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Theileria orientalis Ikeda has caused an epidemic of bovine anemia and abortion across several U.S. states. This apicomplexan hemoparasite is transmitted by Haemaphysalis longicornis ticks; however, it is unknown if other North American ticks are competent vectors. Since the disease movement is largely determined by the host tick range(s), the prediction of the T. orientalis spread among U.S. cattle populations requires determination of additional competent tick vectors. Although Rhipicephalus microplus has mostly been eradicated from the U.S., outbreaks in populations occur frequently, and the U.S. remains at risk for reintroduction. Since R. microplus is a vector of Theileria equi and T. orientalis DNA has been detected in R. microplus, the goal of this study was to determine whether R. microplus is a competent vector of T. orientalis. Larval R. microplus were applied to a splenectomized, T. orientalis Ikeda-infected calf for parasite acquisition, removed as molted adults, and applied to two T. orientalis naïve, splenectomized calves for transmission. After 60 days, the naïve calves remained negative for T. orientalis by PCR and cytology. Additionally, T. orientalis was not detected in the salivary glands or larval progeny of acquisition-fed adults. These data suggest that R. microplus is not a competent vector of the U.S. T. orientalis Ikeda isolate.

Equine theileriosis, caused by Theileria haneyi and Theileria equi, leads to anemia, exercise intolerance, and occasionally, death. Theileriosis-free countries prohibit the importation of infected horses, resulting in significant costs for the equine industry. Imidocarb dipropionate is the only treatment for T. equi in the United States, but lacks efficacy against T. haneyi. The goal of this study was to assess the in vivo efficacy of tulathromycin and diclazuril against T. haneyi. Fourteen T. haneyi-infected horses were utilized. Six were treated with eight weekly 2.5 mg/kg doses of tulathromycin. Three were treated daily for eight weeks with 2.5 mg/kg diclazuril. Three were pre-treated with 0.5 mg/kg diclazuril daily for one month to determine whether low-dose diclazuril prevents infection. Following infection, the dose was increased to 2.5 mg/kg for eight weeks. Two infected horses remained untreated as controls. The horses were assessed via nested PCR, physical exams, complete blood counts, serum chemistry panels, and cytology. Tulathromycin and diclazuril failed to clear T. haneyi and the treated and control groups exhibited similar parasitemia and packed cell volume declines. To obtain additional safety data on tulathromycin use in adult horses, necropsy and histopathology were performed on tulathromycin-treated horses. No significant lesions were detected.

Background Influenza is associated with excess morbidity and mortality of individuals each year. Few therapies exist for treatment of influenza infection, and each require initiation as early as possible in the course of infection, making efficacy difficult to estimate in the hospitalized patient with lower respiratory tract infection. Using causal machine learning methods, we re-analyze data from a randomized trial of oseltamivir versus standard of care aimed at reducing clinical failure in hospitalized patients with lower respiratory tract infection during the influenza season. Methods This was a secondary analysis of the Rapid Empiric Treatment with Oseltamivir Study (RETOS). Conditional average treatment effects (CATE) and 95% confidence intervals were computed from causal forest including 85 clinical and demographic variables. RETOS was a multicenter, randomized, unblinded, trial of adult patients hospitalized with lower respiratory tract infections in Kentucky from 2009 through 2012. Adult hospitalized patients with lower respiratory tract infection were randomized to standard of care or standard of care plus oseltamivir as early as possible after hospital admission but within 24 h of enrollment. After randomization, oseltamivir was initiated in the treatment arm per package insert. The primary outcome was clinical failure, a composite measure including failure to reach clinical improvement within 7 days, transfer to intensive care 24 h after admission, or rehospitalization or death within 30 days. Results A total of 691 hospitalized patients with lower respiratory tract infections were included in the study. The only subgroup of patients with a statistically significant CATE was those with laboratory-confirmed influenza infection with a 26% lower risk of clinical failure when treated with oseltamivir (95% CI 3.2–48.0%). Conclusions This study suggests that addition of oseltamivir to standard of care may decrease clinical failure in hospitalized patients with influenza-associated lower respiratory tract infection versus standard of care alone. These results are supportive of current recommendations to initiate antiviral treatment in hospitalized patients with confirmed or suspected influenza as soon as possible after admission. Trial registration Original trial: Clinical Trials.Gov; Rapid Empiric Treatment With Oseltamivir Study (RETOS) (RETOS); ClinicalTrials.gov Identifier: NCT01248715 https://clinicaltrials.gov/ct2/show/NCT01248715

The COVID-19 pandemic and subsequent implementation of nonpharmaceutical interventions (e.g., cessation of global travel, mask use, physical distancing, and staying home) reduced transmission of some viral respiratory pathogens (1). In the United States, influenza activity decreased in March 2020, was historically low through the summer of 2020 (2), and remained low during October 2020-May 2021 (

Dark spots on Neptune observed by Voyager and the Hubble Space Telescope are thought to be anticyclones with lifetimes of a few years, in contrast with very long-lived anticyclones in Jupiter and Saturn. The full life cycle of any Neptune dark spot has not been captured due to limited temporal coverage, but our Hubble observations of a recent feature, NDS-2018, provide the most complete long-term observational history of any dark vortex on Neptune. Past observations suggest some dark spots meet their demise by fading and dissipating without migrating meridionally. On the other hand, simulations predict a second pathway with equatorward migration and disruption. Our HST observations suggest NDS-2018 is following the second pathway. Some of the HST observations reveal transient dark features with widths of about 4000 to 9000 km, at latitudes between NDS-2018 and the equator. The secondary dark features appeared before changes in the meridional migration of NDS-2018 were seen. These features have somewhat smaller size and much smaller contrast compared to the main dark spot. Discrete secondary dark features of this scale have never been seen near previous dark spots, but global-scale dark bands are associated with several previous dark spots in addition to NDS-2018. The absolute photometric contrast of NDS-2018 (as large as 19%) is greater than previous dark spots, including the Great Dark Spot seen by Voyager. New simulations suggest that vortex internal circulation is weak relative to the background vorticity, presenting a clearly different case from stronger anticyclones observed on Jupiter and Saturn.

Progress in the study of the immune response to pathogens and candidate vaccines has been impeded by limitations in the methods to study the functional activity of T-cell subsets proliferating in response to antigens processed and presented by antigen presenting cells (APC). As described in this review, during our studies of the bovine immune response to a candidate peptide-based vaccine and candidate rel deletion mutants in Mycobacterium avium paratuberculosis (Map) and Mycbacterium bovis (BCG), we developed methods to study the primary and recall CD4 and CD8 T-cell responses using an ex vivo platform. An assay was developed to study intracellular killing of bacteria mediated by CD8 T cells using quantitative PCR to distinguish live bacteria from dead bacteria in a mixed population of live and dead bacteria. Through use of these assays, we were able to demonstrate vaccination with live rel Map and BCG deletion mutants and a Map peptide-based vaccine elicit development of CD8 cytotoxic T cells with the ability to kill intracellular bacteria using the perforin-granzyme B pathway. We also demonstrated tri-directional signaling between CD4 and CD8 T cells and antigen-primed APC is essential for eliciting CD8 cytotoxic T cells. Herein, we describe development of the assays and review progress made through their use in the study of the immune response to mycobacterial pathogens and candidate vaccines. The methods obviate some of the major difficulties encountered in characterizing the cell-mediated immune response to pathogens and development of attenuated and peptide-based vaccines.

