The impact of coding germline variants on contralateral breast cancer risk and survival.

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

Safety of varicella vaccination strategies: An overview of reviews.

The safety of new vaccines under development as well as existing vaccines is a key priority for national and international public health agencies. A number of countries have implemented universal childhood varicella vaccination programmes over the past 30 years. However, strategies differ in terms of the number of doses, type of vaccine(s) recommended, age at vaccination and interval between doses for a two-dose schedule. An overview of reviews was undertaken to assess the existing systematic review evidence of the safety of varicella vaccination strategies. The review was restricted to immunocompetent children aged 9 months to 6 years inclusive. A comprehensive search of databases, registries and grey literature was conducted up to 2 February 2022. Two reviewers independently screened, extracted data and assessed the methodological quality of included reviews. Overlap of included reviews was also assessed. A total of 17 reviews, incorporating both the monovalent varicella only and quadrivalent measles-mumps-rubella-varicella (MMRV) vaccines were included in the overview; six assessed the safety of one-dose strategies, four assessed the safety of two-dose strategies and 14 reviews did not specify the dosing strategy. The evidence suggests that mild local and systemic reactions are relatively common with varicella vaccination. Febrile seizures are also possible adverse effects of both the monovalent and quadrivalent MMRV vaccine, but serious adverse reactions are rare. While most reviews contained methodological flaws, and analysis by vaccine type and dosing strategy was restricted due to lack of detail in reporting of the reviews, there was clear and consistent evidence from a substantial evidence base, comprising 34 randomised controlled trials and 62 other primary studies/reviews, that varicella vaccination is safe.

Clinical efficacy and effectiveness of alternative varicella vaccination strategies: An overview of reviews.

A number of countries have implemented universal childhood varicella vaccination programmes over the past 30 years. However, strategies differ in terms of dosing schedule (one- or two-dose), type of vaccine(s) recommended (monovalent, quadrivalent measles-mumps-rubella-varicella, or both), age at vaccination, and dosing interval for a two-dose schedule. An overview of reviews was undertaken to assess the existing systematic review evidence of the clinical efficacy/effectiveness of alternative varicella vaccination strategies. A comprehensive search of databases, registries and grey literature was conducted up to 2 February 2022. Two reviewers independently screened, extracted data and assessed the methodological quality of included reviews. A total of 20 reviews were included in the overview; 17 assessed the efficacy/effectiveness of one-dose strategies and 10 assessed the efficacy/effectiveness of two-dose strategies. Although the quality of most reviews was deemed 'critically low', there was clear and consistent evidence that vaccination is very effective at reducing varicella. While the analysis was restricted due to lack of detail in reporting of the reviews, the evidence suggests that two-dose strategies are more efficacious/effective than one-dose strategies in preventing varicella of any severity, but that both strategies have similar high efficacy/effectiveness in preventing moderate or severe varicella. Based on this evidence in this overview of reviews, a key consideration for policymakers on the possible introduction of a childhood varicella vaccination programme and the choice between a one- or two-dose strategy, will be whether the objective of a programme is to prevent varicella of any severity or to prevent moderate to severe varicella.

Systematic review of the efficacy, effectiveness and safety of MF59® adjuvanted seasonal influenza vaccines for the prevention of laboratory-confirmed influenza in individuals ≥18 years of age.

