Wastewater pandemic preparedness: Toward an end-to-end pathogen monitoring program.

Molecular analysis of public wastewater has great potential as a harbinger for community health and health threats. Long-used to monitor the presence of enteric viruses, in particular polio, recent successes of wastewater as a reliable lead indicator for trends in SARS-CoV-2 levels and hospital admissions has generated optimism and emerging evidence that similar science can be applied to other pathogens of pandemic potential (PPPs), especially respiratory viruses and their variants of concern (VOC). However, there are substantial challenges associated with implementation of this ideal, namely that multiple and distinct fields of inquiry must be bridged and coordinated. These include engineering, molecular sciences, temporal-geospatial analytics, epidemiology and medical, and governmental and public health messaging, all of which present their own caveats. Here, we outline a framework for an integrated, state-wide, end-to-end human pathogen monitoring program using wastewater to track viral PPPs.

Effect of covid-19 vaccination on long covid: systematic review

Objective To determine the effect of covid-19 vaccination, given before and after acute infection with the SARS-CoV-2 virus, or after a diagnosis of long covid, on the rates and symptoms of long covid. Design Systematic review. Data sources PubMed, Embase, and Cochrane covid-19 trials, and Europe PubMed Central (Europe PMC) for preprints, from 1 January 2020 to 3 August 2022. Eligibility criteria for selecting studies Trials, cohort studies, and case-control studies reporting on patients with long covid and symptoms of long covid, with vaccination before and after infection with the SARS-CoV-2 virus, or after a diagnosis of long covid. Risk of bias was assessed with the ROBINS-I tool. Results 1645 articles were screened but no randomised controlled trials were found. 16 observational studies from five countries (USA, UK, France, Italy, and the Netherlands) were identified that reported on 614 392 patients. The most common symptoms of long covid that were studied were fatigue, cough, loss of sense of smell, shortness of breath, loss of taste, headache, muscle ache, difficulty sleeping, difficulty concentrating, worry or anxiety, and memory loss or confusion. 12 studies reported data on vaccination before infection with the SARS-CoV-2 virus, and 10 showed a significant reduction in the incidence of long covid: the odds ratio of developing long covid with one dose of vaccine ranged from 0.22 to 1.03;with two doses, odds ratios were 0.25-1;with three doses, 0.16;and with any dose, 0.48-1.01. Five studies reported on vaccination after infection, with odds ratios of 0.38-0.91. The high heterogeneity between studies precluded any meaningful meta-analysis. The studies failed to adjust for potential confounders, such as other protective behaviours and missing data, thus increasing the risk of bias and decreasing the certainty of evidence to low. Conclusions Current studies suggest that covid-19 vaccines might have protective and therapeutic effects on long covid. More robust comparative observational studies and trials are needed, however, to clearly determine the effectiveness of vaccines in preventing and treating long covid. Protocol registration Open Science Framework https://osf.io/e8jdy.

Physical interventions to interrupt or reduce the spread of respiratory viruses.