Transplant recipients are among the groups for whom the updated recommendations for 2020–2021 influenza vaccination should generally be considered essential, notably in the face of the COVID‐19 pandemic.

This exploratory study examined whether social learning increases similarity in adolescent siblings' behavior and neural patterns during risky decision making. Participants included 86 adolescents (43 sibling dyads; younger siblings:M-age = 12.2 years; 22 females; older siblings:M-age = 14.6 years; 20 females) who completed questionnaires, and a decision-making task during an fMRI scan. Younger siblings became more similar to their older siblings' risky decision making after observing their older sibling take risks). Younger siblings who reported greater modeling of their older sibling, and less differentiation from them, showed increased neural similarity to their older siblings in the ventromedial prefrontal cortex, and the right anterior insula and ventral striatum, respectively. These findings highlight siblings as salient social agents in how adolescents process risky decision making. National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01DA039923]; National Science FoundationNational Science Foundation (NSF) [SES 1459719] We greatly appreciate Elise Breitfeld, Sue Hyun Kwon, and Madison Marcus for their diligence in recruitment, data management, and data collection. We also thank Amanda Carter Benjamin, Susannah Ivory, and Virnaliz Jimenez for their assistance in collecting data. This work was supported by grants from the National Institutes of Health (R01DA039923) and National Science Foundation (SES 1459719).

After recognition of widespread community transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), by mid- to late February 2020, indicators of influenza activity began to decline in the Northern Hemisphere. These changes were attributed to both artifactual changes related to declines in routine health seeking for respiratory illness as well as real changes in influenza virus circulation because of widespread implementation of measures to mitigate transmission of SARS-CoV-2. Data from clinical laboratories in the United States indicated a 61% decrease in the number of specimens submitted (from a median of 49,696 per week during September 29, 2019-February 29, 2020, to 19,537 during March 1-May 16, 2020) and a 98% decrease in influenza activity as measured by percentage of submitted specimens testing positive (from a median of 19.34% to 0.33%). Interseasonal (i.e., summer) circulation of influenza in the United States (May 17-August 8, 2020) is currently at historical lows (median = 0.20% tests positive in 2020 versus 2.35% in 2019, 1.04% in 2018, and 2.36% in 2017). Influenza data reported to the World Health Organization's (WHO's) FluNet platform from three Southern Hemisphere countries that serve as robust sentinel sites for influenza from Oceania (Australia), South America (Chile), and Southern Africa (South Africa) showed very low influenza activity during June-August 2020, the months that constitute the typical Southern Hemisphere influenza season. In countries or jurisdictions where extensive community mitigation measures are maintained (e.g., face masks, social distancing, school closures, and teleworking), those locations might have little influenza circulation during the upcoming 2020-21 Northern Hemisphere influenza season. The use of community mitigation measures for the COVID-19 pandemic, plus influenza vaccination, are likely to be effective in reducing the incidence and impact of influenza, and some of these mitigation measures could have a role in preventing influenza in future seasons. However, given the novelty of the COVID-19 pandemic and the uncertainty of continued community mitigation measures, it is important to plan for seasonal influenza circulation in the United States this fall and winter. Influenza vaccination of all persons aged ≥6 months remains the best method for influenza prevention and is especially important this season when SARS-CoV-2 and influenza virus might cocirculate (1).

We develop new estimates of monthly water balance components from 1950 to 2019 for the Laurentian Great Lakes, the largest surface freshwater system on Earth. For each of the Great Lakes, lake storage changes and water balance components were estimated using the Large Lakes Statistical Water Balance Model (L2SWBM). Multiple independent data sources, contributed by a binational community of research scientists and practitioners, were assimilated into the L2SWBM to infer feasible values of water balance components through a Bayesian framework. A conventional water balance model was used to constrain the new estimates, ensuring that the water balance can be reconciled over multiple time periods. The new estimates are useful for investigating changes in water availability, or benchmarking new hydrological models and data products developed for the Laurentian Great Lakes Region. The source code and inputs of the L2SWBM model are also made available, and can be adapted to include new data sources for the Great Lakes, or to address water balance problems on other large lake systems., Measurement(s) hydrological process • water balance Technology Type(s) computational modeling technique Factor Type(s) monthly water balance estimates Sample Characteristic - Environment lake Sample Characteristic - Location Great Lakes Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12764342

Equine theileriosis, a tick-transmitted disease caused by the hemoprotozoan parasites Theileria equi and Theileria haneyi, affects equids throughout tropical and subtropical regions of the world. It is a significant regulatory concern in non-endemic countries, where testing for equine theileriosis is required prior to horse import to prevent parasite entry. Within endemic areas, infection causes significant morbidity and mortality, leading to economic losses. No vaccine for equine theileriosis is available, and current drug treatment protocols are inconsistent and associated with significant side effects. Recent work has revealed substantial genetic variability among equine theileriosis organisms, and analysis of ribosomal DNA from affected animals around the world indicates that the organisms can be grouped into five distinct clades. As these diverse parasites are capable of infecting a wide range of both tick and mammalian hosts, movement of different equine Theileria species between endemic countries, and eventually into non-endemic countries, is a significant concern. Furthermore, the substantial genetic variability of these organisms will likely render currently utilized importation diagnostic tests unable to detect all equine Theileria spp. To this end, more complete characterization of these diverse parasites is critical to the continued global control of equine theileriosis. This review discusses current knowledge of equine Theileria spp. in this context, and highlights new opportunities and challenges for workers in this field.

Since SARS-CoV-2, the novel coronavirus that causes coronavirus disease 2019 (COVID-19), was first detected in December 2019 (1), approximately 1.3 million cases have been reported worldwide (2), including approximately 330,000 in the United States (3). To conduct population-based surveillance for laboratory-confirmed COVID-19-associated hospitalizations in the United States, the COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) was created using the existing infrastructure of the Influenza Hospitalization Surveillance Network (FluSurv-NET) (4) and the Respiratory Syncytial Virus Hospitalization Surveillance Network (RSV-NET). This report presents age-stratified COVID-19-associated hospitalization rates for patients admitted during March 1-28, 2020, and clinical data on patients admitted during March 1-30, 2020, the first month of U.S. surveillance. Among 1,482 patients hospitalized with COVID-19, 74.5% were aged ≥50 years, and 54.4% were male. The hospitalization rate among patients identified through COVID-NET during this 4-week period was 4.6 per 100,000 population. Rates were highest (13.8) among adults aged ≥65 years. Among 178 (12%) adult patients with data on underlying conditions as of March 30, 2020, 89.3% had one or more underlying conditions; the most common were hypertension (49.7%), obesity (48.3%), chronic lung disease (34.6%), diabetes mellitus (28.3%), and cardiovascular disease (27.8%). These findings suggest that older adults have elevated rates of COVID-19-associated hospitalization and the majority of persons hospitalized with COVID-19 have underlying medical conditions. These findings underscore the importance of preventive measures (e.g., social distancing, respiratory hygiene, and wearing face coverings in public settings where social distancing measures are difficult to maintain)† to protect older adults and persons with underlying medical conditions, as well as the general public. In addition, older adults and persons with serious underlying medical conditions should avoid contact with persons who are ill and immediately contact their health care provider(s) if they have symptoms consistent with COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html) (5). Ongoing monitoring of hospitalization rates, clinical characteristics, and outcomes of hospitalized patients will be important to better understand the evolving epidemiology of COVID-19 in the United States and the clinical spectrum of disease, and to help guide planning and prioritization of health care system resources.