The most effective means of preventing seasonal influenza is through vaccination. In this systematic review, we investigated the efficacy, effectiveness and safety of MF59® adjuvanted trivalent and quadrivalent influenza vaccines to prevent laboratory-confirmed influenza. A systematic literature search was conducted in electronic databases and grey literature sources up to 7 February 2020. Randomised controlled trials and non-randomised studies of interventions (NRSIs) were eligible for inclusion. The search returned 28,846 records, of which 48 studies on MF59® adjuvanted vaccines met our inclusion criteria. No efficacy trials were identified. In terms of vaccine effectiveness (VE), MF59® adjuvanted trivalent influenza vaccines were effective in preventing laboratory-confirmed influenza in older adults (aged ≥65 years) compared with no vaccination (VE = 45%, 95% confidence interval (CI) 23%-61%, 5 NRSIs across 3 influenza seasons). By subtype, significant effect was found for influenza A(H1N1) (VE = 61%, 95% CI 44%-73%) and B (VE = 29%, 95% CI 5%-46%), but not for A(H3N2). In terms of relative VE, there was no significant difference comparing MF59® adjuvanted trivalent vaccines with either non-adjuvanted trivalent or quadrivalent vaccines. Compared with traditional trivalent influenza vaccines, MF59® adjuvanted trivalent influenza vaccines were associated with a greater number of local adverse events (RR = 1.90, 95% CI 1.50-2.39) and systemic reactions (RR = 1.18, 95% CI 1.02-1.38). In conclusion, MF59® adjuvanted trivalent influenza vaccines were found to be more effective than 'no vaccination'. Based on limited data, there was no significant difference comparing the effectiveness of MF59® adjuvanted vaccines with their non-adjuvanted counterparts.

Systematic review of the efficacy, effectiveness and safety of recombinant haemagglutinin seasonal influenza vaccines for the prevention of laboratory-confirmed influenza in individuals ≥18 years of age.

The most effective means of preventing seasonal influenza is through vaccination. In this systematic review, we investigated the efficacy, effectiveness and safety of recombinant haemagglutinin (HA) seasonal influenza vaccines to prevent laboratory-confirmed influenza. A systematic literature search was conducted in electronic databases and grey literature sources up to 7 February 2020. Randomised controlled trials and non-randomised studies of interventions were eligible for inclusion. The search returned 28,846 records, of which 10 studies on recombinant HA influenza vaccine met our inclusion criteria. One study found that the quadrivalent recombinant HA influenza vaccine had higher relative vaccine efficacy (rVE) in preventing laboratory-confirmed influenza during the 2014-15 season compared with traditional quadrivalent vaccination in adults aged ≥50 years (rVE = 30%, 95% CI 10%-47%, moderate-certainty evidence). In a subgroup analysis, higher rVE was reported for influenza A (rVE = 36%, 95% CI 14% to 53%), but not for B (non-significant). Another study reported higher efficacy for the trivalent recombinant HA vaccine compared with placebo (VE = 45%, 95% CI 19-63, 1 RCT, low-certainty evidence) in adults aged 18-55 years. With the exception of a higher rate of chills (RR = 1.33, 95% CI 1.03-1.72), the safety profile of recombinant HA vaccines was comparable to that of traditional influenza vaccines. The evidence base for the efficacy and effectiveness of recombinant HA influenza vaccines is limited at present, although one study found that the quadrivalent recombinant HA influenza vaccine had higher rVE compared with traditional quadrivalent vaccination in adults aged ≥50 years.

Systematic review of the efficacy, effectiveness and safety of high-dose seasonal influenza vaccines for the prevention of laboratory-confirmed influenza in individuals ≥18 years of age.

This review sought to assess the efficacy, effectiveness and safety of high-dose inactivated influenza vaccines (HD-IIV) for the prevention of laboratory-confirmed influenza in individuals aged 18 years or older. A systematic literature search was conducted in electronic databases and grey literature sources up to 7 February 2020. Randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) were included. The search returned 28,846 records, of which 36 studies were included. HD-IIV was shown to have higher relative vaccine efficacy in preventing influenza compared with standard-dose influenza vaccines (SD-IIV3) in older adults (Vaccine effectiveness (VE) = 24%, 95% CI 10-37, one RCT). One NRSI demonstrated significant effect for HD-IIV3 against influenza B (VE = 89%, 95% CI 47-100), but not for influenza A(H3N2) (VE = 22%, 95% CI -82 to 66) when compared with no vaccination in older adults. HD-IIV3 showed significant relative effect compared with SD-IIV3 for influenza-related hospitalisation (VE = 11.8%, 95% CI 6.4-17.0, two NRSIs), influenza- or pneumonia-related hospitalisation (VE = 13.7%, 95% CI 9.5-17.7, three NRSIs), influenza-related hospital encounters (VE = 13.1%, 95% CI 8.4-17.7, five NRSIs), and influenza-related office visits (VE = 3.5%, 95% CI 1.5-5.5, two NRSIs). For safety, HD-IIV were associated with significantly higher rates of local and systemic adverse events compared with SD-IIV (combined local reactions, pain at injection site, swelling, induration, headache, chills and malaise). From limited data, compared with SD-IIV, HD-IIV were found to be more effective in the prevention of laboratory-confirmed influenza, for a range of proxy outcome measures, and associated with more adverse events.

