Effects of radiofrequency electromagnetic field (RF-EMF) exposure on male fertility: A systematic review of experimental studies on non-human mammals and human sperm in vitro.

BACKGROUND: The World Health Organization is coordinating an international project aimed at systematically reviewing the evidence regarding the association between radiofrequency electromagnetic field (RF-EMF) exposure and adverse health effects. Reproductive health outcomes have been identified among the priority topics to be addressed. OBJECTIVES: To evaluate the effect of RF-EMF exposure on male fertility of experimental mammals and on human sperm exposed in vitro. METHODS: Three electronic databases (PubMed, Scopus and EMF Portal) were last searched on September 17, 2022. Two independent reviewers screened the studies, which were considered eligible if met the following criteria: 1) Peer-reviewed publications of sham controlled experimental studies, 2) Non-human male mammals exposed at any stage of development or human sperm exposed in vitro, 3) RF-EMF exposure within the frequency range of 100 kHz-300 GHz, including electromagnetic pulses (EMP), 4) one of the following indicators of reproductive system impairment:Two reviewers extracted study characteristics and outcome data. We assessed risk of bias (RoB) using the Office of Health Assessment and Translation (OHAT) guidelines. We categorized studies into 3 levels of overall RoB: low, some or high concern. We pooled study results in a random effects meta-analysis comparing average exposure to no-exposure and in a dose-response meta-analysis using all exposure doses. For experimental animal studies, we conducted subgroup analyses for species, Specific Absorption Rate (SAR) and temperature increase. We grouped studies on human sperm exposed in vitro by the fertility status of sample donors and SAR. We assessed the certainty of the evidence using the GRADE approach after excluding studies that were rated as "high concern" for RoB. RESULTS: One-hundred and seventeen papers on animal studies and 10 papers on human sperm exposed in vitro were included in this review. Only few studies were rated as "low concern" because most studies were at RoB for exposure and/or outcome assessment. Subgrouping the experimental animal studies by species, SAR, and temperature increase partly accounted for the heterogeneity of individual studies in about one third of the meta-analyses. In no case was it possible to conduct a subgroup analysis of the few human sperm in vitro studies because there were always 1 or more groups including less than 3 studies. Among all the considered endpoints, the meta-analyses of animal studies provided evidence of adverse effects of RF-EMF exposure in all cases but the rate of infertile males and the size of the sired litters. The assessment of certainty according to the GRADE methodology assigned a moderate certainty to the reduction of pregnancy rate and to the evidence of no-effect on litter size, a low certainty to the reduction of sperm count, and a very low certainty to all the other meta-analysis results. Studies on human sperm exposed in vitro indicated a small detrimental effect of RF-EMF exposure on vitality and no-effect on DNA/chromatin alterations. According to GRADE, a very low certainty was attributed to these results. The few studies that used EMP exposure did not show effects on the outcomes. A low to very low certainty was attributed to these results. DISCUSSION: Many of the studies examined suffered of severe limitations that led to the attribution of uncertainty to the results of the meta-analyses and did not allow to draw firm conclusions on most of the endpoints. Nevertheless, the associations between RF-EMF exposure and decrease of pregnancy rate and sperm count, to which moderate and low certainty were attributed, are not negligible, also in view of the indications that in Western countries human male fertility potential seems to be progressively declining. It was beyond the scope of our systematic review to determine the shape of the dose-response relationship or to identify a minimum effective exposure level. The subgroup and the dose-response fitting analyses did not show a consistent relationship between the exposure levels and the observed effects. Notably, most studies evaluated RF-EMF exposure levels that were higher than the levels to which human populations are typically exposed, and the limits set in international guidelines. For these reasons we cannot provide suggestions to confirm or reconsider current human exposure limits. Considering the outcomes of this systematic review and taking into account the limitations found in several of the studies, we suggest that further investigations with better characterization of exposure and dosimetry including several exposure levels and blinded outcome assessment were conducted. PROTOCOL REGISTRATION: Protocols for the systematic reviews of animal studies and of human sperm in vitro studies were published in Pacchierotti et al., 2021. The former was also registered in PROSPERO (CRD42021227729 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID = 227729) and the latter in Open Science Framework (OSF Registration DOI https://doi.org/10.17605/OSF.IO/7MUS3).

A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E).