We describe the contact investigation for an early confirmed case of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the United States. Contacts of the case-patient were identified, actively monitored for symptoms, interviewed for a detailed exposure history, and tested for SARS-CoV-2 infection by real-time reverse transcription PCR (rRT-PCR) and ELISA. Fifty contacts were identified and 38 (76%) were interviewed, of whom 11 (29%) reported unprotected face-to-face interaction with the case-patient. Thirty-seven (74%) had respiratory specimens tested by rRT-PCR, and all tested negative. Twenty-three (46%) had ELISA performed on serum samples collected ≈6 weeks after exposure, and none had detectable antibodies to SARS-CoV-2. Among contacts who were tested, no secondary transmission was identified in this investigation, despite unprotected close interactions with the infectious case-patient.

Despite the fact that the Great Lakes contain roughly 20% of the world's surface freshwater, there is a relatively limited body of recent work in peer reviewed literature that addresses recent trends in lake levels. This work is largely coming from a handful of authors who are most well-versed in the complexities of monitoring and modeling in a basin that spans an international border and contains vast areas of surface water connected by both natural and managed connecting channel flows. At the same time, the recent dramatic changes from record low water levels in the early 2010's to record high water levels across the Great Lakes in 2019 and 2020 have brought significant attention to the hydroclimatic conditions in the basin, underscoring the need to bring new approaches and diverse perspectives (including from outside the basin) to address hydroclimate research challenges in the Great Lakes. Significant effort has led to advancements in data and model coordination among U.S. and Canadian federal agencies throughout the decades, and at the same time research from the broader community has led to higher resolution gridded data products. In this paper, we aim to present the current state of data and models for use in hydrological simulation with the objective of providing a guide to navigating the waters of Great Lakes hydroclimate data. We focus on data for use in modeling water levels, but we expect the information to be more broadly applicable to other hydroclimate research. We approach this by including perspectives from both the Great Lakes water management community and the broader earth science community.

Arthropod-borne apicomplexan pathogens remain a great concern and challenge for disease control in animals and humans. In order to prevent Babesia infection, the discovery of antigens that elicit protective immunity is essential to establish approaches to stop disease dissemination. In this study, we determined that poly-N-acetylglucosamine (PNAG) is conserved among tick-borne pathogens including B. bovis, B. bigemina, B. divergens, B. microti, and Babesia WA1. Calves immunized with synthetic ß-(1→6)-linked glucosamine oligosaccharides conjugated to tetanus toxoid (5GlcNH2-TT) developed antibodies with in vitro opsonophagocytic activity against Staphylococcus aureus. Sera from immunized calves reacted to B. bovis. These results suggest strong immune responses against PNAG. However, 5GlcNH2-TT-immunized bovines challenged with B. bovis developed acute babesiosis with the cytoadhesion of infected erythrocytes to brain capillary vessels. While this antigen elicited antibodies that did not prevent disease, we are continuing to explore other antigens that may mitigate these vector-borne diseases for the cattle industry.

SARS-CoV-2 transmission from contaminated surfaces, or fomites, has been a concern during the COVID-19 pandemic. Households have been important sites of transmission throughout the COVID-19 pandemic, but there is limited information on SARS-CoV-2 contamination of surfaces in these settings. We describe environmental detection of SARS-CoV-2 in households of persons with COVID-19 to better characterize the potential risks of fomite transmission. Ten households with ≥1 person with laboratory-confirmed COVID-19 and with ≥2 members total were enrolled in Utah, U.S.A. Nasopharyngeal and anterior nasal swabs were collected from members and tested for the presence of SARS-CoV-2 by RT-PCR. Fifteen surfaces were sampled in each household and tested for presence and viability of SARS-CoV-2. SARS-CoV-2 RNA was detected in 23 (15%) of 150 environmental swab samples, most frequently on nightstands (4/6, 67%), pillows (4/23, 17%), and light switches (3/21, 14%). Viable SARS-CoV-2 was cultured from one sample. All households with SARS-CoV-2-positive surfaces had ≥1 person who first tested positive for SARS-CoV-2 ≤ 6 days prior to environmental sampling. SARS-CoV-2 surface contamination occurred early in the course of infection when respiratory transmission is most likely, notably on surfaces in close, prolonged contact with persons with COVID-19. While fomite transmission might be possible, risk is low.

Key Points Question Are rates of severe influenza disease associated with race and ethnicity? Findings In this cross-sectional study of influenza-associated outcomes among 113 352 patients hospitalized with influenza over the course of 10 influenza seasons, Black, Hispanic, and American Indian or Alaska Natives persons had higher rates of hospitalization and intensive care unit admission, even after adjusting for age. The greatest disparities were found in the youngest age groups. Meaning These findings suggest that targeted prevention and intervention efforts, such as improved influenza vaccine coverage and early use of antiviral treatment, could improve influenza-associated outcomes among racial and ethnic minority groups identified in this study as having higher rates of severe influenza disease., This cross-sectional study examines rates of influenza-associated hospitalization, intensive care unit (ICU) admission, and in-hospital death by race and ethnicity in the US from 2009 to 2019., Importance Racial and ethnic minority groups, such as Black, Hispanic, American Indian or Alaska Native, and Asian or Pacific Islander persons, often experience higher rates of severe influenza disease. Objective To describe rates of influenza-associated hospitalization, intensive care unit (ICU) admission, and in-hospital death by race and ethnicity over 10 influenza seasons. Design, Setting, and Participants This cross-sectional study used data from the Influenza-Associated Hospitalization Surveillance Network (FluSurv-NET), which conducts population-based surveillance for laboratory-confirmed influenza-associated hospitalizations in selected counties, representing approximately 9% of the US population. Influenza hospitalizations from the 2009 to 2010 season to the 2018 to 2019 season were analyzed. Data were analyzed from October 2020 to July 2021. Main Outcomes and Measures The main outcomes were age-adjusted and age-stratified rates of influenza-associated hospitalization, ICU admission, and in-hospital death by race and ethnicity overall and by influenza season. Results Among 113 352 persons with an influenza-associated hospitalization (34 436 persons [32.0%] aged ≥75 years; 61 009 [53.8%] women), 70 225 persons (62.3%) were non-Hispanic White (White), 24 850 persons (21.6%) were non-Hispanic Black (Black), 11 903 persons (10.3%) were Hispanic, 5517 persons (5.1%) were non-Hispanic Asian or Pacific Islander, and 857 persons (0.7%) were non-Hispanic American Indian or Alaska Native. Among persons aged younger than 75 years and compared with White persons of the same ages, Black persons were more likely to be hospitalized (eg, age 50-64 years: rate ratio [RR], 2.50 95% CI, 2.43-2.57) and to be admitted to an ICU (eg, age 50-64 years: RR, 2.09; 95% CI, 1.96-2.23). Among persons aged younger than 50 years and compared with White persons of the same ages, American Indian or Alaska Native persons were more likely to be hospitalized (eg, age 18-49 years: RR, 1.72; 95% CI, 1.51-1.96) and to be admitted to an ICU (eg, age 18-49 years: RR, 1.84; 95% CI, 1.40-2.42). Among children aged 4 years or younger and compared with White children, hospitalization rates were higher in Black children (RR, 2.21; 95% CI, 2.10-2.33), Hispanic children (RR, 1.87; 95% CI, 1.77-1.97), American Indian or Alaska Native children (RR, 3.00; 95% CI, 2.55-3.53), and Asian or Pacific Islander children (RR, 1.26; 95% CI, 1.16-1.38), as were rates of ICU admission (Black children: RR, 2.74; 95% CI, 2.43-3.09; Hispanic children: RR, 1.96; 95% CI, 1.73-2.23; American Indian and Alaska Native children: RR, 3.51; 95% CI, 2.45-5.05). In this age group and compared with White children, in-hospital death rates were higher among Hispanic children (RR, 2.98; 95% CI, 1.23-7.19), Black children (RR, 3.39; 95% CI, 1.40-8.18), and Asian or Pacific Islander children (RR, 4.35; 95% CI, 1.55-12.22). Few differences were observed in rates of severe influenza-associated outcomes by race and ethnicity among adults aged 75 years or older. For example, in this age group, compared with White adults, hospitalization rates were slightly higher only among Black adults (RR, 1.05; 95% CI 1.02-1.09). Overall, Black persons had the highest age-adjusted hospitalization rate (68.8 [95% CI, 68.0-69.7] hospitalizations per 100 000 population) and ICU admission rate (11.6 [95% CI, 11.2-11.9] admissions per 100 000 population). Conclusions and Relevance This cross-sectional study found racial and ethnic disparities in rates of severe influenza-associated disease. These data identified subgroups for whom improvements in influenza prevention efforts could be targeted.