Systematic review of the efficacy, effectiveness and safety of cell-based seasonal influenza vaccines for the prevention of laboratory-confirmed influenza in individuals ≥18 years of age.

The most effective means of preventing seasonal influenza is through strain-specific vaccination. In this study, we investigated the efficacy, effectiveness and safety of cell-based trivalent and quadrivalent influenza vaccines. A systematic literature search was conducted in electronic databases and grey literature sources up to 7 February 2020. Randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) were eligible for inclusion. Two reviewers independently screened, extracted data and assessed the risk of bias of included studies. Certainty of evidence for key outcomes was assessed using the GRADE methodology. The search returned 28,846 records, of which 868 full-text articles were assessed for relevance. Of these, 19 studies met the inclusion criteria. No relative efficacy data were identified for the direct comparison of cell-based vaccines compared with traditional vaccines (egg-based). Efficacy data were available comparing cell-based trivalent influenza vaccines with placebo in adults (aged 18-49 years). Overall vaccine efficacy was 70% against any influenza subtype (95% CI 61%-77%, two RCTS), 82% against influenza A(H1N1) (95% CI 71%-89%, 2 RCTs), 72% against influenza A(H3N2) (95% CI 39%-87%, 2 RCTs) and 52% against influenza B (95% CI 30%-68%, 2 RCTs). Limited and heterogeneous data were presented for effectiveness when compared with no vaccination. One NRSI compared cell-based trivalent and quadrivalent vaccination with traditional trivalent and quadrivalent vaccination, finding a small but significant difference in favour of cell-based vaccines for influenza-related hospitalisation, hospital encounters and physician office visits. The safety profile of cell-based trivalent vaccines was comparable to traditional trivalent influenza vaccines. Compared with placebo, cell-based trivalent influenza vaccines have demonstrated greater efficacy in adults aged 18-49 years. Overall cell-based vaccines are well-tolerated in adults, however, evidence regarding the effectiveness of these vaccines compared with traditional seasonal influenza vaccines is limited.

Challenges encountered during the systematic review of newer and enhanced influenza vaccines and recommendations for the future.

There are a variety of challenges in the conduct of systematic reviews of influenza vaccines. We describe our experience of completing four systematic reviews of newer and enhanced inactivated seasonal influenza vaccines. The reporting of the included studies created significant challenges for study identification, data extraction and analysis. Those challenges have implications for the resources required to conduct reviews and, more significantly, for the accuracy of the estimated treatment effect. There is a substantial burden of morbidity and mortality associated with seasonal influenza, and the evidence used to support vaccination strategies requires regular review. An improved review process will facilitate robust decision-making both nationally and internationally. We recommend the development of reporting guidelines, increased engagement between researchers and decision makers, a database of identified trials, and research into search optimisation.

A rapid review of measures to support people in isolation or quarantine during the Covid-19 pandemic and the effectiveness of such measures.