BACKGROUND: Viral epidemics or pandemics of acute respiratory infections (ARIs) pose a global threat. Examples are influenza (H1N1) caused by the H1N1pdm09 virus in 2009, severe acute respiratory syndrome (SARS) in 2003, and coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in 2019. Antiviral drugs and vaccines may be insufficient to prevent their spread. This is an update of a Cochrane Review last published in 2020. We include results from studies from the current COVID-19 pandemic. OBJECTIVES: To assess the effectiveness of physical interventions to interrupt or reduce the spread of acute respiratory viruses. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, CINAHL, and two trials registers in October 2022, with backwards and forwards citation analysis on the new studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster-RCTs investigating physical interventions (screening at entry ports, isolation, quarantine, physical distancing, personal protection, hand hygiene, face masks, glasses, and gargling) to prevent respiratory virus transmission.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included 11 new RCTs and cluster-RCTs (610,872 participants) in this update, bringing the total number of RCTs to 78. Six of the new trials were conducted during the COVID-19 pandemic; two from Mexico, and one each from Denmark, Bangladesh, England, and Norway. We identified four ongoing studies, of which one is completed, but unreported, evaluating masks concurrent with the COVID-19 pandemic. Many studies were conducted during non-epidemic influenza periods. Several were conducted during the 2009 H1N1 influenza pandemic, and others in epidemic influenza seasons up to 2016. Therefore, many studies were conducted in the context of lower respiratory viral circulation and transmission compared to COVID-19. The included studies were conducted in heterogeneous settings, ranging from suburban schools to hospital wards in high-income countries; crowded inner city settings in low-income countries; and an immigrant neighbourhood in a high-income country. Adherence with interventions was low in many studies. The risk of bias for the RCTs and cluster-RCTs was mostly high or unclear. Medical/surgical masks compared to no masks We included 12 trials (10 cluster-RCTs) comparing medical/surgical masks versus no masks to prevent the spread of viral respiratory illness (two trials with healthcare workers and 10 in the community). Wearing masks in the community probably makes little or no difference to the outcome of influenza-like illness (ILI)/COVID-19 like illness compared to not wearing masks (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.84 to 1.09; 9 trials, 276,917 participants; moderate-certainty evidence. Wearing masks in the community probably makes little or no difference to the outcome of laboratory-confirmed influenza/SARS-CoV-2 compared to not wearing masks (RR 1.01, 95% CI 0.72 to 1.42; 6 trials, 13,919 participants; moderate-certainty evidence). Harms were rarely measured and poorly reported (very low-certainty evidence). N95/P2 respirators compared to medical/surgical masks We pooled trials comparing N95/P2 respirators with medical/surgical masks (four in healthcare settings and one in a household setting). We are very uncertain on the effects of N95/P2 respirators compared with medical/surgical masks on the outcome of clinical respiratory illness (RR 0.70, 95% CI 0.45 to 1.10; 3 trials, 7779 participants; very low-certainty evidence). N95/P2 respirators compared with medical/surgical masks may be effective for ILI (RR 0.82, 95% CI 0.66 to 1.03; 5 trials, 8407 participants; low-certainty evidence). Evidence is limited by imprecision and heterogeneity for these subjective outcomes. The use of a N95/P2 respirators compared to medical/surgical masks probably makes little or no difference for the objective and more precise outcome of laboratory-confirmed influenza infection (RR 1.10, 95% CI 0.90 to 1.34; 5 trials, 8407 participants; moderate-certainty evidence). Restricting pooling to healthcare workers made no difference to the overall findings. Harms were poorly measured and reported, but discomfort wearing medical/surgical masks or N95/P2 respirators was mentioned in several studies (very low-certainty evidence).  One previously reported ongoing RCT has now been published and observed that medical/surgical masks were non-inferior to N95 respirators in a large study of 1009 healthcare workers in four countries providing direct care to COVID-19 patients.  Hand hygiene compared to control Nineteen trials compared hand hygiene interventions with controls with sufficient data to include in meta-analyses. Settings included schools, childcare centres and homes. Comparing hand hygiene interventions with controls (i.e. no intervention), there was a 14% relative reduction in the number of people with ARIs in the hand hygiene group (RR 0.86, 95% CI 0.81 to 0.90; 9 trials, 52,105 participants; moderate-certainty evidence), suggesting a probable benefit. In absolute terms this benefit would result in a reduction from 380 events per 1000 people to 327 per 1000 people (95% CI 308 to 342). When considering the more strictly defined outcomes of ILI and laboratory-confirmed influenza, the estimates of effect for ILI (RR 0.94, 95% CI 0.81 to 1.09; 11 trials, 34,503 participants; low-certainty evidence), and laboratory-confirmed influenza (RR 0.91, 95% CI 0.63 to 1.30; 8 trials, 8332 participants; low-certainty evidence), suggest the intervention made little or no difference. We pooled 19 trials (71, 210 participants) for the composite outcome of ARI or ILI or influenza, with each study only contributing once and the most comprehensive outcome reported. Pooled data showed that hand hygiene may be beneficial with an 11% relative reduction of respiratory illness (RR 0.89, 95% CI 0.83 to 0.94; low-certainty evidence), but with high heterogeneity. In absolute terms this benefit would result in a reduction from 200 events per 1000 people to 178 per 1000 people (95% CI 166 to 188). Few trials measured and reported harms (very low-certainty evidence). We found no RCTs on gowns and gloves, face shields, or screening at entry ports. AUTHORS' CONCLUSIONS: The high risk of bias in the trials, variation in outcome measurement, and relatively low adherence with the interventions during the studies hampers drawing firm conclusions. There were additional RCTs during the pandemic related to physical interventions but a relative paucity given the importance of the question of masking and its relative effectiveness and the concomitant measures of mask adherence which would be highly relevant to the measurement of effectiveness, especially in the elderly and in young children. There is uncertainty about the effects of face masks. The low to moderate certainty of evidence means our confidence in the effect estimate is limited, and that the true effect may be different from the observed estimate of the effect. The pooled results of RCTs did not show a clear reduction in respiratory viral infection with the use of medical/surgical masks. There were no clear differences between the use of medical/surgical masks compared with N95/P2 respirators in healthcare workers when used in routine care to reduce respiratory viral infection. Hand hygiene is likely to modestly reduce the burden of respiratory illness, and although this effect was also present when ILI and laboratory-confirmed influenza were analysed separately, it was not found to be a significant difference for the latter two outcomes. Harms associated with physical interventions were under-investigated. There is a need for large, well-designed RCTs addressing the effectiveness of many of these interventions in multiple settings and populations, as well as the impact of adherence on effectiveness, especially in those most at risk of ARIs.