BACKGROUND: Observational epidemiologic studies provide critical data for the evaluation of the potential effects of environmental, occupational and behavioural exposures on human health. Systematic reviews of these studies play a key role in informing policy and practice. Systematic reviews should incorporate assessments of the risk of bias in results of the included studies. OBJECTIVE: To develop a new tool, Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) to assess risk of bias in estimates from cohort studies of the causal effect of an exposure on an outcome. METHODS AND RESULTS: ROBINS-E was developed by a large group of researchers from diverse research and public health disciplines through a series of working groups, in-person meetings and pilot testing phases. The tool aims to assess the risk of bias in a specific result (exposure effect estimate) from an individual observational study that examines the effect of an exposure on an outcome. A series of preliminary considerations informs the core ROBINS-E assessment, including details of the result being assessed and the causal effect being estimated. The assessment addresses bias within seven domains, through a series of 'signalling questions'. Domain-level judgements about risk of bias are derived from the answers to these questions, then combined to produce an overall risk of bias judgement for the result, together with judgements about the direction of bias. CONCLUSION: ROBINS-E provides a standardized framework for examining potential biases in results from cohort studies. Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies). We believe that ROBINS-E represents an important development in the integration of exposure assessment, evidence synthesis and causal inference.

Intermethod agreement of self-reports compared to register data collection for return to work and sickness absence: a systematic review and meta-analysis.

OBJECTIVES: To determine the intermethod agreement of self-reported vs. register data of 'sickness absence' (SA) and 'return to work' (RTW) outcome measurements. STUDY DESIGN AND SETTING: We conducted a systematic review and a meta-analysis of studies reporting mean differences (MDs) and sensitivity and specificity for self-report vs. register data and an inductive analysis of the self-report question formulations. An information specialist searched Medline, Embase, PsycINFO for studies published from inception to November 2022. Screening and data extraction was done by two authors independently. RESULTS: Twenty-three studies were included of which eighteen with an overall high risk of bias. Self-reports had a pooled MD of 1.84 SA days (95% confidence interval [CI] 0.26-3.41, I2 98%, 18 studies, 38,716 participants) compared to registries which varied among studies from 204 more to 17 days less. The median average sick leave in studies in the self-report group was 8 days (interquartile range 4-23 days). Being absent from work measured with self-report had a sensitivity of 0.83 (0.76-0.88 95% CI) and a specificity of 0.92 (0.88-0.94 95% CI) compared to registry data. The high heterogeneity amongst the studies could not be explained by recall time, gender, register type, prospective or retrospective self-reports, health problem, SA at baseline or risk of bias. Studies lacked standard outcome reporting, had unclearly formulated questions in self-reports and there was little information on the registers' quality. CONCLUSION: Current self-reports may differ from register-based absence data but in an inconsistent way. Due to inconsistency and high risk of bias the evidence is judged to be of very low certainty. Further research is needed to develop clear standard questions which can be used for SA and RTW self-reports. Quality of registers needs to be better evaluated. Percentage positive and negative agreement, MDs and 2 × 2 tables should be reported for studies investigating agreement between SA and RTW outcome measures.

Effects of Radiofrequency Electromagnetic Field (RF-EMF) exposure on pregnancy and birth outcomes: A systematic review of experimental studies on non-human mammals.

