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BackgroundAlthough much of the public health effort to combat coronavirus disease 2019 (COVID-19) has focused on disease control strategies in public settings, transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within households remains an important problem. The nature and determinants of household transmission are poorly understood.MethodsTo address this gap, we gathered and analyzed data from 22 published and prepublished studies from 10 countries (20 291 household contacts) that were available through 2 September 2020. Our goal was to combine estimates of the SARS-CoV-2 household secondary attack rate (SAR) and to explore variation in estimates of the household SAR.ResultsThe overall pooled random-effects estimate of the household SAR was 17.1% (95% confidence interval [CI], 13.7–21.2%). In study-level, random-effects meta-regressions stratified by testing frequency (1 test, 2 tests, >2 tests), SAR estimates were 9.2% (95% CI, 6.7–12.3%), 17.5% (95% CI, 13.9–21.8%), and 21.3% (95% CI, 13.8–31.3%), respectively. Household SARs tended to be higher among older adult contacts and among contacts of symptomatic cases.ConclusionsThese findings suggest that SARs reported using a single follow-up test may be underestimated, and that testing household contacts of COVID-19 cases on multiple occasions may increase the yield for identifying secondary cases.

Additional file 2 Figure S1: Sensitivity analysis for economic feasibility analysis. Figure S2: Sensitivity of the proportion of counties with ω

The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141 , IGF1R , TTN , and TNKS. Several loci where variants were deemed insignificant in univariate genome-wide association analyses are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we found strong gene co-expression correlations between these statistical epistasis contributors in healthy hearts and a significant connectivity decrease in failing hearts. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R . Our results expand the scope of genetic regulation of cardiac structure to epistasis.

The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141 , IGF1R , TTN , and TNKS. Several loci not prioritized by univariate genome-wide association analysis are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we show that these interactions are preserved at the level of the cardiac transcriptome. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R . Our results expand the scope of genetic regulation of cardiac structure to epistasis., Competing Interests: Competing interests E.A.A. is a Founder of Personalis, Deepcell, Svexa, RCD Co, and Parameter Health; Advisor to Oxford Nanopore, SequenceBio, and Pacific Biosciences; and a non-executive director for AstraZeneca. C.S.W. is a consultant for Tensixteen Bio and Renovacor. V.N.P. is an SAB member for and receives research support from BioMarin, Inc, and is a consultant for Constantiam, Inc. and viz.ai. The remaining authors declare no competing interests.

B Ackground: Prisons and jails are high-risk settings for Covid-19 transmission, morbidity, and mortality. We evaluate protection conferred by prior infection and vaccination against the SARS-CoV-2 Omicron variant within the California state prison system., M Ethods: We employed a test-negative design to match resident and staff cases during the Omicron wave (December 24, 2021-April 14, 2022) to controls according to a case's test-week as well as demographic, clinical, and carceral characteristics. We estimated protection against infection using conditional logistic regression, with exposure status defined by vaccination, stratified by number of mRNA doses received, and prior infection, stratified by periods before or during Delta variant predominance., R Esults: We matched 15,783 resident and 8,539 staff cases to 180,169 resident and 90,409 staff controls. Among cases, 29.7% and 2.2% were infected before or during the emergence of the Delta variant, respectively; 30.6% and 36.3% were vaccinated with two or three doses, respectively. Estimated protection from Omicron infection for two and three doses were 14.9% (95% Confidence Interval [CI], 12.3-19.7%) and 43.2% (42.2-47.4%) for those without known prior infections, 47.8% (95% CI, 46.6-52.8%) and 61.3% (95% CI, 60.7-64.8%) for those infected before the emergence of Delta, and 73.1% (95% CI, 69.8-80.1%) and 86.8% (95% CI, 82.1-92.7) for those infected during the period of Delta predominance., C Onclusion: A third mRNA dose provided significant, additional protection over two doses, including among individuals with prior infection. Our findings suggest that vaccination should remain a priority-even in settings with high levels of transmission and prior infection.