Cassini/ISS imagery and Cassini/VIMS spectral imaging observations from 0.35 to 5.12 microns show that between 2012 and 2017 the region poleward of the Saturn's northern hexagon changed from dark blue/green to a moderately brighter gold color, except for the inner eye region (88.2 deg - 90 deg N), which remained relatively unchanged. These and even more dramatic near-IR changes can be reproduced by an aerosol model of four compact layers consisting of a stratospheric haze at an effective pressure near 50 mbar, a deeper haze of putative diphosphine particles typically near 300 mbar, an ammonia cloud layer with a base pressure between 0.4 bar and 1.3 bar, and a deeper cloud of a possible mix of NH4SH and water ice particles within the 2.7 to 4.5 bar region. Our analysis of the background clouds between the discrete features shows that between 2013 and 2016 the effective pressures of most layers changed very little, except for the ammonia ice layer, which decreased from about 1 bar to 0.4 bar near the edge of the eye, but increased to 1 bar inside the eye. Inside the hexagon there were large increases in optical depth, by up to a factor of 10 near the eye for the putative diphosphine layer and by a factor of four over most of the hexagon interior. Inside the eye, aerosol optical depths were very low, suggesting downwelling motions. The high contrast between eye and surroundings in 2016 was due to substantial increases in optical depths outside the eye. The color change from blue/green to gold inside most of the hexagon region can be explained in our model almost entirely by changes in the stratospheric haze, which increased between 2013 and 2016 by a factor of four in optical depth and by almost a factor of three in the short-wavelength peak imaginary index., 47 pages, 38 figures, 7 tables

Background In the United States, Coronavirus Disease 2019 (COVID-19) deaths are captured through the National Notifiable Disease Surveillance System and death certificates reported to the National Vital Statistics System (NVSS). However, not all COVID-19 deaths are recognized and reported because of limitations in testing, exacerbation of chronic health conditions that are listed as the cause of death, or delays in reporting. Estimating deaths may provide a more comprehensive understanding of total COVID-19–attributable deaths. Methods We estimated COVID-19 unrecognized attributable deaths, from March 2020—April 2021, using all-cause deaths reported to NVSS by week and six age groups (0–17, 18–49, 50–64, 65–74, 75–84, and ≥85 years) for 50 states, New York City, and the District of Columbia using a linear time series regression model. Reported COVID-19 deaths were subtracted from all-cause deaths before applying the model. Weekly expected deaths, assuming no SARS-CoV-2 circulation and predicted all-cause deaths using SARS-CoV-2 weekly percent positive as a covariate were modelled by age group and including state as a random intercept. COVID-19–attributable unrecognized deaths were calculated for each state and age group by subtracting the expected all-cause deaths from the predicted deaths. Findings We estimated that 766,611 deaths attributable to COVID-19 occurred in the United States from March 8, 2020—May 29, 2021. Of these, 184,477 (24%) deaths were not documented on death certificates. Eighty-two percent of unrecognized deaths were among persons aged ≥65 years; the proportion of unrecognized deaths were 0•24–0•31 times lower among those 0–17 years relative to all other age groups. More COVID-19–attributable deaths were not captured during the early months of the pandemic (March–May 2020) and during increases in SARS-CoV-2 activity (July 2020, November 2020—February 2021). Interpretation Estimating COVID-19–attributable unrecognized deaths provides a better understanding of the COVID-19 mortality burden and may better quantify the severity of the COVID-19 pandemic. Funding None

During May 19-September 28, 2019,* low levels of influenza activity were reported in the United States, with cocirculation of influenza A and influenza B viruses. In the Southern Hemisphere seasonal influenza viruses circulated widely, with influenza A(H3) predominating in many regions; however, influenza A(H1N1)pdm09 and influenza B viruses were predominant in some countries. In late September, the World Health Organization (WHO) recommended components for the 2020 Southern Hemisphere influenza vaccine and included an update to the A(H3N2) and B/Victoria-lineage components. Annual influenza vaccination is the best means for preventing influenza illness and its complications, and vaccination before influenza activity increases is optimal. Health care providers should recommend vaccination for all persons aged ≥6 months who do not have contraindications to vaccination (1).

CDC collects, compiles, and analyzes data on influenza activity and viruses in the United States. During September 30, 2018-February 2, 2019,* influenza activity† in the United States was low during October and November, increased in late December, and remained elevated through early February. As of February 2, 2019, this has been a low-severity influenza season (1), with a lower percentage of outpatient visits for influenza-like illness (ILI), lower rates of hospitalization, and fewer deaths attributed to pneumonia and influenza, compared with recent seasons. Influenza-associated hospitalization rates among children are similar to those observed in influenza A(H1N1)pdm09 predominant seasons; 28 influenza-associated pediatric deaths occurring during the 2018-19 season have been reported to CDC. Whereas influenza A(H1N1)pdm09 viruses predominated in most areas of the country, influenza A(H3N2) viruses have predominated in the southeastern United States, and in recent weeks accounted for a growing proportion of influenza viruses detected in several other regions. Small numbers of influenza B viruses (

Background Stool consistency is an important diagnostic criterion in both research and clinical medicine and is often used to define diarrheal disease. Methods We examine the pediatric enteric virome across stool consistencies to evaluate differences in richness and community composition using fecal samples collected from children aged 0 to 5 years participating in a clinical trial in the Amhara region of Ethiopia. The consistency of each sample was graded according to the modified Bristol Stool Form Scale for children (mBSFS-C) before a portion of stool was preserved for viral metagenomic analysis. Stool samples were grouped into 29 pools according to stool consistency type. Differential abundance was determined using negative-binomial modeling. Results Of 446 censused children who were eligible to participate, 317 presented for the study visit examination and 269 provided stool samples. The median age of children with stool samples was 36 months. Species richness was highest in watery-consistency stool and decreased as stool consistency became firmer (Spearman’s r = − 0.45, p = 0.013). The greatest differential abundance comparing loose or watery to formed stool was for norovirus GII (7.64, 95% CI 5.8, 9.5) followed by aichivirus A (5.93, 95% CI 4.0, 7.89) and adeno-associated virus 2 (5.81, 95%CI 3.9, 7.7). Conclusions In conclusion, we documented a difference in pediatric enteric viromes according to mBSFS-C stool consistency category, both in species richness and composition. Electronic supplementary material The online version of this article (10.1186/s12879-019-3674-3) contains supplementary material, which is available to authorized users.

