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Accurate estimates of the burden of SARS-CoV-2 infection are critical to informing pandemic response. Confirmed COVID-19 case counts in the U.S. do not capture the total burden of the pandemic because testing has been primarily restricted to individuals with moderate to severe symptoms due to limited test availability. Here, we use a semi-Bayesian probabilistic bias analysis to account for incomplete testing and imperfect diagnostic accuracy. We estimate 6,454,951 cumulative infections compared to 721,245 confirmed cases (1.9% vs. 0.2% of the population) in the United States as of April 18, 2020. Accounting for uncertainty, the number of infections during this period was 3 to 20 times higher than the number of confirmed cases. 86% (simulation interval: 64–99%) of this difference is due to incomplete testing, while 14% (0.3–36%) is due to imperfect test accuracy. The approach can readily be applied in future studies in other locations or at finer spatial scale to correct for biased testing and imperfect diagnostic accuracy to provide a more realistic assessment of COVID-19 burden. Estimating the extent of SARS-CoV-2 infection in a population is challenging due to the limitations of testing. Here, the authors estimate that the true number of infections in the United States in mid-April was up to 20 times higher than the number of confirmed cases.

Since their discovery, CRISPR systems have been repurposed for programmable targeted genomic editing, leading to applications for gene disruption, single base editing, insertion, deletion, and manipulation of short genomic sequences. Pairing Cas9 nickase with reverse transcriptase allows applications for insertion, substitution, and deletion of short genomic sequences from an RNA template without generating double stranded breaks however this technology typically shows reduced efficacy in post mitotic cells, limiting its translatability in vivo. Here we present a novel, ligase-based method that addresses these limiations. We introduce edits through delivery and ligation of a synthetic DNA donor to genomic nicks created with Cas9 nickase and report editing activity in cell lines, primary cell cultures, and adult mice via nonviral delivery. With favorable on target outcomes compared to transcription-based editing in key cell types, good tolerability, and deliverability, ligation-mediated gene editing has the potential to further advance genomic medicine. Therapeutic gene editing in vivo is an ongoing challenge. Here, authors demonstrate Cas9 nickase guided DNA ligation as a nonviral method for installing permanent genomic corrections with favorable on target edit profiles in model animal cell types and adult mice.

We measured the effectiveness of a city-wide school-located influenza vaccination (SLIV) program implemented in over 102 elementary schools in Oakland, California. We conducted a retrospective cohort study among Kaiser Permanente Northern California (KPNC) members of all ages residing in either the intervention or a multivariate-matched comparison site from September 2011 - August 2017. Outcomes included medically attended acute respiratory illness (MAARI), influenza hospitalization, and Oseltamivir prescriptions. We estimated difference-in-differences (DIDs) in 2014–15, 2015–16, and 2016–17 using generalized linear models and adjusted for race, ethnicity, age, sex, health plan, and language. Pre-intervention member characteristics were similar between sites. The proportion of KPNC members vaccinated for influenza by KPNC or the SLIV program was 8–11% higher in the intervention site than the comparison site during the intervention period. Among school-aged children, SLIV was associated with lower Oseltamivir prescriptions per 1,000 (DIDs: −3.5 (95% CI −5.5, −1.5) in 2015–16; −4.0 (95% CI −6.5, −1.6) in 2016–17) but not with other outcomes. SLIV was associated with lower MAARI per 1,000 in adults 65 + years (2014–15: −13.2, 95% CI –23.2, −3.2; 2015–16: −21.5, 95% CI −31.1, −11.9; 2016–17: −13.0, 95% CI –23.2, −2.9). There were few significant associations with other outcomes among adults. A city-wide SLIV intervention was associated with higher influenza vaccination coverage, lower Oseltamivir prescriptions in school-aged children, and lower MAARI among people over 65 years, suggesting possible indirect effects of SLIV among older adults.