Assessment of a SARS-CoV-2 wastewater monitoring program in El Paso, Texas, from November 2020 to June 2022.

The border city of El Paso, Texas, and its water utility, El Paso Water, initiated a SARS-CoV-2 wastewater monitoring program to assess virus trends and the appropriateness of a wastewater monitoring program for the community. Nearly weekly sample collection at four wastewater treatment facilities (WWTFs), serving distinct regions of the city, was analyzed for SARS-CoV-2 genes using the CDC 2019-Novel coronavirus Real-Time RT-PCR diagnostic panel. Virus concentrations ranged from 86.7 to 268,000 gc/L, varying across time and at each WWTF. The lag time between virus concentrations in wastewater and reported COVID-19 case rates (per 100,00 population) ranged from 4-24 days for the four WWTFs, with the strongest trend occurring from November 2021 - June 2022. This study is an assessment of the utility of a geographically refined SARS-CoV-2 wastewater monitoring program to supplement public health efforts that will manage the virus as it becomes endemic in El Paso.

Telehealth Versus Face-to-face Psychotherapy for Less Common Mental Health Conditions: Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Mental disorders are a leading cause of distress and disability worldwide. To meet patient demand, there is a need for increased access to high-quality, evidence-based mental health care. Telehealth has become well established in the treatment of illnesses, including mental health conditions. OBJECTIVE: This study aims to conduct a robust evidence synthesis to assess whether there is evidence of differences between telehealth and face-to-face care for the management of less common mental and physical health conditions requiring psychotherapy. METHODS: In this systematic review, we included randomized controlled trials comparing telehealth (telephone, video, or both) versus the face-to-face delivery of psychotherapy for less common mental health conditions and physical health conditions requiring psychotherapy. The psychotherapy delivered had to be comparable between the telehealth and face-to-face groups, and it had to be delivered by general practitioners, primary care nurses, or allied health staff (such as psychologists and counselors). Patient (symptom severity, overall improvement in psychological symptoms, and function), process (working alliance and client satisfaction), and financial (cost) outcomes were included. RESULTS: A total of 12 randomized controlled trials were included, with 931 patients in aggregate; therapies included cognitive behavioral and family therapies delivered in populations encompassing addiction disorders, eating disorders, childhood mental health problems, and chronic conditions. Telehealth was delivered by video in 7 trials, by telephone in 3 trials, and by both in 1 trial, and the delivery mode was unclear in 1 trial. The risk of bias for the 12 trials was low or unclear for most domains, except for the lack of the blinding of participants, owing to the nature of the comparison. There were no significant differences in symptom severity between telehealth and face-to-face therapy immediately after treatment (standardized mean difference [SMD] 0.05, 95% CI -0.17 to 0.27) or at any other follow-up time point. Similarly, there were no significant differences immediately after treatment between telehealth and face-to-face care delivery on any of the other outcomes meta-analyzed, including overall improvement (SMD 0.00, 95% CI -0.40 to 0.39), function (SMD 0.13, 95% CI -0.16 to 0.42), working alliance client (SMD 0.11, 95% CI -0.34 to 0.57), working alliance therapist (SMD -0.16, 95% CI -0.91 to 0.59), and client satisfaction (SMD 0.12, 95% CI -0.30 to 0.53), or at any other time point (3, 6, and 12 months). CONCLUSIONS: With regard to effectively treating less common mental health conditions and physical conditions requiring psychological support, there is insufficient evidence of a difference between psychotherapy delivered via telehealth and the same therapy delivered face-to-face. However, there was no includable evidence in this review for some serious mental health conditions, such as schizophrenia and bipolar disorders, and further high-quality research is needed to determine whether telehealth is a viable, equivalent treatment option for these conditions.

The effectiveness of telehealth versus face-to face interventions for anxiety disorders: A systematic review and meta-analysis.