The apicomplexan hemoparasite, Theileria parva, causes East Coast fever (ECF), a frequently fatal disease of African cattle. Vaccine development has been impeded by incomplete understanding of protective immunity following natural exposure or the infection and treatment method (ITM) of immunization. This is attributable to a paucity of methods to characterize the memory T-cell repertoire following infection. To overcome this impediment, assays developed to study the immune response to other intracellular pathogens were adapted for use in studies with T. parva to enable definition of the phenotype and function of effector T cells in T. parva-immune cattle, facilitating vaccine development. As reported herein, stimulation of peripheral blood mononuclear cells (PBMC) from ITM-immunized steers with irradiated, autologous, T. parva-infected cell lines elicited a proliferative recall response comprised of CD45R0+/CCR7− CD4+ and CD8+ T cells. Subsequent co-incubation of stimulated cultures with infected cells demonstrated the presence of cytotoxic T cells (CTLs) with the ability to kill infected cells. Comparison of CTL activity in cultures depleted of CD4+ or CD8+ T cells demonstrated CTL activity was primarily attributed to CD8+ T cells. Importantly, stimulation of PBMC from vaccinated steers always elicited proliferation of CD4+ and CD8+ T cells. This was the first important observation obtained from the use of the assay described herein.

Background Information is limited regarding the effectiveness of the two-dose messenger RNA (mRNA) vaccines BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna) in preventing infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in attenuating coronavirus disease 2019 (Covid-19) when administered in real-world conditions. Methods We conducted a prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers. From December 14, 2020, to April 10, 2021, the participants completed weekly SARS-CoV-2 testing by providing mid-turbinate nasal swabs for qualitative and quantitative reverse-transcriptase–polymerase-chain-reaction (RT-PCR) analysis. The formula for calculating vaccine effectiveness was 100%×(1−hazard ratio for SARS-CoV-2 infection in vaccinated vs. unvaccinated participants), with adjustments for the propensity to be vaccinated, study site, occupation, and local viral circulation. Results SARS-CoV-2 was detected in 204 participants (5%), of whom 5 were fully vaccinated (≥14 days after dose 2), 11 partially vaccinated (≥14 days after dose 1 and

Background The Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), evolved rapidly in the United States. This report describes the demographic, clinical, and epidemiologic characteristics of 544 U.S. persons under investigation (PUI) for COVID-19 with complete SARS-CoV-2 testing in the beginning stages of the pandemic from January 17 through February 29, 2020. Methods In this surveillance cohort, the U.S. Centers for Disease Control and Prevention (CDC) provided consultation to public health and healthcare professionals to identify PUI for SARS-CoV-2 testing by quantitative real-time reverse-transcription PCR. Demographic, clinical, and epidemiologic characteristics of PUI were reported by public health and healthcare professionals during consultation with on-call CDC clinicians and subsequent submission of a CDC PUI Report Form. Characteristics of laboratory-negative and laboratory-positive persons were summarized as proportions for the period of January 17−February 29, and characteristics of all PUI were compared before and after February 12 using prevalence ratios. Results A total of 36 PUI tested positive for SARS-CoV-2 and were classified as confirmed cases. Confirmed cases and PUI testing negative for SARS-CoV-2 had similar demographic, clinical, and epidemiologic characteristics. Consistent with changes in PUI evaluation criteria, 88% (13/15) of confirmed cases detected before February 12, 2020, reported travel from China. After February 12, 57% (12/21) of confirmed cases reported no known travel- or contact-related exposures. Conclusions These findings can inform preparedness for future pandemics, including capacity for rapid expansion of novel diagnostic tests to accommodate broad surveillance strategies to assess community transmission, including potential contributions from asymptomatic and presymptomatic infections.

Published reports suggest efforts designed to prevent the occurrence of harmful algal blooms and hypoxia by reducing non-point and point source phosphorus (P) pollution are not delivering water quality improvements in many areas. Part of the uncertainty in evaluating watershed responses to management practices is the lack of standardized estimates of phosphorus inputs and outputs. To assess P trends across the conterminous United States, we compiled an inventory using publicly available datasets of agricultural P fluxes, atmospheric P deposition, human P demand and waste, and point source discharges for 2002, 2007, and 2012 at the scale of the 8-digit Hydrologic Unit Code subbasin (~1,800 km(2)). Estimates of agricultural legacy P surplus accumulated from 1945 to 2001 were also developed. Fertilizer and manure inputs were found to exceed crop removal rates by up to 50% in many agricultural regions. This excess in inputs has led to the continued accumulation of legacy P in agricultural lands. Atmospheric P deposition increased throughout the Rockies, potentially contributing to reported increases in surface water P concentrations in undisturbed watersheds. In some urban areas, P fluxes associated with human waste and non-farm fertilizer use has declined despite population growth, likely due, in part, to various sales bans on P-containing detergents and fertilizers. Although regions and individual subbasins have different contemporary and legacy P sources, a standardized method of accounting for large and small fluxes and ready to use inventory numbers provide essential infromation to coordinate targeted interventions to reduce P concentrations in the nation’s waters.

The apicomplexan parasite Theileria haneyi is one of two known causative agents of equine theileriosis. It causes milder clinical disease than its more virulent counterpart, Theileria equi, in experimentally infected horses, and can superinfect T. equi-positive horses. The current equi merozoite antigen 1 (EMA1)-based competitive enzyme-linked immunosorbent assay (ELISA)used in the U.S. to detect equine theileriosis detects T. equi but not T. haneyi, and the complexity of molecular assays precludes widespread use for epidemiologic studies. In order to facilitate urgently needed studies on the prevalence of T. haneyi, the goal of this study was to develop a sensitive and specific serologic assay for the diagnosis of T. haneyi based on the equi merozoite antigen 11 (ThEMA11). To achieve this objective, ThEMA11 was recombinantly expressed in eukaryotic cells and its antigenicity assessed using sera from T. haneyi-experimentally infected horses. Confirmation of sera reactivity enabled design and optimization of an indirect ELISA. Specificity of the ELISA for T. haneyi was assessed using a cohort of sera from horses experimentally infected and confirmed PCR-positive for either T. equi or T. haneyi. Data from field samples further demonstrate that the ThEMA11 ELISA is capable of identifying T. haneyi antibodies in horses from multiple continents around the world.

Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that BRCA1 silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to codepletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1. Silencing of MAD2L1 phenocopied BRCA1 and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex vivo vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in BRCA1/MAD2L1-positive explants compared with 0% in BRCA1/MAD2L1-negative explants. In 48 patients, BRCA1 and/or MAD2L1 loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double-positive patients (5.9 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.

BackgroundExperimental studies have shown that vaccination can reduce viral replication to attenuate progression of influenza-associated lower respiratory tract illness (LRTI). However, clinical studies are conflicting, possibly due to use of non-specific outcomes reflecting a mix of large and small airway LRTI lacking specificity for acute lung or organ injury.MethodsWe developed a global ordinal scale to differentiate large and small airway LRTI in hospitalized adults with influenza using physiologic features and interventions (PFIs): vital signs, laboratory and radiographic findings, and clinical interventions. We reviewed the literature to identify common PFIs across 9 existing scales of pneumonia and sepsis severity. To characterize patients using this scale, we applied the scale to an antiviral clinical trial dataset where these PFIs were measured through routine clinical care in adults hospitalized with influenza-associated LRTI during the 2010–2013 seasons.ResultsWe evaluated 12 clinical parameters among 1020 adults; 210 (21%) had laboratory-confirmed influenza, with a median severity score of 4.5 (interquartile range, 2–8). Among influenza cases, median age was 63 years, 20% were hospitalized in the prior 90 days, 50% had chronic obstructive pulmonary disease, and 22% had congestive heart failure. Primary influencers of higher score included pulmonary infiltrates on imaging (48.1%), heart rate ≥110 beats/minute (41.4%), oxygen saturation 24 breaths/minute (21.0%). Key PFIs distinguishing patients with severity < or ≥8 (upper quartile) included infiltrates (27.1% vs 90.0%), temperature ≥ 39.1°C or 24 breaths/minute (7.9% vs 47.1%), heart rate ≥110 beats/minute (29.3% vs 65.7%), oxygen saturation 15,000 (5.0% vs 27.2%), and need for invasive or non-invasive mechanical ventilation (2.1% vs 15.7%).ConclusionWe developed a scale in adults hospitalized with influenza-associated LRTI demonstrating a broad distribution of physiologic severity which may be useful for future studies evaluating the disease attenuating effects of influenza vaccination or other therapeutics.

Background Medical Financial Assistance (MFA) provides health insurance and financial support for millions of low income and disabled Chinese people, yet there has been little systematic analysis focused on this vulnerable population. This study aims to advance our understanding of MFA recipients’ access to health care and whether their inpatient care use varies by remoteness. Methods Data were collected from the Surveillance System of Civil Affairs of Shaanxi province in 2016. To better proxy remoteness (geographic access), drive time from the respondent’s village to the nearest county-level or city-level hospital was obtained by a web crawler. Multilevel models were used to explore the impacts of remoteness on inpatient services utilization by MFA recipients. Furthermore, the potential moderating role of hospital grade (i.e. the grade of medical institution where recipient’s latest inpatient care services were taken in the previous year) on the relationship between geographic access and inpatient care use was explored. Results The analytical sample consisted of 9516 inpatient claims within 73 counties of Shaanxi province in 2016. We find that drive time to the nearest hospital and hospital grade are salient predictors of inpatient care use and there is a significant moderation effect of hospital grade. Compared to those with shortest drive time to the nearest hospital, longer drive time is associated with a longer inpatient stay but fewer admissions and lower annual total and out-of-pocket (OOP) inpatient costs. In addition, these associations are lower when recipients are admitted to a tertiary hospital, for annual total and OOP inpatient expenditures, but higher for length of the most recent inpatient stay no matter what medical treatments are taken in secondary or tertiary hospitals for the most remote recipients. Conclusion Our results suggest that remoteness has a significant and negative association with the frequency of inpatient care use. These findings advance our understanding of inpatient care use of the extremely poor and provide meaningful insights for further MFA program development as well as pro-poor health strategies.

Equine piroplasmosis (EP), caused by the hemoparasites Theileria equi, Theileria haneyi, and Babesia caballi, is an important tick-borne disease of equines that is prevalent in most parts of the world. Infection may affect animal welfare and has economic impacts related to limitations in horse transport between endemic and non-endemic regions, reduced performance of sport horses and treatment costs. Here, we analyzed the epidemiological, serological, and molecular diagnostic data published in the last 20 years, and all DNA sequences submitted to GenBank database, to describe the current global prevalence of these parasites. We demonstrate that EP is endemic in most parts of the world, and that it is spreading into more temperate climates. We emphasize the importance of using DNA sequencing and genotyping to monitor the spread of parasites, and point to the necessity of further studies to improve genotypic characterization of newly recognized parasite species and strains, and their linkage to virulence.

Background Glass slide preparations from a variety of specimens (blood, masses, effusions) are commonly made as part of the diagnostic work-up, however the effects of various drying methods in veterinary practice and diagnostic laboratory settings is not clear. Objective Compare the effects of four drying methods on results of microscopic examination of canine blood smears and direct smears of pleural or peritoneal effusion fluid. Methods Twelve canine blood samples (6 from healthy dogs, 6 from sick dogs) and 6 canine peritoneal or pleural effusion samples. Four smears were prepared from each of the 18 samples and dried using the following methods: air-dry, hair dryer with or without heat, and heat block at 58 °C. Observers, blinded to the drying method, independently reviewed the slides microscopically, using a scoring system to evaluate cell morphology and (for blood smears) echinocyte numbers; scoring results were analyzed statistically. Results For blood smears, several comparisons showed more adverse effects on morphology using the heat block method than for one or more other drying methods. For effusion fluid smears, RBCs dried with the heat block or air-dry methods had more poorly preserved morphology than RBCs dried by the hair dryer method without heat. Conclusions and clinical relevance The results (1) indicate that different drying methods had a significant effect, (2) support using a hair dryer without heat for both blood smears and effusion fluid smears, and (3) discourage using a 58 °C heat block.

Background New influenza vaccine formulations are designed to improve vaccine effectiveness and protect those most vulnerable to infection. High dose trivalent inactivated influenza vaccine (HD-IIV3), licensed for ages ≥65 years, produces greater antibody responses and efficacy in clinical trials, but post-licensure vaccine effectiveness (VE) compared to standard dose (SD-IIV3/4) vaccine remains an open question. Methods Using a test-negative, case control design and propensity analyses to adjust for confounding, US Influenza VE Network data from the 2015–2016 through 2018–2019 seasons were analyzed to determine relative VE (rVE) between HD-IIV3 and SD-IIV3/4 among outpatients ≥65 years old presenting with acute respiratory illness. Influenza vaccination status was derived from electronic medical records and immunization registries. Results Among 3861 enrollees, 2993 (78%) were vaccinated; 1573 (53%) received HD-IIV3 and 1420 (47%) received SD-IIV3/4. HD-IIV3 recipients differed from SD-IIV3/4 recipients by race, previous vaccination, number of outpatient visits in the previous year and timing of vaccination, and were balanced in the propensity model except the timing of vaccination. Compared with no vaccination, significant protection against any influenza A was observed from both HD-IIV3 (VE = 29%; 95%CI = 10%, 44%) and SD-IIV3/4 (VE = 24%; 95%CI = 5%, 39%); rVE = 18% (95%CI = 0%, 33%, SD as referent). When stratified by virus type, against A/H1N1, HD-IIV3 VE was 30% (95%CI = −7%, 54%), SD-IIV3/4 VE was 40% (95%CI = 10%, 61%), and rVE = −32%; (95%CI = −94%, 11%); Against A/H3N2, HD-IIV3 VE was 31% (95%CI = 9%, 47%), SD-IIV3/4 VE was 19% (95%CI = −5%, 37%), and rVE = 27%; (95% CI = 9%, 42%). Conclusions Among adults ≥65 years of age, recipients of standard and high dose influenza vaccines differed significantly in their characteristics. After adjusting for these differences, high dose vaccine offered more protection against A/H3N2 and borderline significant protection against all influenza A requiring outpatient care during the 2015–2018 influenza seasons.