Background: Prisons and jails are high-risk settings for COVID-19 transmission, morbidity, and mortality. COVID-19 vaccines may substantially reduce these risks, but evidence is needed of their effectiveness for incarcerated people, who are confined in large, risky congregate settings., Methods: We conducted a retrospective cohort study to estimate effectiveness of mRNA vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), against confirmed SARS-CoV-2 infections among incarcerated people in California prisons from December 22, 2020 through March 1, 2021. The California Department of Corrections and Rehabilitation provided daily data for all prison residents including demographic, clinical, and carceral characteristics, as well as COVID-19 testing, vaccination status, and outcomes. We estimated vaccine effectiveness using multivariable Cox models with time-varying covariates that adjusted for resident characteristics and infection rates across prisons., Findings: Among 60,707 residents in the cohort, 49% received at least one BNT162b2 or mRNA-1273 dose during the study period. Estimated vaccine effectiveness was 74% (95% confidence interval [CI], 64-82%) from day 14 after first dose until receipt of second dose and 97% (95% CI, 88-99%) from day 14 after second dose. Effectiveness was similar among the subset of residents who were medically vulnerable (74% [95% CI, 62-82%] and 92% [95% CI, 74-98%] from 14 days after first and second doses, respectively), as well as among the subset of residents who received the mRNA-1273 vaccine (71% [95% CI, 58-80%] and 96% [95% CI, 67-99%])., Conclusions: Consistent with results from randomized trials and observational studies in other populations, mRNA vaccines were highly effective in preventing SARS-CoV-2 infections among incarcerated people. Prioritizing incarcerated people for vaccination, redoubling efforts to boost vaccination and continuing other ongoing mitigation practices are essential in preventing COVID-19 in this disproportionately affected population., Funding: Horowitz Family Foundation, National Institute on Drug Abuse, Centers for Disease Control and Prevention, National Science Foundation, Open Society Foundation, Advanced Micro Devices.

Background: Airline travel has been significantly reduced during the COVID-19 pandemic due to concern for individual risk of SARS-CoV-2 infection and population-level transmission risk from importation. Routine viral testing strategies for COVID-19 may facilitate safe airline travel through reduction of individual and/or population-level risk, although the effectiveness and optimal design of these "test-and-travel" strategies remain unclear., Methods: We developed a microsimulation of SARS-CoV-2 transmission in a cohort of airline travelers to evaluate the effectiveness of various testing strategies to reduce individual risk of infection and population-level risk of transmission. We evaluated five testing strategies in asymptomatic passengers: i) anterior nasal polymerase chain reaction (PCR) within 3 days of departure; ii) PCR within 3 days of departure and PCR 5 days after arrival; iii) rapid antigen test on the day of travel (assuming 90% of the sensitivity of PCR during active infection); iv) rapid antigen test on the day of travel and PCR 5 days after arrival; and v) PCR within 3 days of arrival alone. The travel period was defined as three days prior to the day of travel and two weeks following the day of travel, and we assumed passengers followed guidance on mask wearing during this period. The primary study outcome was cumulative number of infectious days in the cohort over the travel period (population-level transmission risk); the secondary outcome was the proportion of infectious persons detected on the day of travel (individual-level risk of infection). Sensitivity analyses were conducted., Findings: Assuming a community SARS-CoV-2 incidence of 50 daily infections, we estimated that in a cohort of 100,000 airline travelers followed over the travel period, there would be a total of 2,796 (95% UI: 2,031, 4,336) infectious days with 229 (95% UI: 170, 336) actively infectious passengers on the day of travel. The pre-travel PCR test (within 3 days prior to departure) reduced the number of infectious days by 35% (95% UI: 27, 42) and identified 88% (95% UI: 76, 94) of the actively infectious travelers on the day of flight; the addition of PCR 5 days after arrival reduced the number of infectious days by 79% (95% UI: 71, 84). The rapid antigen test on the day of travel reduced the number of infectious days by 32% (95% UI: 25, 39) and identified 87% (95% UI: 81, 92) of the actively infectious travelers; the addition of PCR 5 days after arrival reduced the number of infectious days by 70% (95% UI: 65, 75). The post-travel PCR test alone (within 3 days of landing) reduced the number of infectious days by 42% (95% UI: 31, 51). The ratio of true positives to false positives varied with the incidence of infection. The overall study conclusions were robust in sensitivity analysis., Interpretation: Routine asymptomatic testing for COVID-19 prior to travel can be an effective strategy to reduce individual risk of COVID-19 infection during travel, although post-travel testing with abbreviated quarantine is likely needed to reduce population-level transmission due to importation of infection when traveling from a high to low incidence setting.

Routine asymptomatic testing strategies for COVID-19 have been proposed to prevent outbreaks in high-risk healthcare environments. We used simulation modeling to evaluate the optimal frequency of viral testing. We found that routine testing substantially reduces risk of outbreaks, but may need to be as frequent as twice weekly.