BACKGROUND: The World Health Organization is coordinating an international project aimed at systematically reviewing the evidence regarding the association between radiofrequency electromagnetic field (RF-EMF) exposure and adverse health effects. Within the project, 6 topics have been prioritized by an expert group, which include reproductive health outcomes. OBJECTIVES: According to the protocol published in 2021, a systematic review and meta-analyses on the adverse effects of RF-EMF exposure during pregnancy in offspring of experimental animals were conducted. METHODS: Three electronic databases (PubMed, Scopus and EMF Portal) were last searched on September 8 or 17, 2022. Based on predefined selection criteria, the obtained references were screened by two independent reviewers. Studies were included if they met the following criteria: 1) original, sham controlled experimental study on non-human mammals exposed in utero, published in peer-reviewed journals, 2) the experimental RF-EMF exposure was within the frequency range 100 kHz-300 GHz, 3) the effects of RF-EMF exposure on fecundity (litter size, embryonic/fetal losses), on the offspring health at birth (decrease of weight or length, congenital malformations, changes of sex ratio) or on delayed effects (neurocognitive alterations, female infertility or early-onset cancer) were studied. Study characteristics and outcome data were extracted by two reviewers. Risk of bias (RoB) was assessed using the Office of Health Assessment and Translation (OHAT) guidelines. Study results were pooled in a random effects meta-analysis comparing average exposure to no-exposure and in a dose-response meta-analysis using all exposure doses, after exclusion of studies that were rated at "high concern" for RoB. Subgroup analyses were conducted for species, Specific Absorption Rate (SAR) and temperature increase. The certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. RESULTS: Eighty-eight papers could be included in this review. Effects on fecundity. The meta-analysis of studies on litter size, conducted at a whole-body average SAR of 4.92 W/kg, did not show an effect of RF-EMF exposure (MD 0.05; 95% CI -0.21 to 0.30). The meta-analysis of studies on resorbed and dead fetuses, conducted at a whole-body average SAR of 20.26 W/kg, showed a significant increase of the incidence in RF-EMF exposed animals (OR 1.84; 95% CI 1.27 to 2.66). The results were similar in the dose-response analysis. Effects on the offspring health at birth. The meta-analysis of studies on fetal weight, conducted at a whole-body average SAR of 9.83 W/kg, showed a small decrease in RF-EMF exposed animals (SMD 0.31; 95% CI 0.15 to 0.48). The meta-analysis of studies on fetal length, conducted at a whole-body average SAR of 4.55 W/kg, showed a moderate decrease in length at birth (SMD 0.45; 95% CI 0.07 to 0.83). The meta-analysis of studies on the percentage of fetuses with malformations, conducted at a whole-body average SAR of 6.75 W/kg, showed a moderate increase in RF-EMF exposed animals (SMD -0.45; 95% CI -0.68 to -0.23). The meta-analysis of studies on the incidence of litters with malformed fetuses, conducted at a whole-body average SAR of 16.63 W/kg, showed a statistically significant detrimental RF-EMF effect (OR 3.22; 95% CI 1.9 to 5.46). The results were similar in the dose-response analyses. Delayed effects on the offspring health. RF-EMF exposure was not associated with detrimental effects on brain weight (SMD 0.10; 95% CI -0.09 to 0.29) and on learning and memory functions (SMD -0.54; 95% CI -1.24 to 0.17). RF-EMF exposure was associated with a large detrimental effect on motor activity functions (SMD 0.79; 95% CI 0.21 to 1.38) and a moderate detrimental effect on motor and sensory functions (SMD -0.66; 95% CI -1.18 to -0.14). RF-EMF exposure was not associated with a decrease of the size of litters conceived by F2 female offspring (SMD 0.08; 95% CI -0.39 to 0.55). Notably, meta-analyses of neurobehavioural effects were based on few studies, which suffered of lack of independent replication deriving from only few laboratories. DISCUSSION: There was high certainty in the evidence for a lack of association of RF-EMF exposure with litter size. We attributed a moderate certainty to the evidence of a small detrimental effect on fetal weight. We also attributed a moderate certainty to the evidence of a lack of delayed effects on the offspring brain weight. For most of the other endpoints assessed by the meta-analyses, detrimental RF-EMF effects were shown, however the evidence was attributed a low or very low certainty. The body of evidence had limitations that did not allow an assessment of whether RF-EMF may affect pregnancy outcomes at exposure levels below those eliciting a well-known adverse heating impact. In conclusion, in utero RF-EMF exposure does not have a detrimental effect on fecundity and likely affects offspring health at birth, based on the meta-analysis of studies in experimental mammals on litter size and fetal weight, respectively. Regarding possible delayed effects of in utero exposure, RF-EMF probably does not affect offspring brain weight and may not decrease female offspring fertility; on the other hand, RF-EMF may have a detrimental impact on neurobehavioural functions, varying in magnitude for different endpoints, but these last findings are very uncertain. Further research is needed on the effects at birth and delayed effects with sample sizes adequate for detecting a small effect. Future studies should use standardized endpoints for testing prenatal developmental toxicity and developmental neurotoxicity (OECD TG 414 and 426), improve the description of the exposure system design and exposure conditions, conduct appropriate dosimetry characterization, blind endpoint analysis and include several exposure levels to better enable the assessment of a dose-response relationship. PROTOCOL REGISTRATION AND PUBLICATION: The protocol was published in Pacchierotti et al., 2021 and registered in PROSPERO CRD42021227746 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=227746).

GRADE GUIDANCE 38: Updated guidance for rating up certainty of evidence due to a dose-response gradient.

INTRODUCTION: This updated guidance from the Grading of Recommendations Assessment, Development, and Evaluation addresses rating up certainty of evidence due to a dose-response gradient (DRG) observed in synthesis of intervention and exposure studies. STUDY DESIGN AND SETTING: This guidance was developed using iterative discussions and consensus in multiple meetings and was presented to attendees of the Grading of Recommendations Assessment, Development, and Evaluation Working Group meeting for feedback in November 2022 and for final approval in May 2023. RESULTS: The guidance consists of two steps. The first is to determine whether the DRG is credible. We describe five items for assessing credibility: a) is DRG identified using a proper analytical approach; b) is confounding the cause of the DRG; c) is there serious concern about ecological bias; d) is the DRG consistent across studies; and e) is there indirect evidence supporting the DRG. The first two of these items are the most critical. If the DRG was judged to be credible, then the second step is to apply the DRG domain and consider rating up, but only by one level due to the concern about residual confounding. CONCLUSION: Systematic review authors should only rate up certainty in evidence when a DRG is deemed credible.