BackgroundIdentification of risk factors for COVID-19-associated hospitalization is needed to guide prevention and clinical care.ObjectiveTo examine if age, sex, race/ethnicity, and underlying medical conditions is independently associated with COVID-19-associated hospitalizations.DesignCross-sectional.Setting70 counties within 12 states participating in the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET) and a population-based sample of non-hospitalized adults residing in the COVID-NET catchment area from the Behavioral Risk Factor Surveillance System.ParticipantsU.S. community-dwelling adults (≥18 years) with laboratory-confirmed COVID-19-associated hospitalizations, March 1- June 23, 2020.MeasurementsAdjusted rate ratios (aRR) of hospitalization by age, sex, race/ethnicity and underlying medical conditions (hypertension, coronary artery disease, history of stroke, diabetes, obesity [BMI ≥30 kg/m2], severe obesity [BMI≥40 kg/m2], chronic kidney disease, asthma, and chronic obstructive pulmonary disease).ResultsOur sample included 5,416 adults with COVID-19-associated hospitalizations. Adults with (versus without) severe obesity (aRR:4.4; 95%CI: 3.4, 5.7), chronic kidney disease (aRR:4.0; 95%CI: 3.0, 5.2), diabetes (aRR:3.2; 95%CI: 2.5, 4.1), obesity (aRR:2.9; 95%CI: 2.3, 3.5), hypertension (aRR:2.8; 95%CI: 2.3, 3.4), and asthma (aRR:1.4; 95%CI: 1.1, 1.7) had higher rates of hospitalization, after adjusting for age, sex, and race/ethnicity. In models adjusting for the presence of an individual underlying medical condition, higher hospitalization rates were observed for adults ≥65 years, 45-64 years (versus 18-44 years), males (versus females), and non-Hispanic black and other race/ethnicities (versus non-Hispanic whites).LimitationsInterim analysis limited to hospitalizations with underlying medical condition data.ConclusionOur findings elucidate groups with higher hospitalization risk that may benefit from targeted preventive and therapeutic interventions.

Background Improved understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spectrum of disease is essential for clinical and public health interventions. There are limited data on mild or asymptomatic infections, but recognition of these individuals is key as they contribute to viral transmission. We describe the symptom profiles from individuals with mild or asymptomatic SARS-CoV-2 infection. Methods From 22 March to 22 April 2020 in Wisconsin and Utah, we enrolled and prospectively observed 198 household contacts exposed to SARS-CoV-2. We collected and tested nasopharyngeal specimens by real-time reverse-transcription polymerase chain reaction (rRT-PCR) 2 or more times during a 14-day period. Contacts completed daily symptom diaries. We characterized symptom profiles on the date of first positive rRT-PCR test and described progression of symptoms over time. Results We identified 47 contacts, median age 24 (3–75) years, with detectable SARS-CoV-2 by rRT-PCR. The most commonly reported symptoms on the day of first positive rRT-PCR test were upper respiratory (n = 32 [68%]) and neurologic (n = 30 [64%]); fever was not commonly reported (n = 9 [19%]). Eight (17%) individuals were asymptomatic at the date of first positive rRT-PCR collection; 2 (4%) had preceding symptoms that resolved and 6 (13%) subsequently developed symptoms. Children less frequently reported lower respiratory symptoms (21%, 60%, and 69% for Conclusions Household contacts with laboratory-confirmed SARS-CoV-2 infection reported mild symptoms. When assessed at a single timepoint, several contacts appeared to have asymptomatic infection; however, over time all developed symptoms. These findings are important to inform infection control, contact tracing, and community mitigation strategies.

Background Preventing severe complications of influenza such as hospitalization is a public health priority; however, estimates of influenza vaccine effectiveness (VE) against influenza-associated acute lower respiratory tract infection (LRTI) hospitalizations are limited. We examined influenza VE against influenza-associated LRTIs in hospitalized adult patients. Methods We retrospectively analyzed data from a randomized trial of oseltamivir treatment in adults hospitalized with LRTI in Louisville, Kentucky, from 2010 to 2013. Patients were systematically tested for influenza at the time of enrollment. We estimated VE as 1 – the adjusted odds ratio (aOR) of antecedent vaccination in influenza-positives vs negatives × 100%. Vaccination status was obtained by patient self-report. Using logistic regression adjusting for age, sex, season, timing of illness, history of chronic lung disease, and activities of daily living, we estimated VE against hospitalized influenza-associated LRTIs and community-acquired pneumonia (CAP) with radiographic findings of infiltrate. Results Of 810 patients with LRTI (median age, 62 years), 184 (23%) were influenza-positive and 57% had radiographically confirmed CAP. Among influenza-positives and -negatives, respectively, 61% and 69% were vaccinated. Overall, 29% were hospitalized in the prior 90 days and >80% had comorbidities. Influenza-negatives were more likely to have a history of chronic obstructive pulmonary disease than influenza-positives (59% vs 48%; P = .01), but baseline medical conditions were otherwise similar. Overall, VE was 35% (95% CI, 4% to 56%) against influenza-associated LRTI and 51% (95% CI, 13% to 72%) against influenza-associated radiographically confirmed CAP. Conclusions Vaccination reduced the risk of hospitalization for influenza-associated LRTI and radiographically confirmed CAP. Clinicians should maintain high rates of influenza vaccination to prevent severe influenza-associated complications.