•We used a matched cohort design to study the differential impacts of SLIV by race and ethnicity.•Racial disparities in vaccine coverage and hospitalizations persisted in the presence of SLIV.•Vaccine hesitance remained a common reason for non-vaccination in school-aged children. Increasing influenza vaccination coverage in school-aged children may substantially reduce community transmission. School-located influenza vaccinations (SLIV) aim to promote vaccinations by increasing accessibility, which may be especially beneficial to race/ethnicity groups that face high barriers to preventative care. Here, we evaluate the effectiveness of a city-wide SLIV program by race/ethnicity from 2014 to 2018. We used multivariate matching to pair schools in the intervention district in Oakland, CA with schools in a comparison district in West Contra Costa County, CA. We distributed cross-sectional surveys to measure caregiver-reported student vaccination status and estimated differences in vaccination coverage levels and reasons for non-vaccination between districts stratifying by race/ethnicity. We estimated difference-in-differences (DID) of laboratory confirmed influenza hospitalization incidence between districts stratified by race/ethnicity using surveillance data. Differences in influenza vaccination coverage in the intervention vs. comparison district were larger among White (2017–18: 21.0% difference [95% CI: 9.7%, 32.3%]) and Hispanic/Latino (13.4% [8.8%, 18.0%]) students than Asian/Pacific Islander (API) (8.9% [1.3%, 16.5%]), Black (5.9% [−2.2%, 14.0%]), and multiracial (6.3% [−1.8%, 14.3%)) students. Concerns about vaccine effectiveness or safety were more common among Black and multiracial caregivers. Logistical barriers were less common in the intervention vs. comparison district, with the largest difference among White students. In both districts, hospitalizations in 2017–18 were higher in Blacks (Intervention: 111.5 hospitalizations per 100,00; Comparison: 134.1 per 100,000) vs. other races/ethnicities. All-age influenza hospitalization incidence was lower in the intervention site vs. comparison site among White/API individuals in 2016–17 (DID −25.14 per 100,000 [95% CI: −40.14, −10.14]) and 2017–18 (−36.6 per 100,000 [−52.7, −20.5]) and Black older adults in 2017–18 (−282.2 per 100,000 (−508.4, −56.1]), but not in other groups. SLIV was associated with higher vaccination coverage and lower influenza hospitalization, but associations varied by race/ethnicity. SLIV alone may be insufficient to ensure equitable influenza outcomes.

Globally, 149 million children under 5 years of age are estimated to be stunted (length more than 2 standard deviations below international growth standards) 1 , 2 . Stunting, a form of linear growth faltering, increases the risk of illness, impaired cognitive development and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering—a key consideration for defining critical windows to deliver preventive interventions. Here we completed a pooled analysis of longitudinal studies in low- and middle-income countries ( n  = 32 cohorts, 52,640 children, ages 0–24 months), allowing us to identify the typical age of onset of linear growth faltering and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to the age of 3 months, with substantially higher stunting at birth in South Asia. From 0 to 15 months, stunting reversal was rare; children who reversed their stunting status frequently relapsed, and relapse rates were substantially higher among children born stunted. Early onset and low reversal rates suggest that improving children’s linear growth will require life course interventions for women of childbearing age and a greater emphasis on interventions for children under 6 months of age. A pooled analysis of longitudinal studies in low- and middle-income countries identifies the typical age of onset of linear growth faltering and investigates recurrent faltering in early life.

Growth faltering in children (low length for age or low weight for length) during the first 1,000 days of life (from conception to 2 years of age) influences short-term and long-term health and survival 1 , 2 . Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Identification of age windows and population subgroups on which to focus will benefit future preventive efforts. Here we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age z -scores of up to 0.40 and weight-for-length z -scores of up to 0.15 by 24 months of age. Boys had consistently higher risk of all forms of growth faltering than girls. Early postnatal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits exhibited higher mortality rates from birth to 2 years of age than children without growth deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes and severe consequences for children who experienced early growth faltering support a focus on pre-conception and pregnancy as a key opportunity for new preventive interventions. Analysis of data from 33 longitudinal cohorts from low- and middle-income countries indicates that conditions during pre-conception, pregnancy and the first few months of life are crucial in determining the risk of growth faltering in young children.

Sustainable Development Goal 2.2—to end malnutrition by 2030—includes the elimination of child wasting, defined as a weight-for-length z -score that is more than two standard deviations below the median of the World Health Organization standards for child growth 1 . Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery and persistence—key features that inform preventive interventions and estimates of disease burden. Here we analyse 21 longitudinal cohorts and show that wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. Many more children experience an episode of wasting at some point during their first 24 months than prevalent cases at a single point in time suggest. For example, at the age of 24 months, 5.6% of children were wasted, but by the same age (24 months), 29.2% of children had experienced at least one wasting episode and 10.0% had experienced two or more episodes. Children who were wasted before the age of 6 months had a faster recovery and shorter episodes than did children who were wasted at older ages; however, early wasting increased the risk of later growth faltering, including concurrent wasting and stunting (low length-for-age z -score), and thus increased the risk of mortality. In diverse populations with high seasonal rainfall, the population average weight-for-length z -score varied substantially (more than 0.5 z in some cohorts), with the lowest mean z -scores occurring during the rainiest months; this indicates that seasonally targeted interventions could be considered. Our results show the importance of establishing interventions to prevent wasting from birth to the age of 6 months, probably through improved maternal nutrition, to complement current programmes that focus on children aged 6–59 months. An analysis of longitudinal cohort data across diverse populations suggests that the incidence of wasting between birth and 24 months is higher than previously thought, and highlights the role of seasonal factors that affect child growth.