[How can general practitioners best help their depressed patients to resume work?] / Hausärztliche Betreuung bei der Rückkehr zur Arbeit.

How can general practitioners best help their depressed patients to resume work? Abstract. A recent Cochrane Review summarized the evidence of the effects of interventions to support depressed patients to return to work. The evidence base was quite large with 43 randomized controlled trials often leading to moderate and even high certainty evidence. For both return to work and depressive symptoms an integration of workplace interventions with clinical psychological treatment was most beneficial. Compared to care as usual, this could save 25 sick leave days on an annual basis for depressed patients. For general practitioners, it is worthwhile investing in organizing improved care with psychological treatment integrated with return-to-work measures. Simple workplace interventions such as decreased amount of working time or decreasing job demands will help if integrated in clinical care. The workplace accommodations are usually realized through the supervisor or the human resources department. Good relations with the supervisor are therefore essential. There is no evidence that antidepressant medication will help to decrease the time needed to return to work.

Which outcomes should always be measured in intervention studies for improving work participation for people with a health problem? An international multistakeholder Delphi study to develop a core outcome set for Work participation (COS for Work).

OBJECTIVE: Synthesising evidence of the effects of interventions to improve work participation among people with health problems is currently difficult due to heterogeneity in outcome measurements. A core outcome set for work participation is needed. STUDY DESIGN AND SETTING: Following the Core Outcome Measures in Effectiveness Trials methodology, we used a five-step approach to reach international multistakeholder consensus on a core outcome set for work participation. Five subgroups of stakeholders took part in two rounds of discussions and completed two Delphi voting rounds on 26 outcomes. A consensus of ≥80% determined core outcomes and 50%-80% consensus was required for candidate outcomes. RESULTS: Fifty-eight stakeholders took part in the Delphi rounds. Core outcomes were: 'any type of employment including self-employment', 'proportion of workers that return to work after being absent because of illness' and 'time to return to work'. Ten candidate outcomes were proposed, among others: 'sustainable employment', 'work productivity' and 'workers' perception of return to work'. CONCLUSION: As a minimum, all studies evaluating the impact of interventions on work participation should include one employment outcome and two return to work outcomes if workers are on sick leave prior to the intervention.

A general framework for selecting work participation outcomes in intervention studies among persons with health problems: a concept paper.

BACKGROUND: Work participation is important for health and can be considered as engagement in a major area of life which is of significance for most people, but it can also be thought of as fulfilling or discharging a role. Currently, academic research lacks a comprehensive classification of work participation outcomes. The International Classification of Functioning is the foremost model in defining work functioning and its counterpart work disability, but it does not provide a critical (core) set of outcomes. Standardizing the definitions and nomenclature used in the research of work participation would ensure that the outcomes of studies are comparable, and practitioners and guideline developers can better decide what works best. As work participation is a broad umbrella term including outcome categories which need unambiguous differentiation, a framework needs to be developed first. AIM: To propose a framework which can be used to develop a generic core outcome set for work participation. METHODS: First, we performed a systematic literature search on the concept of (work) participation, views on how to measure it, and on existing classifications for outcome measurements. Next, we derived criteria for the framework and proposed a framework based on the criteria. Last, we applied the framework to six case studies as a proof of concept. RESULTS: Our literature search provided 2106 hits and we selected 59 studies for full-text analysis. Based on the literature and the developed criteria we propose four overarching outcome categories: (1) initiating employment, (2) having employment, (3) increasing or maintaining productivity at work, and (4) return to employment. These categories appeared feasible in our proof-of-concept assessment with six different case studies. CONCLUSION: We propose to use the framework for work participation outcomes to develop a core outcome set for intervention studies to improve work participation.

Case studies to explore the optimal use of randomized and nonrandomized studies in evidence syntheses that use GRADE.

OBJECTIVES: Randomized controlled trials (RCTs) are the preferred source of evidence for the relative effect of healthcare interventions summarized in knowledge syntheses. Nonrandomized studies of interventions (NRSI) may provide replacement, sequential, or complementary evidence to RCTs. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach can provide different options for properly using RCTs and NRSI integrated in health syntheses. In this article, we discuss different implications on the certainty of evidence when authors consider the use of NRSI and RCTs in systematic reviews using GRADE. Although this is a GRADE-related article, it is not an official GRADE guidance or concept article. STUDY DESIGN AND SETTING: We present case studies used during GRADE working group meetings for discussion of the effects of using NRSI and RCTs on GRADE domains and on the certainty of evidence. Several concepts were discussed through iterative feedback with experts in GRADE methods and Cochrane authors. We compared suggested solutions for possible scenarios that can be met in evidence syntheses informing decisions and future guidance. RESULTS: Different scenarios for the use of RCTs and NRSI in evidence syntheses are presented, focusing on how different GRADE ratings between RCTs and NRSI affect the overall assessment of the evidence and possible health recommendations. CONCLUSIONS: Considering differences and similarities grounded in the GRADE approach between NRSI and RCTs may help complement one another and maximize the value of knowledge syntheses and health recommendations.