INTRODUCTION: Worldwide, it is estimated that 264 million people meet the diagnostic criteria for anxiety conditions. Effective treatment regimens consist of cognitive and behavioural therapies. During the COVID-19 pandemic, treatment delivery relied heavily on telemedicine technologies which enabled remote consultation with patients via phone or video platforms. We aim to identify, appraise and synthesise randomised controlled trials comparing telehealth to face-to-face delivery of care to individuals of any age or gender, diagnosed with anxiety disorders, and disorders with anxiety features. METHODS: To conduct this systematic review and meta-analysis, we searched three electronic databases, clinical trial registries and citing-cited references of included studies. RESULTS: A total of five small randomised controlled trials were includable; telehealth was conducted by video in three studies, and by telephone in two. The risk of bias for the 5 studies was low to moderate for most domains. Outcomes related to anxiety, depression symptom severity, obsessive-compulsive disorder, function, working alliance, and satisfaction were comparable between the two modes of delivery at each follow-up time point (immediately post-intervention, 3 months, 6 months and 12 months), with no significant differences reported (p > 0.05). None of the trials reported on the costs of telehealth compared to face-to-face care. DISCUSSION: For effectively treating anxiety and related conditions, interventions delivered by telehealth appear to be as effective as the same therapy delivered in-person. However, further high-quality trials are warranted to determine the effectiveness, acceptability, feasibility, and cost-effectiveness of telehealth interventions for the management of a wider range of anxiety disorders and treatments.

The effect of eye protection on SARS-CoV-2 transmission: a systematic review.

BACKGROUND: The effect of eye protection to prevent SARS-CoV-2 infection in the real-world remains uncertain. We aimed to synthesize all available research on the potential impact of eye protection on transmission of SARS-CoV-2. METHODS: We searched PROSPERO, PubMed, Embase, The Cochrane Library for clinical trials and comparative observational studies in CENTRAL, and Europe PMC for pre-prints. We included studies that reported sufficient data to estimate the effect of any form of eye protection including face shields and variants, goggles, and glasses, on subsequent confirmed infection with SARS-CoV-2. RESULTS: We screened 898 articles and included 6 reports of 5 observational studies from 4 countries (USA, India, Columbia, and United Kingdom) that tested face shields, goggles, and wraparound eyewear on 7567 healthcare workers. The three before-and-after and one retrospective cohort studies showed statistically significant and substantial reductions in SARS-CoV-2 infections favouring eye protection with odds ratios ranging from 0.04 to 0.6, corresponding to relative risk reductions of 96% to 40%. These reductions were not explained by changes in the community rates. However, the one case-control study reported odds ratio favouring no eye protection (OR 1.7, 95% CI 0.99, 3.0). The high heterogeneity between studies precluded any meaningful meta-analysis. None of the studies adjusted for potential confounders such as other protective behaviours, thus increasing the risk of bias, and decreasing the certainty of evidence to very low. CONCLUSIONS: Current studies suggest that eye protection may play a role in prevention of SARS-CoV-2 infection in healthcare workers. However, robust comparative trials are needed to clearly determine effectiveness of eye protections and wearability issues in both healthcare and general populations.

Systematic review automation tools improve efficiency but lack of knowledge impedes their adoption: a survey.

OBJECTIVE: We investigated systematic review automation tool use by systematic reviewers, health technology assessors and clinical guideline developerst. STUDY DESIGN AND SETTING: An online, 16-question survey was distributed across several evidence synthesis, health technology assessment and guideline development organizations. We asked the respondents what tools they use and abandon, how often and when do they use the tools, their perceived time savings and accuracy, and desired new tools. Descriptive statistics were used to report the results. RESULTS: A total of 253 respondents completed the survey; 89% have used systematic review automation tools - most frequently whilst screening (79%). Respondents' "top 3" tools included: Covidence (45%), RevMan (35%), Rayyan and GRADEPro (both 22%); most commonly abandoned were Rayyan (19%), Covidence (15%), DistillerSR (14%) and RevMan (13%). Tools saved time (80%) and increased accuracy (54%). Respondents taught themselves to how to use the tools (72%); lack of knowledge was the most frequent barrier to tool adoption (51%). New tool development was suggested for the searching and data extraction stages. CONCLUSION: Automation tools will likely have an increasingly important role in high-quality and timely reviews. Further work is required in training and dissemination of automation tools and ensuring they meet the desirable features of those conducting systematic reviews.

Tuberculosis related disability: a systematic review and meta-analysis.

BACKGROUND: The sustainable development goals aim to improve health for all by 2030. They incorporate ambitious goals regarding tuberculosis (TB), which may be a significant cause of disability, yet to be quantified. Therefore, we aimed to quantify the prevalence and types of TB-related disabilities. METHODS: We performed a systematic review of TB-related disabilities. The pooled prevalence of disabilities was calculated using the inverse variance heterogeneity model. The maps of the proportions of common types of disabilities by country income level were created. RESULTS: We included a total of 131 studies (217,475 patients) that were conducted in 49 countries. The most common type of disabilities were mental health disorders (23.1%), respiratory impairment (20.7%), musculoskeletal impairment (17.1%), hearing impairment (14.5%), visual impairment (9.8%), renal impairment (5.7%), and neurological impairment (1.6%). The prevalence of respiratory impairment (61.2%) and mental health disorders (42.0%) was highest in low-income countries while neurological impairment was highest in lower middle-income countries (25.6%). Drug-resistant TB was associated with respiratory (58.7%), neurological (37.2%), and hearing impairments (25.0%) and mental health disorders (26.0%), respectively. CONCLUSIONS: TB-related disabilities were frequently reported. More uniform reporting tools for TB-related disability and further research to better quantify and mitigate it are urgently needed. PROSPERO REGISTRATION NUMBER: CRD42019147488.

