio [RR] 0·83 [95% CI 0·21-3·33]; two randomised controlled trials; CoE low), with approximately 0·23-1·2 events per 100 000 administered vaccines reported in real-life observations. Evidence on the risk of myocarditis was uncertain (RR 4·6 [0·1-156·1]; one NRSI; CoE low), with 0·13-1·04 observed events per 100 000 administered vaccines. The risk of solicited local reactions was 2·07 (1·80-2·39; two RCTs; CoE moderate) after one dose and 2·06 (1·70-2·49; two RCTs; CoE moderate) after two doses. The risk of solicited systemic reactions was 1·09 (1·04-1·16; two RCTs; CoE moderate) after one dose and 1·49 (1·34-1·65; two RCTs; CoE moderate) after two doses. The risk of unsolicited adverse events after two doses (RR 1·21 [1·07-1·38]; CoE moderate) was higher among mRNA-vaccinated compared with unvaccinated children. INTERPRETATION: In children aged 5-11 years, mRNA vaccines are moderately effective against infections with the omicron variant, but probably protect well against COVID-19 hospitalisations. Vaccines were reactogenic but probably safe. Findings of this systematic review can serve as a basis for public health policy and individual decision making on COVID-19 vaccination in children aged 5-11 years. FUNDING: German Federal Joint Committee.

Effect of opioids for breathlessness in heart failure: a systematic review and meta-analysis.

BACKGROUND: For the treatment of breathlessness in heart failure (HF), most textbooks advocate the use of opioids. Yet, meta-analyses are lacking. METHODS: A systematic review was performed for randomised controlled trials (RCTs) assessing effects of opioids on breathlessness (primary outcome) in patients with HF. Key secondary outcomes were quality of life (QoL), mortality and adverse effects. Cochrane Central Register of Controlled Trials, MEDLINE and Embase were searched in July 2021. Risk of bias (RoB) and certainty of evidence were assessed by the Cochrane RoB 2 Tool and Grading of Recommendations Assessment, Development and Evaluation criteria, respectively. The random-effects model was used as primary analysis in all meta-analyses. RESULTS: After removal of duplicates, 1180 records were screened. We identified eight RCTs with 271 randomised patients. Seven RCTs could be included in the meta-analysis for the primary endpoint breathlessness with a standardised mean difference of 0.03 (95% CI -0.21 to 0.28). No study found statistically significant differences between the intervention and placebo. Several key secondary outcomes favoured placebo: risk ratio of 3.13 (95% CI 0.70 to 14.07) for nausea, 4.29 (95% CI 1.15 to 16.01) for vomiting, 4.77 (95% CI 1.98 to 11.53) for constipation and 4.42 (95% CI 0.79 to 24.87) for study withdrawal. All meta-analyses revealed low heterogeneity (I2 in all these meta-analyses was <8%). CONCLUSION: Opioids for treating breathlessness in HF are questionable and may only be the very last option if other options have failed or in case of an emergency. PROSPERO REGISTRATION NUMBER: CRD42021252201.

User experience of applying AMSTAR 2 to appraise systematic reviews of healthcare interventions: a commentary.

BACKGROUND: 'A Measurement Tool to Assess Systematic Reviews, version 2' (AMSTAR 2) is a validated 16-item scale designed to appraise systematic reviews (SRs) of healthcare interventions and to rate the overall confidence in their results. This commentary aims to describe the challenges with rating of the individual items and the application of AMSTAR 2 from the user perspective. DISCUSSION: A group of six experienced users (methodologists working in different clinical fields for at least 10 years) identified and discussed the challenges in rating of each item and the general use of AMSTAR 2 to appraise SRs. A group discussion was used to develop recommendations on how users could deal with the identified challenges. We identified various challenges with the content of items 2-16 and with the derivation of the overall confidence ratings on AMSTAR 2. These challenges include the need (1) to provide additional definitions (e.g., what constitutes major deviations from SR protocol on item 2), (2) to choose a rating strategy for multiple conditions on single items (e.g., how to rate item 5 if studies were selected in duplicate, but consensus between two authors was not reported), and (3) to determine rules for deriving the confidence ratings (e.g., what items are critical for such ratings). Based on these challenges we formulated specific recommendations for items 2-16 that AMSTAR 2 users could consider before applying the tool. Our commentary adds to the existing literature by providing the first in-depth examination of the AMSTAR 2 tool from the user perspective. The identified challenges could be addressed by additional decision rules including definitions for ambiguous items and guidance for rating of complex items and derivation of confidence ratings. We recommend that a team consensus regarding such decision rules is required before appraisal procedure begins. TRIAL REGISTRATION: Not applicable.