Preprocedural mouth rinses for preventing transmission of infectious diseases through aerosols in dental healthcare providers.

BACKGROUND: Aerosols and spatter are generated in a dental clinic during aerosol-generating procedures (AGPs) that use high-speed hand pieces. Dental healthcare providers can be at increased risk of transmission of diseases such as tuberculosis, measles and severe acute respiratory syndrome (SARS) through droplets on mucosae, inhalation of aerosols or through fomites on mucosae, which harbour micro-organisms. There are ways to mitigate and contain spatter and aerosols that may, in turn, reduce any risk of disease transmission. In addition to personal protective equipment (PPE) and aerosol-reducing devices such as high-volume suction, it has been hypothesised that the use of mouth rinse by patients before dental procedures could reduce the microbial load of aerosols that are generated during dental AGPs. OBJECTIVES: To assess the effects of preprocedural mouth rinses used in dental clinics to minimise incidence of infection in dental healthcare providers and reduce or neutralise contamination in aerosols. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 4 February 2022. SELECTION CRITERIA: We included randomised controlled trials and excluded laboratory-based studies. Study participants were dental patients undergoing AGPs. Studies compared any preprocedural mouth rinse used to reduce contaminated aerosols versus placebo, no mouth rinse or another mouth rinse. Our primary outcome was incidence of infection of dental healthcare providers and secondary outcomes were reduction in the level of contamination of the dental operatory environment, cost, change in mouth microbiota, adverse events, and acceptability and feasibility of the intervention. DATA COLLECTION AND ANALYSIS: Two review authors screened search results, extracted data from included studies, assessed the risk of bias in the studies and judged the certainty of the available evidence. We used mean differences (MDs) and 95% confidence intervals (CIs) as the effect estimate for continuous outcomes, and random-effects meta-analysis to combine data  MAIN RESULTS:  We included 17 studies with 830 participants aged 18 to 70 years. We judged three trials at high risk of bias, two at low risk and 12 at unclear risk of bias.  None of the studies measured our primary outcome of the incidence of infection in dental healthcare providers.  The primary outcome in the studies was reduction in the level of bacterial contamination measured in colony-forming units (CFUs) at distances of less than 2 m (intended to capture larger droplets) and 2 m or more (to capture droplet nuclei from aerosols arising from the participant's oral cavity). It is unclear what size of CFU reduction represents a clinically significant amount. There is low- to very low-certainty evidence that chlorhexidine (CHX) may reduce bacterial contamination, as measured by CFUs, compared with no rinsing or rinsing with water. There were similar results when comparing cetylpyridinium chloride (CPC) with no rinsing and when comparing CPC, essential oils/herbal mouthwashes or boric acid with water. There is very low-certainty evidence that tempered mouth rinses may provide a greater reduction in CFUs than cold mouth rinses. There is low-certainty evidence that CHX may reduce CFUs more than essential oils/herbal mouthwashes. The evidence for other head-to-head comparisons was limited and inconsistent.  The studies did not provide any information on costs, change in micro-organisms in the patient's mouth or adverse events such as temporary discolouration, altered taste, allergic reaction or hypersensitivity. The studies did not assess acceptability of the intervention to patients or feasibility of implementation for dentists.  AUTHORS' CONCLUSIONS: None of the included studies measured the incidence of infection among dental healthcare providers. The studies measured only reduction in level of bacterial contamination in aerosols. None of the studies evaluated viral or fungal contamination. We have only low to very low certainty for all findings. We are unable to draw conclusions regarding whether there is a role for preprocedural mouth rinses in reducing infection risk or the possible superiority of one preprocedural rinse over another. Studies are needed that measure the effect of rinses on infectious disease risk among dental healthcare providers and on contaminated aerosols at larger distances with standardised outcome measurement.

Workplace interventions to reduce the risk of SARS-CoV-2 infection outside of healthcare settings.