A catalogue of tools and variables from crisis and routine care to support decision-making about allocation of intensive care beds and ventilator treatment during pandemics: Scoping review.

PURPOSE: This scoping review sought to identify objective factors to assist clinicians and policy-makers in making consistent, objective and ethically sound decisions about resource allocation when healthcare rationing is inevitable. MATERIALS AND METHODS: Review of guidelines and tools used in ICUs, hospital wards and emergency departments on how to best allocate intensive care beds and ventilators either during routine care or developed during previous epidemics, and association with patient outcomes during and after hospitalisation. RESULTS: Eighty publications from 20 countries reporting accuracy or validity of prognostic tools/algorithms, or significant correlation between prognostic variables and clinical outcomes met our eligibility criteria: twelve pandemic guidelines/triage protocols/consensus statements, twenty-two pandemic algorithms, and 46 prognostic tools/variables from non-crisis situations. Prognostic indicators presented here can be combined to create locally-relevant triage algorithms for clinicians and policy makers deciding about allocation of ICU beds and ventilators during a pandemic. No consensus was found on the ethical issues to incorporate in the decision to admit or triage out of intensive care. CONCLUSIONS: This review provides a unique reference intended as a discussion starter for clinicians and policy makers to consider formalising an objective a locally-relevant triage consensus document that enhances confidence in decision-making during healthcare rationing of critical care and ventilator resources.

Comparison of seroprevalence of SARS-CoV-2 infections with cumulative and imputed COVID-19 cases: Systematic review.

BACKGROUND: Accurate seroprevalence estimates of SARS-CoV-2 in different populations could clarify the extent to which current testing strategies are identifying all active infection, and hence the true magnitude and spread of the infection. Our primary objective was to identify valid seroprevalence studies of SARS-CoV-2 infection and compare their estimates with the reported, and imputed, COVID-19 case rates within the same population at the same time point. METHODS: We searched PubMed, Embase, the Cochrane COVID-19 trials, and Europe-PMC for published studies and pre-prints that reported anti-SARS-CoV-2 IgG, IgM and/or IgA antibodies for serosurveys of the general community from 1 Jan to 12 Aug 2020. RESULTS: Of the 2199 studies identified, 170 were assessed for full text and 17 studies representing 15 regions and 118,297 subjects were includable. The seroprevalence proportions in 8 studies ranged between 1%-10%, with 5 studies under 1%, and 4 over 10%-from the notably hard-hit regions of Gangelt, Germany; Northwest Iran; Buenos Aires, Argentina; and Stockholm, Sweden. For seropositive cases who were not previously identified as COVID-19 cases, the majority had prior COVID-like symptoms. The estimated seroprevalences ranged from 0.56-717 times greater than the number of reported cumulative cases-half of the studies reported greater than 10 times more SARS-CoV-2 infections than the cumulative number of cases. CONCLUSIONS: The findings show SARS-CoV-2 seroprevalence is well below "herd immunity" in all countries studied. The estimated number of infections, however, were much greater than the number of reported cases and deaths in almost all locations. The majority of seropositive people reported prior COVID-like symptoms, suggesting that undertesting of symptomatic people may be causing a substantial under-ascertainment of SARS-CoV-2 infections.

Impact of COVID-19 pandemic on utilisation of healthcare services: a systematic review.