This rapid review aimed to identify measures available to support those in isolation or quarantine during the coronavirus disease 2019 (Covid-19) pandemic, and determine their effectiveness in improving adherence to these recommendations and or reducing transmission. The rapid review consisted of two elements, the first was a review of guidance published by national and international agencies relating to measures to support those in isolation (due to case status) or quarantine (due to close contact status) during the Covid-19 pandemic. Five categories of support measures were identified in the international guidance, they were: Psychological, addiction and safety supports, Essential supplies, Financial aid, Information provision and Enforcement. The second element was a rapid literature review of the effectiveness of measures used to support individuals in isolation or quarantine during any pandemic or epidemic setting, due to respiratory pathogens. A systematic search of published peer-reviewed articles and nonpeer-reviewed pre-prints was undertaken from 1 January 2000 to 26 January 2021. Two Australian publications met the inclusion criteria, both based on data from a survey undertaken during the 2009 H1N1 pandemic. The first reported that 55% of households were fully compliant with quarantine recommendations, and that there was increased compliance reported in households that understood what they were meant to do compared with those who reported that they did not (odds ratio [OR]: 2.27, 95% confidence interval [CI]: 1.35-3.80). The second reported that access to paid sick and or carer's leave did not predict compliance with quarantine recommendations (OR: 2.07, 95% CI: 0.82-5.23). Neither reported on reduction in transmission.

Quantifying the risk of SARS-CoV-2 reinfection over time.

Despite over 140 million SARS-CoV-2 infections worldwide since the beginning of the pandemic, relatively few confirmed cases of SARS-CoV-2 reinfection have been reported. While immunity from SARS-CoV-2 infection is probable, at least in the short term, few studies have quantified the reinfection risk. To our knowledge, this is the first systematic review to synthesise the evidence on the risk of SARS-CoV-2 reinfection over time. A standardised protocol was employed, based on Cochrane methodology. Electronic databases and preprint servers were searched from 1 January 2020 to 19 February 2021. Eleven large cohort studies were identified that estimated the risk of SARS-CoV-2 reinfection over time, including three that enrolled healthcare workers and two that enrolled residents and staff of elderly care homes. Across studies, the total number of PCR-positive or antibody-positive participants at baseline was 615,777, and the maximum duration of follow-up was more than 10 months in three studies. Reinfection was an uncommon event (absolute rate 0%-1.1%), with no study reporting an increase in the risk of reinfection over time. Only one study estimated the population-level risk of reinfection based on whole genome sequencing in a subset of patients; the estimated risk was low (0.1% [95% CI: 0.08-0.11%]) with no evidence of waning immunity for up to 7 months following primary infection. These data suggest that naturally acquired SARS-CoV-2 immunity does not wane for at least 10 months post-infection. However, the applicability of these studies to new variants or to vaccine-induced immunity remains uncertain.

Laboratory-based testing for hepatitis C infection using dried blood spot samples: A systematic review and meta-analysis of diagnostic accuracy.

The use of dried blood spot (DBS) samples can facilitate the implementation of reflex testing by circumventing the need for centrifugation and freezing of venous blood samples. This systematic review assessed the accuracy of using DBS samples to diagnose chronic hepatitis C virus (HCV) infection. A comprehensive search was undertaken to identify articles published up to July 2020 evaluating the diagnostic accuracy of anti-HCV, HCV-RNA and HCV core antigen tests using DBS. Screening, data extraction, quality appraisal and Grading of Recommendations, Assessment, Development and Evaluations certainty of the evidence assessment were performed independently by two reviewers. Meta-analysis, meta-regression and sensitivity analyses were conducted. The evidence demonstrates that laboratory-based anti-HCV and HCV-RNA tests using DBS samples have high diagnostic accuracy. All comparisons were between DBS and venous samples. For the detection of anti-HCV, sensitivity was 95% (95% CI: 92%-97%) and specificity was 99% ([95% CI: 98%-99%]; n = 25; I2  = 81%; moderate certainty). For the detection of HCV-RNA, the sensitivity was 95% (95% CI: 93%-97%) and specificity was 97% ([95% CI: 94%-98%]; n = 20; I2  = 52%; moderate certainty). The sensitivity of HCV core antigen tests was 86% (95% CI: 79%-91%) and specificity was 98% ([95% CI: 94%-99%]; n = 5; I2  = 37%; low certainty) compared with HCV-RNA (the gold standard for detecting chronic HCV). DBS samples could facilitate diagnosis of chronic HCV infection as the necessary sequential tests (anti-HCV and then HCV-RNA or HCV core antigen) can be undertaken using the same blood sample. This could reduce loss of patient follow-up and support international efforts towards HCV elimination in both high and low prevalence settings.