BACKGROUND: Although many people infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) experience no or mild symptoms, some individuals can develop severe illness and may die, particularly older people and those with underlying medical problems. Providing evidence-based interventions to prevent SARS-CoV-2 infection has become more urgent with the spread of more infectious SARS-CoV-2 variants of concern (VoC), and the potential psychological toll imposed by the coronavirus disease 2019 (COVID-19) pandemic.   Controlling exposures to occupational hazards is the fundamental method of protecting workers. When it comes to the transmission of viruses, such as SARS-CoV-2, workplaces should first consider control measures that can potentially have the most significant impact. According to the hierarchy of controls, one should first consider elimination (and substitution), then engineering controls, administrative controls, and lastly, personal protective equipment (PPE). OBJECTIVES: To assess the benefits and harms of interventions in non-healthcare-related workplaces to reduce the risk of SARS-CoV-2 infection relative to other interventions, or no intervention. SEARCH METHODS: We searched MEDLINE, Embase, Web of Science, Cochrane COVID-19 Study Register, the Canadian Centre for Occupational Health and Safety (CCOHS), Clinicaltrials.gov, and the International Clinical Trials Registry Platform to 14 September 2021. We will conduct an update of this review in six months. SELECTION CRITERIA: We included randomised control trials (RCT) and planned to include non-randomised studies of interventions. We included adult workers, both those who come into close contact with clients or customers (e.g. public-facing employees, such as cashiers or taxi drivers), and those who do not, but who could be infected by co-workers. We excluded studies involving healthcare workers. We included any intervention to prevent or reduce workers' exposure to SARS-CoV-2 in the workplace, defining categories of intervention according to the hierarchy of hazard controls, i.e. elimination; engineering controls; administrative controls; personal protective equipment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were incidence rate of SARS-CoV-2 infection (or other respiratory viruses), SARS-CoV-2-related mortality, adverse events, and absenteeism from work. Our secondary outcomes were all-cause mortality, quality of life, hospitalisation, and uptake, acceptability, or adherence to strategies. We used the Cochrane RoB 2 tool to assess the risk of bias, and GRADE methods to assess the certainty of evidence for each outcome. MAIN RESULTS: Elimination of exposure interventions We included one study examining an intervention that focused on elimination of hazards. This study is an open-label, cluster-randomised, non-inferiority trial, conducted in England in 2021. The study compared standard 10-day self-isolation after contact with an infected person to a new strategy of daily rapid antigen testing and staying at work if the test is negative (test-based attendance). The trialists hypothesised that this would lead to a similar rate of infections, but lower COVID-related absence. Staff (N = 11,798) working at 76 schools were assigned to standard isolation, and staff (N = 12,229) at 86 schools to the test-based attendance strategy.  The results between test-based attendance and standard 10-day self-isolation were inconclusive for the rate of symptomatic PCR-positive SARS-COV-2 infection rate ratio ((RR) 1.28, 95% confidence interval (CI) 0.74 to 2.21; 1 study, very low-certainty evidence)). The results between test-based attendance and standard 10-day self-isolation were inconclusive for the rate of any PCR-positive SARS-COV-2 infection (RR 1.35, 95% CI 0.82 to 2.21; 1 study, very low-certainty evidence). COVID-related absenteeism rates were 3704 absence days in 566,502 days-at-risk (6.5 per 1000 days at risk) in the control group and 2932 per 539,805 days-at-risk (5.4 per 1000 days at risk) in the intervention group (RR 0.83; 95% CI 0.55 to 1.25). The certainty of the evidence was downgraded to low, due to imprecision. Uptake of the intervention was 71 % in the intervention group, but not reported for the control intervention.  The trial did not measure other outcomes, SARS-CoV-2-related mortality, adverse events, all-cause mortality, quality of life, and hospitalisation. We found one ongoing RCT about screening in schools, using elimination of hazard strategies. Personal protective equipment We found one ongoing non-randomised study on the effects of closed face shields to prevent COVID-19 transmission. Other intervention categories We did not find studies in the other intervention categories. AUTHORS' CONCLUSIONS: We are uncertain whether a test-based attendance policy affects rates of PCR-postive SARS-CoV-2 infection (any infection; symptomatic infection) compared to standard 10-day self-isolation amongst school and college staff. Test-based attendance policy may result in little to no difference in absence rates compared to standard 10-day self-isolation. As a large part of the population is exposed in the case of a pandemic, an apparently small relative effect that would not be worthwhile from the individual perspective may still affect many people, and thus, become an important absolute effect from the enterprise or societal perspective.  The included study did not report on any other primary outcomes of our review, i.e. SARS-CoV-2-related mortality and adverse events. No completed studies were identified on any other interventions specified in this review, but two eligible studies are ongoing. More controlled studies are needed on testing and isolation strategies, and working from home, as these have important implications for work organisations.

Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks.