From standard systematic reviews to living systematic reviews.

Systematic reviews (SRs) have become a central tool for evidence-based health care over the last 30 years. The number of SRs being published has increased steadily. However, concerns have been raised regarding the duplication of work, methodological flaws and the currency of many systematic reviews, also in the context of the COVID-19 pandemic. Living systematic reviews (LSRs) offer a new approach to updating systematic reviews, particularly in high-priority research fields that face the challenge of dynamically evolving and sometimes uncertain evidence. Continual updates serve to ensure that LSRs remain current and methodologically rigorous. As a new element of the evidence ecosystem, LSRs can inform living guidelines and recommendations, user-adapted formats, decisions at the patient and system level as well as gaps in primary research.

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.

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.

Reevaluation of statistically significant meta-analyses in advanced cancer patients using the Hartung-Knapp method and prediction intervals-A methodological study.

Using the Hartung-Knapp method and 95% prediction intervals (PIs) in random-effects meta-analyses is recommended by experts but rarely applied. Therefore, we aimed to reevaluate statistically significant meta-analyses using the Hartung-Knapp method and 95% PIs. In this methodological study, three databases were searched from January 2010 to July 2019. We included systematic reviews reporting a statistically significant meta-analysis of at least four randomized controlled trials in advanced cancer patients using either a fixed-effect or random-effects model. We investigated the impact of switching from fixed-effect to random-effects meta-analysis and of using the recommended Hartung-Knapp method in random-effects meta-analyses. Furthermore, we calculated 95% PIs for all included meta-analyses. We identified 6234 hits, of which 261 statistically significant meta-analyses were included. Our recalculations of these 261 meta-analyses produced statistically significant results in 132 of 138 fixed-effect and 114 of 123 random-effects meta-analyses. When switching to a random-effects model, 19 of 132 fixed-effect meta-analyses (14.4%) were no longer statistically significant. Using the Hartung-Knapp method in random-effects meta-analyses resulted in 34 of 114 nonsignificant meta-analyses (29.8%). In the full sample (N = 261), the null effect was included by the 95% PI in 195 (74.7%) and the opposite effect (e.g., hazard ratio 0.5, opposite effect 2) in 98 meta-analyses (37.5%). Using the Hartung-Knapp method and PIs substantially influenced the interpretation of many published, statistically significant meta-analyses. We strongly encourage researchers to check if using the Hartung-Knapp method and reporting 95% PIs is appropriate in random-effects meta-analyses.

Methodological quality was critically low in 9/10 systematic reviews in advanced cancer patients-A methodological study.

OBJECTIVE: To assess the methodological quality and the consideration of heterogeneity in systematic reviews (SRs). STUDY DESIGN AND SETTING: We conducted a methodological study (CRD42019134904) and searched three databases from January 2010 to July 2019. Interventional SRs with a statistically significant meta-analysis of at least four randomized controlled trials in advanced cancer patients were included. A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) 2 was used to evaluate the SRs' methodological quality. The consideration of heterogeneity was categorized in clinical or/and methodological heterogeneity and not explored. RESULTS: From 6234 identified references, 261 SRs were included. Most SRs had a critically low quality (230, 88.1%). The majority of them (209, 80.1%) was classified as critically low because of non-registration (222, 85.1%) combined with the non-reporting of excluded full-texts and missing justifications for exclusion (218, 83.5%). Heterogeneity in trial results was not explored at all in 51 (19.5%) SRs whereas clinical heterogeneity was considered in 117 (44.8%), methodological heterogeneity in 13 (5.0%), and both clinical and methodological heterogeneity in 80 (30.7%) SRs. CONCLUSION: The consideration of these findings in trainings for review authors and peer reviewers could improve the awareness of quality criteria and the quality of future SRs. TRIAL REGISTRATION: PROSPERO-ID: CRD42019134904.