OBJECTIVES: To determine the extent and nature of changes in utilisation of healthcare services during COVID-19 pandemic. DESIGN: Systematic review. ELIGIBILITY: Eligible studies compared utilisation of services during COVID-19 pandemic to at least one comparable period in prior years. Services included visits, admissions, diagnostics and therapeutics. Studies were excluded if from single centres or studied only patients with COVID-19. DATA SOURCES: PubMed, Embase, Cochrane COVID-19 Study Register and preprints were searched, without language restrictions, until 10 August, using detailed searches with key concepts including COVID-19, health services and impact. DATA ANALYSIS: Risk of bias was assessed by adapting the Risk of Bias in Non-randomised Studies of Interventions tool, and a Cochrane Effective Practice and Organization of Care tool. Results were analysed using descriptive statistics, graphical figures and narrative synthesis. OUTCOME MEASURES: Primary outcome was change in service utilisation between prepandemic and pandemic periods. Secondary outcome was the change in proportions of users of healthcare services with milder or more severe illness (eg, triage scores). RESULTS: 3097 unique references were identified, and 81 studies across 20 countries included, reporting on >11 million services prepandemic and 6.9 million during pandemic. For the primary outcome, there were 143 estimates of changes, with a median 37% reduction in services overall (IQR -51% to -20%), comprising median reductions for visits of 42% (-53% to -32%), admissions 28% (-40% to -17%), diagnostics 31% (-53% to -24%) and for therapeutics 30% (-57% to -19%). Among 35 studies reporting secondary outcomes, there were 60 estimates, with 27 (45%) reporting larger reductions in utilisation among people with a milder spectrum of illness, and 33 (55%) reporting no difference. CONCLUSIONS: Healthcare utilisation decreased by about a third during the pandemic, with considerable variation, and with greater reductions among people with less severe illness. While addressing unmet need remains a priority, studies of health impacts of reductions may help health systems reduce unnecessary care in the postpandemic recovery. PROSPERO REGISTRATION NUMBER: CRD42020203729.

Estimating the extent of asymptomatic COVID-19 and its potential for community transmission: Systematic review and meta-analysis.

Background: Knowing the prevalence of true asymptomatic coronavirus disease 2019 (COVID-19) cases is critical for designing mitigation measures against the pandemic. We aimed to synthesize all available research on asymptomatic cases and transmission rates. Methods: We searched PubMed, Embase, Cochrane COVID-19 trials, and Europe PMC for primary studies on asymptomatic prevalence in which (1) the sample frame includes at-risk populations and (2) follow-up was sufficient to identify pre-symptomatic cases. Meta-analysis used fixed-effects and random-effects models. We assessed risk of bias by combination of questions adapted from risk of bias tools for prevalence and diagnostic accuracy studies. Results: We screened 2,454 articles and included 13 low risk-of-bias studies from seven countries that tested 21,708 at-risk people, of which 663 were positive and 111 asymptomatic. Diagnosis in all studies was confirmed using a real-time reverse transcriptase-polymerase chain reaction test. The asymptomatic proportion ranged from 4% to 41%. Meta-analysis (fixed effects) found that the proportion of asymptomatic cases was 17% (95% CI 14% to 20%) overall and higher in aged care (20%; 95% CI 14% to 27%) than in non-aged care (16%; 95% CI 13% to 20%). The relative risk (RR) of asymptomatic transmission was 42% lower than that for symptomatic transmission (combined RR 0.58; 95% CI 0.34 to 0.99, p = 0.047). Conclusions: Our one-in-six estimate of the prevalence of asymptomatic COVID-19 cases and asymptomatic transmission rates is lower than those of many highly publicized studies but still sufficient to warrant policy attention. Further robust epidemiological evidence is urgently needed, including in subpopulations such as children, to better understand how asymptomatic cases contribute to the pandemic.

Historique: Il est essentiel de connaître la prévalence des véritables cas asymptomatiques de maladie à coronavirus 2019 (COVID-19) pour concevoir des mesures d'atténuation de la pandémie. Les chercheurs ont voulu synthétiser toutes les recherches disponibles sur les cas asymptomatiques et les taux de transmission. Méthodologie: Les chercheurs ont fouillé les bases de données PubMed, Embase, Cochrane pour trouver les études sur la COVID-19, et Europe PMC pour colliger les études primaires sur la prévalence des cas asymptomatiques dans lesquelles 1) le cadre d'échantillonnage incluait une population à risque et 2) le suivi était suffisant pour dépister les cas présymptomatiques. La méta-analyse a fait appel à des modèles d'effets fixes et d'effets aléatoires. Nous avons évalué le risque de biais par une combinaison de questions adaptées d'outils sur les risques de biais des études de prévalence et de précision diagnostique. Résultats: Les chercheurs ont extrait 2 454 articles, dont 13 études à faible risque de biais de sept pays dans lesquelles 21 708 personnes à risque ont subi le test de dépistage, soit 663 cas positifs et 111 cas asymptomatiques. Dans toutes les études, le diagnostic a été confirmé au moyen du test d'amplification en chaîne par polymérase après transcriptase inverse en temps réel. La proportion de cas asymptomatiques se situait entre 4 % et 41 %. La méta-analyse (à effets fixes) a établi que la proportion de cas asymptomatiques s'élevait à 17 % (IC à 95 %, 14 % à 20 %) dans l'ensemble, mais qu'elles étaient plus élevées dans les soins aux aînés (20 %; IC à 95 %, 14 % à 27 %) qu'auprès du reste de la population (16 %; IC à 95 %, 13 % à 20 %). Le risque relatif [RR] de transmission de cas asymptomatiques était plus faible de 42 % que celui de cas symptomatiques (RR combiné de 0,58; IC à 95 %, 0,34 à 0.99, p = 0,047). Conclusions: L'évaluation de la prévalence d'un sixième de cas asymptomatiques de COVID-19 et de taux de transmission de cas asymptomatiques est inférieure à celle de nombreuses études hautement publicisées, mais suffit tout de même pour justifier l'intérêt de la santé publique. D'autres données épidémiologiques solides s'imposent de toute urgence, y compris dans des sous-populations comme les enfants, pour mieux comprendre l'effet des cas asymptomatiques sur la pandémie.