The workshop titled "Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks" was co-organized by the Evidence-based Toxicology Collaboration and the European Food Safety Authority (EFSA) and hosted by EFSA at its headquarters in Parma, Italy on October 2 and 3, 2019. The goal was to explore integration of systematic review with mechanistic evidence evaluation. Participants were invited to work on concrete products to advance the exploration of how evidence-based approaches can support the development and application of adverse outcome pathways (AOP) in chemical risk assessment. The workshop discussions were centered around three related themes: 1) assessing certainty in AOPs, 2) literature-based AOP development, and 3) integrating certainty in AOPs and non-animal evidence into decision frameworks. Several challenges, mostly related to methodology, were identified and largely determined the workshop recommendations. The workshop recommendations included the comparison and potential alignment of processes used to develop AOP and systematic review methodology, including the translation of vocabulary of evidence-based methods to AOP and vice versa, the development and improvement of evidence mapping and text mining methods and tools, as well as a call for a fundamental change in chemical risk and uncertainty assessment methodology if to be conducted based on AOPs and new approach methodologies (NAM). The usefulness of evidence-based approaches for mechanism-based chemical risk assessments was stressed, particularly the potential contribution of the rigor and transparency inherent to such approaches in building stakeholders' trust for implementation of NAM evidence and AOPs into chemical risk assessment.

Preferred Methods of Measuring Work Participation: An International Survey Among Trialists and Cochrane Systematic Reviewers.

Purpose Heterogeneity in work participation (WP) outcomes measurements hampers large scale evidence synthesis in systematic reviews of trials. In this survey we explore authors' reasons for choosing specific WP outcomes and their measurement methods, including employment status, absence from work, at-work productivity loss, and employability. Methods We contacted authors of 260 trials and 69 systematic reviews and asked closed and open-ended questions about previously used WP outcomes and measurement methods as well as their opinion on the best way to measure WP. Results In total, 91 authors from a wide range of professional backgrounds completed the survey. The majority of authors (86%) chose WP outcomes based on their use in previous similar studies. In most studies (88%), patients had not been involved in the process of selecting the WP outcome. Authors judged feasibility to be an important factor for choosing a measurement instrument (67%). Additionally, valid measurement tools should be available, easy to administer and not too time consuming. Although authors preferred registry data for long term follow-up, the availability and validity of registries was seen as a barrier. Most of the reviewers (72%) struggled to pool data because of variation in follow-up times and cut off points and varying definitions of work outcomes. Almost all (92%) respondents support the use of a Core Outcome Set for Work. Conclusions There is strong support from authors of trials and systematic reviews to develop a core outcome set on work participation outcomes for the evaluation of interventions.

The use of the GRADE dose-response gradient domain in nutrition evidence syntheses varies considerably.

OBJECTIVES: This study aimed to identify and describe the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) dose-response gradient domain to upgrade the certainty of evidence (CoE) in nutrition systematic reviews (SRs). STUDY DESIGN AND SETTING: We searched for SRs of observational studies of nutrition topics that used GRADE and upgraded the CoE of at least one outcome for a dose-response gradient or reported reasons for not upgrading. RESULTS: Within eligible SRs (21/281), 123 of 371 outcomes were upgraded for a dose-response gradient. For 118 outcomes, the authors conducted linear dose-response analyses, and for 106 outcomes, the authors conducted nonlinear dose-response analyses. From these, 107 outcomes showed a statistically significant (P < 0.05) association in the linear dose-response model, and for 28 outcomes, the test for nonlinearity was statistically significant. The CoE for 0.8% of all outcomes was rated as high, 47.2% as moderate, 43.9% as low, and 8.1% as very low. Fifty-five percent of outcomes that were upgraded for a dose-response gradient were already downgraded for at least one domain. This is contrary to GRADE guidance. CONCLUSION: The approach for rating up the CoE for dose-response relationship is not consistent in nutrition reviews, likely because of a lack of clear guidance for when and how to do it. Therefore, more comprehensive GRADE guidance is necessary to enhance the correct use and comparability of dose-response upgrading.

Evidence-informed decision about (de-)implementing return-to-work coordination to reduce sick leave: a case study.

BACKGROUND: Coordination of return to work (RtW) is implemented in many countries, but a Cochrane review found no considerable effect on workers' sick leave compared to usual care. The aim of the study is to analyse how the evidence from this review can be used for decisions about (de-)implementing RtW coordination in a country-specific setting, using Finland as an example. METHODS: We conducted a systematic literature search and online survey with two groups of experts to compare interventions included in the Cochrane review to Finnish RtW practice using content analysis methods. We applied the evidence-to-decision (EtD) framework criteria to draw conclusions about (de-)implementing RtW coordination in Finland, including benefits, harms and costs of the intervention compared to usual care. RESULTS: We included seven documents from the literature search and received data from 10 of 42 survey participants. RtW coordination included, both in Finland and in the review, at least one face-to-face meeting between the physician and the worker, a workers' needs assessment, and an individual RtW plan and its implementation. Usual care focuses on medical treatment and may include general RtW advice. RtW coordination would be cost-saving if it decreases sick leave with at least 2 days compared to usual care. The evidence in the Cochrane review was mainly of low certainty, and the effect sizes had relatively wide confidence intervals. Only a new, high-quality and large randomized controlled trial (RCT) can decrease the current uncertainty, but this is unlikely to happen. The EtD framework did not provide arguments for further implementation or for de-implementation of the intervention. CONCLUSIONS: Interventions evaluated in the Cochrane review are similar to RtW coordination and usual care interventions in Finland. Considering all EtD framework criteria, including certainty of the evidence and costs, de-implementation of RtW coordination interventions in Finland seems unnecessary. Better evidence about the costs and stakeholders' values regarding RtW coordination is needed to improve decision-making.