ImportanceReported cases of SARS-CoV-2 infection likely underestimate the prevalence of infection in affected communities. Large-scale seroprevalence studies provide better estimates of the proportion of the population previously infected.ObjectiveTo estimate prevalence of SARS-CoV-2 antibodies in convenience samples from several geographic sites in the United States.DesignSerologic testing of convenience samples using residual sera obtained for routine clinical testing by two commercial laboratory companies.SettingConnecticut (CT), south Florida (FL), Missouri (MO), New York City metro region (NYC), Utah (UT), and Washington State’s (WA) Puget Sound region.ParticipantsPersons of all ages with serum collected during intervals from March 23 through May 3, 2020.ExposureSARS-CoV-2 virus infection.Main outcomes and measuresWe estimated the presence of antibodies to SARS-CoV-2 spike protein using an ELISA assay. We standardized estimates to the site populations by age and sex. Estimates were adjusted for test performance characteristics (96.0% sensitivity and 99.3% specificity). We estimated the number of infections in each site by extrapolating seroprevalence to site populations. We compared estimated infections to number of reported COVID-19 cases as of last specimen collection date.ResultsWe tested sera from 11,933 persons. Adjusted estimates of the proportion of persons seroreactive to the SARS-CoV-2 spike protein ranged from 1.13% (95% confidence interval [CI] 0.70-1.94) in WA to 6.93% (95% CI 5.02-8.92) in NYC (collected March 23-April 1). For sites with later collection dates, estimates ranged from 1.85% (95% CI 1.00-3.23, collected April 6-10) for FL to 4.94% (95% CI 3.61-6.52) for CT (April 26-May 3). The estimated number of infections ranged from 6 to 24 times the number of reported cases in each site.Conclusions and relevanceOur seroprevalence estimates suggest that for five of six U.S. sites, from late March to early May 2020, >10 times more SARS-CoV-2 infections occurred than the number of reported cases. Seroprevalence and under-ascertainment varied by site and specimen collection period. Most specimens from each site had no evidence of antibody to SARS-CoV-2. Tracking population seroprevalence serially, in a variety of specific geographic sites, will inform models of transmission dynamics and guide future community-wide public health measures.Key findingsQuestionWhat proportion of persons in six U.S. sites had detectable antibodies to SARS-CoV-2, March 23-May 3, 2020?FindingsWe tested 11,933 residual clinical specimens. We estimate that from 1.1% of persons in the Puget Sound to 6.9% in New York City (collected March 23-April 1) had detectable antibodies. Estimates ranged from 1.9% in south Florida to 4.9% in Connecticut with specimens collected during intervals from April 6-May 3. Six to 24 times more infections were estimated per site with seroprevalence than with case report data.MeaningFor most sites, evidence suggests >10 times more SARS-CoV-2 infections occurred than reported cases. Most persons in each site likely had no detectable SARS-CoV-2 antibodies.

Background Improving appropriate antibiotic use is crucial for combating antibiotic resistance and unnecessary adverse drug reactions. Acute respiratory illness (ARI) commonly causes outpatient visits and accounts for ~41% of antibiotics used in the United States. We examined the influence of influenza vaccination on reducing antibiotic prescriptions among outpatients with ARI. Methods We enrolled outpatients aged ≥6 months with ARI from 50–60 US clinics during 5 winters (2013–2018) and tested for influenza with RT-PCR; results were unavailable for clinical decision making and clinical influenza testing was infrequent. We collected antibiotic prescriptions and diagnosis codes for ARI syndromes. We calculated vaccine effectiveness (VE) by comparing vaccination odds among influenza-positive cases with test-negative controls. We estimated ARI visits and antibiotic prescriptions averted by influenza vaccination using estimates of VE, coverage, and prevalence of antibiotic prescriptions and influenza. Results Among 37 487 ARI outpatients, 9659 (26%) were influenza positive. Overall, 36% of ARI and 26% of influenza-positive patients were prescribed antibiotics. The top 3 prevalent ARI syndromes included: viral upper respiratory tract infection (47%), pharyngitis (18%), and allergy or asthma (11%). Among patients testing positive for influenza, 77% did not receive an ICD-CM diagnostic code for influenza. Overall, VE against influenza-associated ARI was 35% (95% CI, 32–39%). Vaccination prevented 5.6% of all ARI syndromes, ranging from 2.8% (sinusitis) to 11% (clinical influenza). Influenza vaccination averted 1 in 25 (3.8%; 95% CI, 3.6–4.1%) antibiotic prescriptions among ARI outpatients during influenza seasons. Conclusions Vaccination and accurate influenza diagnosis may curb unnecessary antibiotic use and reduce the global threat of antibiotic resistance.

Intracellular pathogens have evolved intricate mechanisms to subvert host cell signaling pathways and ensure their own propagation. A lineage of the protozoan parasite genus Theileria infects bovine leukocytes and induces their uncontrolled proliferation causing a leukemia-like disease. Given the importance of E2F transcription factors in mammalian cell cycle regulation, we investigated the role of E2F signaling in Theileria-induced host cell proliferation. Using comparative genomics and surface plasmon resonance, we identified parasite-derived peptides that have the sequence-specific ability to increase E2F signaling by binding E2F negative regulator Retinoblastoma-1 (RB). Using these peptides as a tool to probe host E2F signaling, we show that the disruption of RB complexes ex vivo leads to activation of E2F-driven transcription and increased leukocyte proliferation in an infection-dependent manner. This result is consistent with existing models and, together, they support a critical role of E2F signaling for Theileria-induced host cell proliferation, and its potential direct manipulation by one or more parasite proteins.

Summary Background The Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) trial found that biannual mass distribution of azithromycin to children younger than 5 years in Niger reduced the primary outcome of all-cause mortality by 18%. We aimed to determine the causes of mortality among deceased children using verbal autopsy. Methods In this 2-year cluster-randomised controlled trial, 594 community clusters in Niger were randomly allocated (1:1 ratio) to receive biannual mass distributions of either oral azithromycin (approximately 20 mg per kg of bodyweight) or placebo targeted to children aged 1–59 months. Participants, study investigators, and field workers were masked to treatment allocation. Between Nov 23, 2014, and July 31, 2017, 3615 child deaths were recorded by use of biannual house-to-house censuses, and verbal autopsies were done between May 26, 2015, and May 17, 2018, to identify cause of death. Cause-specific mortality, as assessed by verbal autopsy, was a prespecified secondary outcome. This trial is completed and is registered with ClinicalTrials.gov , NCT02047981 . Findings Between Nov 23, 2014, and July 31, 2017, 303 communities (n=40 375 children at baseline) in Niger received mass azithromycin and 291 communities (n=35 747 children at baseline) received placebo. Treatment coverage was 90·3% (SD 10·6) in the azithromycin group and 90·4% (10·1) in the placebo group. No communities were lost to follow-up. In total, 1727 child deaths in the azithromycin group and 1888 child deaths in the placebo group were reported from the population censuses. Of these, the cause of death for 1566 (90·7%) children in the azithromycin group and 1735 (91·9%) children in the placebo group were ascertained by verbal autopsy interviews. In the azithromycin group, 437 (27·9%) deaths were due to malaria, 252 (16·1%) deaths were due to pneumonia, and 234 (14·9%) deaths were due to diarrhoea. In the placebo group, 493 (28·4%) deaths were due to malaria, 275 (15·9%) deaths were due to pneumonia, and 251 (14·5%) deaths were due to diarrhoea. Relative to communities that received placebo, child mortality in communities that received azithromycin was lower for malaria (incidence rate ratio 0·78, 95% CI 0·66–0·92; p=0·0029), dysentery (0·65, 0·44–0·94; p=0·025), meningitis (0·67, 0·46–0·97; p=0·036), and pneumonia (0·83, 0·68–1·00; p=0·051). The distribution of causes of death did not differ significantly between the two study groups (p=0·98). Interpretation Mass azithromycin distribution resulted in approximately a third fewer deaths in children aged 1–59 months due to meningitis and dysentery, and a fifth fewer deaths due to malaria and pneumonia. The lack of difference in the distribution of causes of death between the azithromycin and placebo groups could be attributable to the broad spectrum of azithromycin activity and the study setting, in which most childhood deaths were due to infections. Funding Bill & Melinda Gates Foundation.