Downsides of face masks and possible mitigation strategies: a systematic review and meta-analysis.

OBJECTIVE: To identify, appraise and synthesise studies evaluating the downsides of wearing face masks in any setting. We also discuss potential strategies to mitigate these downsides. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, CENTRAL and EuropePMC were searched (inception-18 May 2020), and clinical registries were searched via CENTRAL. We also did a forward-backward citation search of the included studies. INCLUSION CRITERIA: We included randomised controlled trials and observational studies comparing face mask use to any active intervention or to control. DATA EXTRACTION AND ANALYSIS: Two author pairs independently screened articles for inclusion, extracted data and assessed the quality of included studies. The primary outcomes were compliance, discomforts, harms and adverse events of wearing face masks. RESULTS: We screened 5471 articles, including 37 (40 references); 11 were meta-analysed. For mask wear adherence, 47% (95% CI 25% to 68%, p<0.0001), more people wore face masks in the face mask group compared with control; adherence was significantly higher (26%, 95% CI 8% to 46%, p<0.01) in the surgical/medical mask group than in N95/P2 group. The largest number of studies reported on the discomfort and irritation outcome (20 studies); fewest reported on the misuse of masks, and none reported on mask contamination or risk compensation behaviour. Risk of bias was generally high for blinding of participants and personnel and low for attrition and reporting biases. CONCLUSIONS: There are insufficient data to quantify all of the adverse effects that might reduce the acceptability, adherence and effectiveness of face masks. New research on face masks should assess and report the harms and downsides. Urgent research is also needed on methods and designs to mitigate the downsides of face mask wearing, particularly the assessment of possible alternatives. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework website https://osf.io/sa6kf/ (timestamp 20-05-2020).

Physical interventions to interrupt or reduce the spread of respiratory viruses.