Effectiveness of rapid antigen testing for screening of asymptomatic individuals to limit the transmission of SARS-CoV-2: A rapid review.

Rapid antigen detection tests (RADTs) offer advantages over gold-standard reverse transcription polymerase chain reaction (RT-PCR) tests in that they are cheaper and provide faster results, thus enabling prompt isolation of positive SARS-CoV-2 cases and quarantine of close contacts. The aim of this study was to collate and synthesise empirical evidence on the effectiveness of rapid antigen testing for the screening (including serial testing) and surveillance of asymptomatic individuals to limit the transmission of SARS-CoV-2. A rapid review was undertaken in MEDLINE (EBSCO), EMBASE (OVID), Cochrane Library, Europe PMC and Google Scholar up until 19 July 2021, supplemented by a grey literature search. Of the identified 1222 records, 19 reports referring to 16 studies were included. Eight included studies examined the effectiveness of RADTs for population-level screening, four for pre-event screening and four for serial testing (schools, a prison, a university sports programme and in care homes). Overall, there is uncertainty regarding the effectiveness of rapid antigen testing for the screening of asymptomatic individuals to limit the transmission of SARS-CoV-2. This uncertainty is due to the inconsistent results, the relatively low number of studies identified, the predominantly observational and/or uncontrolled nature of the study designs used, and concerns regarding methodological quality. Given this uncertainty, more real-world research evidence in relevant settings, which is of good quality and timely, as well as economic evaluation, is required to inform public policy on the widespread use of RADTs in asymptomatic individuals.

Pharmacological interventions to prevent Covid-19 disease: A rapid review.

The aim of this rapid review was to determine the effectiveness of pharmacological interventions (excluding vaccines) to prevent coronavirus disease 2019 (Covid-19) or reduce the severity of disease. A systematic search of published peer-reviewed articles and non-peer-reviewed pre-prints was undertaken from 1 January 2020 to 17 August 2021. Four randomised controlled trials (RCTs) and one non-RCT were included; three trials (two RCTs and one non-RCT) tested ivermectin with or without carrageenan. While all reported some potential protective effect of ivermectin, these trials had a high risk of bias and the certainty of evidence was deemed to be 'very low'. One RCT tested bamlanivimab compared to placebo and reported a significantly reduced incidence of Covid-19 in the intervention group; this trial had a low risk of bias however the certainty of evidence was deemed 'very low'. The fifth RCT tested casirivimab plus imdevimab versus placebo and reported that the combination of monoclonal antibodies significantly reduced the incidence of symptomatic and asymptomatic SARS-CoV-2 infection, viral load, duration of symptomatic disease and the duration of a high viral load; this trial was deemed to have a low risk of bias, and the certainty of evidence was 'low'. The designations 'low' and 'very low' regarding the certainty of evidence indicate that the estimate of effect is uncertain and therefore is unsuitable for informing decision-making. At the time of writing, there is insufficient high quality evidence to support the use of pharmacological interventions to prevent Covid-19.

Effectiveness of public health measures to prevent the transmission of SARS-CoV-2 at mass gatherings: A rapid review.

Mass gatherings play an important role in society, but since the onset of the Covid-19 pandemic, they have generally been restricted in order to mitigate transmission of SARS-CoV-2. The aim of this study was to summarise the evidence regarding the effectiveness of public health measures at preventing the transmission of SARS-CoV-2 at mass gatherings, and hence inform guidance on the organisation of these events. A rapid review was undertaken in Cochrane, Embase (OVID), Medline (OVID), Google, Web of Science and Europe PMC from 1 January 2020 to 3 June 2021. Of the identified 1,624 citations, 14 articles referring to 11 unique studies were included. This rapid review found evidence from 11 studies (involving approximately 30,482 participants) that implementing a range of measures may reduce the risk of SARS-CoV-2 transmission at mass gatherings; however, it is unlikely that this risk can be eliminated entirely. All studies adopted a layered mitigation approach involving multiple measures, which may be more effective than relying on any single measure. The number and intensity of measures implemented varied across studies, with most implementing resource intense measures. Importantly, all included studies were only of 'fair' to 'poor' quality. In conclusion, there is currently limited evidence on the effectiveness of measures to prevent SARS-CoV-2 transmission at mass gatherings. As mass gatherings recommence, continued adoption of known mitigation measures is required to limit the risk of transmission, as well as ongoing research and surveillance to monitor the potential impact of these events on the wider population and healthcare system.