Transcutaneous electrical nerve stimulation for advanced cancer pain inpatients in specialist palliative care-a blinded, randomized, sham-controlled pilot cross-over trial.

PURPOSE: Transcutaneous electrical nerve stimulation (TENS) is a treatment option for cancer pain, but the evidence is inconclusive. We aimed to evaluate the efficacy and safety of TENS. METHODS: A blinded, randomized, sham-controlled pilot cross-over trial (NCT02655289) was conducted on an inpatient specialist palliative care ward. We included adult inpatients with cancer pain ≥ 3 on an 11-point numerical rating scale (NRS). Intensity-modulated high TENS (IMT) was compared with placebo TENS (PBT). Patients used both modes according to their preferred application scheme during 24 h with a 24-h washout phase. The primary outcome was change in average pain intensity on the NRS during the preceding 24 h. Responders were patients with at least a "slight improvement." RESULTS: Of 632 patients screened, 25 were randomized (sequence IMT-PBT = 13 and PBT-IMT = 12). Finally, 11 patients in IMT-PBT and 9 in PBT-IMT completed the study (N = 20). The primary outcome did not differ between groups (IMT minus PBT: - 0.2, 95% confidence interval - 0.9 to 0.6). However, responder rates were higher in IMT (17/20 [85%] vs. 10/20 [50%], p = 0.0428). Two patients experienced an uncomfortable feeling caused by the current, one after IMT and one after PBT. Seven patients (35%) desired a TENS prescription. Women and patients with incident pain were most likely to benefit from TENS. CONCLUSION: TENS was safe, but IMT was unlikely to offer more analgesic effects than PBT. Even though many patients desired a TENS prescription, 50% still reported at least "slight pain relief" from PBT. Differences for gender and incident pain aspects demand future trials.

Severe symptoms and very low quality-of-life among outpatients newly diagnosed with advanced cancer: data from a multicenter cohort study.

PURPOSE: The aim of this study was to identify symptoms of severe intensity or very low scores for quality of life (QoL) domains in newly diagnosed outpatients with advanced cancer. METHODS: This multicenter cohort study from a state-wide palliative care network included adult outpatients with advanced cancer diagnosed within the preceding 8 weeks from four comprehensive cancer centers (DRKS00006162, registered on 19 May 2014). We used the Palliative Outcome Scale (POS), Hospital Anxiety and Depression Scale, and European Organization for Research and Treatment of Cancer QoL Questionnaire-C30. For each questionnaire, cut-off scores defined symptoms and QoL domains that were considered "severe" or "very low." RESULTS: Of 3155 patients screened, 481/592 (81.3%) were analyzed (mean age 62.4; women n = 245, 50.9%). We identified 324/481 (67.4%) patients experiencing at least one severe symptom or a very low QoL domain (median 2; range 0 to 16). Role functioning (n = 180, 37.4%), fatigue (n = 162, 33.7%), and social functioning (n = 126, 26.2%) were most commonly affected. QoL was very low in 89 patients (18.5%). Women experienced more anxiety symptoms, fatigue, and had lower POS scores. Patients often mentioned physical symptoms and fears of adverse events resulting from disease-modifying therapies (e.g., chemotherapy) as most relevant problems. CONCLUSIONS: Already within the first 8 weeks after diagnosis, the majority of patients reported at least one severe symptom or a very low QoL domain. Gender differences were evident. The findings illustrate the value of early routine assessment of patient burden and the development of multi-professional and interdisciplinary palliative care.