BACKGROUND: Viral epidemics or pandemics of acute respiratory infections (ARIs) pose a global threat. Examples are influenza (H1N1) caused by the H1N1pdm09 virus in 2009, severe acute respiratory syndrome (SARS) in 2003, and coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in 2019. Antiviral drugs and vaccines may be insufficient to prevent their spread. This is an update of a Cochrane Review published in 2007, 2009, 2010, and 2011. The evidence summarised in this review does not include results from studies from the current COVID-19 pandemic. OBJECTIVES: To assess the effectiveness of physical interventions to interrupt or reduce the spread of acute respiratory viruses. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, CINAHL on 1 April 2020. We searched ClinicalTrials.gov, and the WHO ICTRP on 16 March 2020. We conducted a backwards and forwards citation analysis on the newly included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster-RCTs of trials investigating physical interventions (screening at entry ports, isolation, quarantine, physical distancing, personal protection, hand hygiene, face masks, and gargling) to prevent respiratory virus transmission. In previous versions of this review we also included observational studies. However, for this update, there were sufficient RCTs to address our study aims.   DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. Three pairs of review authors independently extracted data using a standard template applied in previous versions of this review, but which was revised to reflect our focus on RCTs and cluster-RCTs for this update. We did not contact trialists for missing data due to the urgency in completing the review. We extracted data on adverse events (harms) associated with the interventions. MAIN RESULTS: We included 44 new RCTs and cluster-RCTs in this update, bringing the total number of randomised trials to 67. There were no included studies conducted during the COVID-19 pandemic. Six ongoing studies were identified, of which three evaluating masks are being conducted concurrent with the COVID pandemic, and one is completed. Many studies were conducted during non-epidemic influenza periods, but several studies were conducted during the global H1N1 influenza pandemic in 2009, and others in epidemic influenza seasons up to 2016. Thus, studies were conducted in the context of lower respiratory viral circulation and transmission compared to COVID-19. The included studies were conducted in heterogeneous settings, ranging from suburban schools to hospital wards in high-income countries; crowded inner city settings in low-income countries; and an immigrant neighbourhood in a high-income country. Compliance with interventions was low in many studies. The risk of bias for the RCTs and cluster-RCTs was mostly high or unclear. Medical/surgical masks compared to no masks We included nine trials (of which eight were cluster-RCTs) comparing medical/surgical masks versus no masks to prevent the spread of viral respiratory illness (two trials with healthcare workers and seven in the community). There is low certainty evidence from nine trials (3507 participants) that wearing a mask may make little or no difference to the outcome of influenza-like illness (ILI) compared to not wearing a mask (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.82 to 1.18. There is moderate certainty evidence that wearing a mask probably makes little or no difference to the outcome of laboratory-confirmed influenza compared to not wearing a mask (RR 0.91, 95% CI 0.66 to 1.26; 6 trials; 3005 participants). Harms were rarely measured and poorly reported. Two studies during COVID-19 plan to recruit a total of 72,000 people. One evaluates medical/surgical masks (N = 6000) (published Annals of Internal Medicine, 18 Nov 2020), and one evaluates cloth masks (N = 66,000). N95/P2 respirators compared to medical/surgical masks We pooled trials comparing N95/P2 respirators with medical/surgical masks (four in healthcare settings and one in a household setting). There is uncertainty over the effects of N95/P2 respirators when compared with medical/surgical masks on the outcomes of clinical respiratory illness (RR 0.70, 95% CI 0.45 to 1.10; very low-certainty evidence; 3 trials; 7779 participants) and ILI (RR 0.82, 95% CI 0.66 to 1.03; low-certainty evidence; 5 trials; 8407 participants). The evidence is limited by imprecision and heterogeneity for these subjective outcomes. The use of a N95/P2 respirator compared to a medical/surgical mask probably makes little or no difference for the objective and more precise outcome of laboratory-confirmed influenza infection (RR 1.10, 95% CI 0.90 to 1.34; moderate-certainty evidence; 5 trials; 8407 participants). Restricting the pooling to healthcare workers made no difference to the overall findings. Harms were poorly measured and reported, but discomfort wearing medical/surgical masks or N95/P2 respirators was mentioned in several studies. One ongoing study recruiting 576 people compares N95/P2 respirators with medical surgical masks for healthcare workers during COVID-19. Hand hygiene compared to control Settings included schools, childcare centres, homes, and offices. In a comparison of hand hygiene interventions with control (no intervention), there was a 16% relative reduction in the number of people with ARIs in the hand hygiene group (RR 0.84, 95% CI 0.82 to 0.86; 7 trials; 44,129 participants; moderate-certainty evidence), suggesting a probable benefit. When considering the more strictly defined outcomes of ILI and laboratory-confirmed influenza, the estimates of effect for ILI (RR 0.98, 95% CI 0.85 to 1.13; 10 trials; 32,641 participants; low-certainty evidence) and laboratory-confirmed influenza (RR 0.91, 95% CI 0.63 to 1.30; 8 trials; 8332 participants; low-certainty evidence) suggest the intervention made little or no difference. We pooled all 16 trials (61,372 participants) for the composite outcome of ARI or ILI or influenza, with each study only contributing once and the most comprehensive outcome reported. The pooled data showed that hand hygiene may offer a benefit with an 11% relative reduction of respiratory illness (RR 0.89, 95% CI 0.84 to 0.95; low-certainty evidence), but with high heterogeneity. Few trials measured and reported harms. There are two ongoing studies of handwashing interventions in 395 children outside of COVID-19. We identified one RCT on quarantine/physical distancing. Company employees in Japan were asked to stay at home if household members had ILI symptoms. Overall fewer people in the intervention group contracted influenza compared with workers in the control group (2.75% versus 3.18%; hazard ratio 0.80, 95% CI 0.66 to 0.97). However, those who stayed at home with their infected family members were 2.17 times more likely to be infected. We found no RCTs on eye protection, gowns and gloves, or screening at entry ports. AUTHORS' CONCLUSIONS: The high risk of bias in the trials, variation in outcome measurement, and relatively low compliance with the interventions during the studies hamper drawing firm conclusions and generalising the findings to the current COVID-19 pandemic. There is uncertainty about the effects of face masks. The low-moderate certainty of the evidence means our confidence in the effect estimate is limited, and that the true effect may be different from the observed estimate of the effect. The pooled results of randomised trials did not show a clear reduction in respiratory viral infection with the use of medical/surgical masks during seasonal influenza. There were no clear differences between the use of medical/surgical masks compared with N95/P2 respirators in healthcare workers when used in routine care to reduce respiratory viral infection. Hand hygiene is likely to modestly reduce the burden of respiratory illness. Harms associated with physical interventions were under-investigated. There is a need for large, well-designed RCTs addressing the effectiveness of many of these interventions in multiple settings and populations, especially in those most at risk of ARIs.