The effect of radiofrequency electromagnetic fields (RF-EMF) on biomarkers of oxidative stress in vivo and in vitro: A protocol for a systematic review.

BACKGROUND: Oxidative stress is conjectured to be related to many diseases. Furthermore, it is hypothesized that radiofrequency fields may induce oxidative stress in various cell types and thereby compromise human and animal health. This systematic review (SR) aims to summarize and evaluate the literature related to this hypothesis. OBJECTIVES: The main objective of this SR is to evaluate the associations between the exposure to radiofrequency electromagnetic fields and oxidative stress in experimental models (in vivo and in vitro). METHODS: The SR framework has been developed following the guidelines established in the WHO Handbook for Guideline Development and the Handbook for Conducting a Literature-Based Health Assessment). We will include controlled in vivo and in vitro laboratory studies that assess the effects of an exposure to RF-EMF on valid markers for oxidative stress compared to no or sham exposure. The protocol is registered in PROSPERO. We will search the following databases: PubMed, Embase, Web of Science Core Collection, Scopus, and the EMF-Portal. The reference lists of included studies and retrieved review articles will also be manually searched. STUDY APPRAISAL AND SYNTHESIS METHOD: Data will be extracted according to a pre-defined set of forms developed in the DistillerSR online software and synthesized in a meta-analysis when studies are judged sufficiently similar to be combined. If a meta-analysis is not possible, we will describe the effects of the exposure in a narrative way. RISK OF BIAS: The risk of bias will be assessed with the NTP/OHAT risk of bias rating tool for human and animal studies. We will use GRADE to assess the certainty of the conclusions (high, moderate, low, or inadequate) regarding the association between radiofrequency electromagnetic fields and oxidative stress. FUNDING: This work was funded by the World Health Organization (WHO). REGISTRATION: The protocol was registered on the PROSPERO webpage on July 8, 2021.

Extensive variability of work participation outcomes measured in randomized controlled trials: a systematic review.

OBJECTIVE: To investigate how work participation outcomes in randomized controlled trials are measured internationally and across disciplines. STUDY DESIGN AND SETTING: We identified trials that reported on work participation in Medline, Embase, PsycINFO and Cochrane Central published between 2014 and 2019. Screening, selection, and data extraction were done by two authors independently. We grouped outcomes into four categories ("employment status", "absence from work", "at-work productivity loss," and "employability") and created subcategories according to how the outcome was measured. RESULTS: From 10,022 database hits we selected 269 trials reporting on 435 work participation outcomes. Authors used inconsistent outcome terminology to describe the measured constructs. Grouped in four main categories we identified 70 outcomes that reported on "employment status", 196 on "absence from work" and return-to-work, 132 on "at-work productivity loss," and 37 on "employability" outcomes. Variability in measurement methods existed across all categories. Employment status and absenteeism measures consisted mostly of clinimetrically unvalidated tools. "At-work productivity loss" and "employability" were measured by at least 41 different questionnaires. CONCLUSION: Extensive variability exists among trials in the measurement of outcomes, measurement methods and measurement instruments that focus on work participation. This study is a first step towards the development of a Core Outcome Set for work participation.

GRADE guidance 24 optimizing the integration of randomized and non-randomized studies of interventions in evidence syntheses and health guidelines.

BACKGROUND AND OBJECTIVE: This is the 24th in the ongoing series of articles describing the GRADE approach for assessing the certainty of a body of evidence in systematic reviews and health technology assessments and how to move from evidence to recommendations in guidelines. METHODS: Guideline developers and authors of systematic reviews and other evidence syntheses use randomized controlled studies (RCTs) and non-randomized studies of interventions (NRSI) as sources of evidence for questions about health interventions. RCTs with low risk of bias are the most trustworthy source of evidence for estimating relative effects of interventions because of protection against confounding and other biases. However, in several instances, NRSI can still provide valuable information as complementary, sequential, or replacement evidence for RCTs. RESULTS: In this article we offer guidance on the decision regarding when to search for and include either or both types of studies in systematic reviews to inform health recommendations. CONCLUSION: This work aims to help methodologists in review teams, technology assessors, guideline panelists, and anyone conducting evidence syntheses using GRADE.