Another Step Toward Hepatitis C Elimination: An Economic Evaluation of an Irish National Birth Cohort Testing Program.

OBJECTIVES: We aimed to evaluate the cost-effectiveness of offering once-off birth cohort testing for hepatitis C virus (HCV) to people in Ireland born between 1965 and 1985, the cohort with the highest reported prevalence of undiagnosed chronic HCV infection. METHODS: Systematic and opportunistic HCV birth cohort testing programs, implemented over a 4-year timeframe, were compared with the current practice of population risk-based testing only in a closed-cohort decision tree and Markov model hybrid over a lifetime time horizon. Outcomes were expressed in quality-adjusted life-years (QALYs). Costs were presented from the health system's perspective in 2020 euro (€). Uncertainty was assessed via deterministic, probabilistic, scenario, and threshold analyses. RESULTS: In the base case, systematic testing yielded the largest cost and health benefits, followed by opportunistic testing and risk-based testing. Compared with risk-based testing, the incremental cost-effectiveness ratio for opportunistic testing was €14 586 (95% confidence interval €4185-€33 527) per QALY gained. Compared with opportunistic testing, the incremental cost-effectiveness ratio for systematic testing was €16 827 (95% confidence interval €5106-€38 843) per QALY gained. These findings were robust across a range of sensitivity analyses. CONCLUSIONS: Both systematic and opportunistic birth cohort testing would be considered an efficient use of resources, but systematic testing was the optimal strategy at willingness-to-pay threshold values typically used in Ireland. Although cost-effective, any decision to introduce birth cohort testing for HCV (in Ireland or elsewhere) must be balanced with considerations regarding the feasibility and budget impact of implementing a national testing program given high initial costs and resource use.

The effectiveness of non-contact thermal screening as a means of identifying cases of Covid-19: a rapid review of the evidence.

The aim of this rapid review is to summarise the evidence on non-contact thermal screening as a method through which to identify cases and reduce the spread of coronavirus disease (Covid-19). The rapid review was conducted in accordance with Cochrane guidelines, with a systematic search of published peer-reviewed articles and non-peer-reviewed pre-prints undertaken from 1 January 2000 up to 7 October 2020. Eleven studies were included. One observational study and two mathematical modelling studies were conducted in the context of the Covid-19 pandemic; the remaining studies were conducted during the influenza A pandemic (H1N1) 2009 (n = 7) or middle east respiratory syndrome (n = 1) pandemics. One systematic review and three rapid reviews were identified and screened for relevant studies. Evidence on the effectiveness of thermal screening contained within this review was limited to points of entry (i.e., airports); thus the applicability to other community settings is uncertain. Thermal screening, implemented as part of a composite of screening measures (self-report of relevant symptoms, contact/travel history), was ineffective in identifying infectious individuals and limiting the spread of disease. Based on limited, low certainty evidence, non-contact thermal screening is ineffective in limiting the spread of Covid-19.

Airborne transmission of SARS-CoV-2 via aerosols.

A key consideration in the Covid-19 pandemic is the dominant modes of transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The objective of this review was to synthesise the evidence for the potential airborne transmission of SARS-CoV-2 via aerosols. Systematic literature searches were conducted in PubMed, Embase, Europe PMC and National Health Service UK evidence up to 27 July 2020. A protocol was published and Cochrane guidance for rapid review methodology was adhered to throughout. Twenty-eight studies were identified. Seven out of eight epidemiological studies suggest aerosol transmission may occur, with enclosed environments and poor ventilation noted as possible contextual factors. Ten of the 16 air sampling studies detected SARS-CoV-2 ribonucleic acid; however, only three of these studies attempted to culture the virus with one being successful in a limited number of samples. Two of four virological studies using artificially generated aerosols indicated that SARS-CoV-2 is viable in aerosols. The results of this review indicate there is inconclusive evidence regarding the viability and infectivity of SARS-CoV-2 in aerosols. Epidemiological studies suggest possible transmission, with contextual factors noted. Viral particles have been detected in air sampling studies with some evidence of clinical infectivity, and virological studies indicate these particles may represent live virus, adding further plausibility. However, there is uncertainty as to the nature and impact of aerosol transmission of SARS-CoV-2, and its relative contribution to the Covid-19 pandemic compared with other modes of transmission.

Immune response following infection with SARS-CoV-2 and other coronaviruses: A rapid review.

In this review, we systematically searched and summarized the evidence on the immune response and reinfection rate following SARS-CoV-2 infection. We also retrieved studies on SARS-CoV and MERS-CoV to assess the long-term duration of antibody responses. A protocol based on Cochrane rapid review methodology was adhered to and databases were searched from 1/1/2000 until 26/5/2020. Of 4744 citations retrieved, 102 studies met our inclusion criteria. Seventy-four studies were retrieved on SARS-CoV-2. While the rate and timing of IgM and IgG seroconversion were inconsistent across studies, most seroconverted for IgG within 2 weeks and 100% (N = 62) within 4 weeks. IgG was still detected at the end of follow-up (49-65 days) in all patients (N = 24). Neutralizing antibodies were detected in 92%-100% of patients (up to 53 days). It is not clear if reinfection with SARS-CoV-2 is possible, with studies more suggestive of intermittent detection of residual RNA. Twenty-five studies were retrieved on SARS-CoV. In general, SARS-CoV-specific IgG was maintained for 1-2 years post-infection and declined thereafter, although one study detected IgG up to 12 years post-infection. Neutralizing antibodies were detected up to 17 years in another study. Three studies on MERS-CoV reported that IgG may be detected up to 2 years. In conclusion, limited early data suggest that most patients seroconvert for SARS-CoV-2-specific IgG within 2 weeks. While the long-term duration of antibody responses is unknown, evidence from SARS-CoV studies suggest SARS-CoV-specific IgG is sustained for 1-2 years and declines thereafter.

Alternative clinical specimens for the detection of SARS-CoV-2: A rapid review.

The collection of nasopharyngeal swabs to test for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an invasive technique with implications for patients and clinicians. Alternative clinical specimens from the upper respiratory tract may offer benefits in terms of collection, comfort and infection risk. The objective of this review was to synthesise the evidence for detection of SARS-CoV-2 ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) tested saliva or nasal specimens compared with RT-PCR tested nasopharyngeal specimens. Searches were conducted in PubMed, Embase, Europe PMC and NHS evidence from December 2019 to 20 July 2020. Eighteen studies were identified; 12 for saliva, four for nasal and two included both specimen types. For saliva-based studies, the proportion of saliva samples testing positive relative to all positive samples in each study ranged from 82.9% to 100%; detection in nasopharyngeal specimens ranged from 76.7% to 100%; positive agreement between specimens for overall detection ranged from 65.4% to 100%. For nasal-based studies, the proportion of nasal swabs testing positive relative to all positive samples in each study ranged from 81.9% to 100%; detection in nasopharyngeal specimens ranged from 70% to 100%; positive agreement between specimens for overall detection ranged from 62.3% to 100%. The results indicate an inconsistency in the detection of SARS-CoV-2 RNA in the specimen types included, often with neither the index nor the reference of interest detecting all known cases. Depending on the test environment, these clinical specimens may offer a viable alternative to standard. However, at present the evidence is limited, of variable quality, and relatively inconsistent.