During the COVID-19 pandemic, forecasting COVID-19 trends to support planning and response was a priority for scientists and decision makers alike. In the United States, COVID-19 forecasting was coordinated by a large group of universities, companies, and government entities led by the Centers for Disease Control and Prevention and the US COVID-19 Forecast Hub (https://covid19forecasthub.org). We evaluated approximately 9.7 million forecasts of weekly state-level COVID-19 cases for predictions 1-4 weeks into the future submitted by 24 teams from August 2020 to December 2021. We assessed coverage of central prediction intervals and weighted interval scores (WIS), adjusting for missing forecasts relative to a baseline forecast, and used a Gaussian generalized estimating equation (GEE) model to evaluate differences in skill across epidemic phases that were defined by the effective reproduction number. Overall, we found high variation in skill across individual models, with ensemble-based forecasts outperforming other approaches. Forecast skill relative to the baseline was generally higher for larger jurisdictions (e.g., states compared to counties). Over time, forecasts generally performed worst in periods of rapid changes in reported cases (either in increasing or decreasing epidemic phases) with 95% prediction interval coverage dropping below 50% during the growth phases of the winter 2020, Delta, and Omicron waves. Ideally, case forecasts could serve as a leading indicator of changes in transmission dynamics. However, while most COVID-19 case forecasts outperformed a naïve baseline model, even the most accurate case forecasts were unreliable in key phases. Further research could improve forecasts of leading indicators, like COVID-19 cases, by leveraging additional real-time data, addressing performance across phases, improving the characterization of forecast confidence, and ensuring that forecasts were coherent across spatial scales. In the meantime, it is critical for forecast users to appreciate current limitations and use a broad set of indicators to inform pandemic-related decision making.

As population immunity to SARS-CoV-2 evolves and new variants emerge, the role and accuracy of antigen tests remain active questions. To describe recent test performance, the detection of SARS-CoV-2 by antigen testing was compared with that by reverse transcription-polymerase chain reaction (RT-PCR) and viral culture testing during November 2022-May 2023. Participants who were enrolled in a household transmission study completed daily symptom diaries and collected two nasal swabs (tested for SARS-CoV-2 via RT-PCR, culture, and antigen tests) each day for 10 days after enrollment. Among participants with SARS-CoV-2 infection, the percentages of positive antigen, RT-PCR, and culture results were calculated each day from the onset of symptoms or, in asymptomatic persons, from the date of the first positive test result. Antigen test sensitivity was calculated using RT-PCR and viral culture as references. The peak percentage of positive antigen (59.0%) and RT-PCR (83.0%) results occurred 3 days after onset, and the peak percentage of positive culture results (52%) occurred 2 days after onset. The sensitivity of antigen tests was 47% (95% CI = 44%-50%) and 80% (95% CI = 76%-85%) using RT-PCR and culture, respectively, as references. Clinicians should be aware of the lower sensitivity of antigen testing compared with RT-PCR, which might lead to false-negative results. This finding has implications for timely initiation of SARS-CoV-2 antiviral treatment, when early diagnosis is essential; clinicians should consider RT-PCR for persons for whom antiviral treatment is recommended. Persons in the community who are at high risk for severe COVID-19 illness and eligible for antiviral treatment should seek testing from health care providers with the goal of obtaining a more sensitive diagnostic test than antigen tests (i.e., an RT-PCR test).

BACKGROUND: Lipid profiling is central for coronary artery disease (CAD) risk assessment. Nonadherence or unreported use of lipid-lowering drugs, particularly statins, can significantly complicate the association between lipid profile measures and CAD clinical outcomes. By combining medication history evaluation with statin analysis in plasma, we determined the effects of inaccurately reported statin use on lipid profile measures and their association with CAD risk. METHODS: We compared medication history of statin use with statin concentration measurements, by liquid chromatography-tandem mass spectrometry, in 690 participants undergoing coronary angiography (63 ± 11 years of age). Nominal logistic regression was employed to model CAD diagnosis with statin measurements, phenotypic, and lipid profile characteristics. RESULTS: Medication history of statin use was confirmed by statin assay for 81% of the patients. Surprisingly, statins were detected in 46% of patients without statin use records. Nonreported statin use was disproportionately higher among older participants. Stratifying samples by statin history resulted in underestimated LDL-lipid measures. Apolipoprotein B concentrations had a significant inverse CAD association, which became nonsignificant upon re-stratification using the statin assay data. CONCLUSIONS: Our study uncovered prominent discrepancies between medication records and actual statin use measured by mass spectrometry. We showed that inaccurate statin use assessments may lead to overestimation and underestimation of LDL levels in statin user and nonuser categories, exaggerating the reverse epidemiology association between LDL levels and CAD diagnosis. Combining medication history and quantitative statin assay data can significantly improve the design, analysis, and interpretation of clinical and epidemiological studies.

In 2015, the Institute of Medicine (now the National Academy of Medicine) released the report Vital Signs: Core Metrics for Health and Health Care Progress as a “basic, minimum slate of core metrics for use as sentinel indices of performance at various levels with respect to the key elements of health and health care progress” (IOM, 2015). Although indicators of pediatric health were included in that report as key elements of healthy behaviors, healthy communities, and preventive services, the core measures in the report emphasized indicators of adult health. This series of papers, “Vital Signs for Pediatric Health”, describes four metrics across the pediatric life course, each measuring how well the health care system is building the physical, cognitive, and socio-emotional health of the pediatric population, thereby laying the foundation for life-long health and well-being. The metrics—infant mortality, school readiness, chronic absenteeism, and high school graduation—were selected to focus on four different developmental stages of growth. A standardized set of core metrics to assess pediatric health could provide data to support health systems in identifying important areas for attention among their pediatric population and enable them to respond in a timely way. This rapid response is especially important in pediatric health systems as children undergo rapid development within a short time span. | | This paper discusses one of those four measures—infant mortality rate (IMR)—as a measure of the early period of life. IMR is used globally as a key indicator of child survival. As a measure, it is sensitive to improvements in care for both women and children, is associated with other well-being indicators in communities, and reflects health inequities in the community (ChildStats, 2021; Ely et al., 2017). | | This paper defines IMR and describes why it is a critical pediatric vital sign, then articulates the value of reducing disparities in IMR. Finally, the paper lays out the challenges to using IMR as an indicator for health system accountability.

The mechanisms of particle-induced pathogenesis in the lung remain poorly understood. Neutrophilic inflammation and oxidative stress in the lung are hallmarks of toxicity. Some investigators have postulated that oxidative stress from particle surface reactive oxygen species (psROS) on the dust produces the toxicopathology in the lungs of dust-exposed animals. This postulate was tested concurrently with the studies to elucidate the toxicity of lunar dust (LD), which is believed to contain psROS due to high-speed micrometeoroid bombardment that fractured and pulverized lunar surface regolith. Results from studies of rats intratracheally instilled (ITI) with three LDs (prepared from an Apollo-14 lunar regolith), which differed 14-fold in levels of psROS, and two toxicity reference dusts (TiO(2) and quartz) indicated that psROS had no significant contribution to the dusts' toxicity in the lung. Reported here are results of further investigations by the LD toxicity study team on the toxicological role of oxidants in alveolar neutrophils that were harvested from rats in the 5-dust ITI study and from rats that were exposed to airborne LD for 4 weeks. The oxidants per neutrophils and all neutrophils increased with dose, exposure time and dust's cytotoxicity. The results suggest that alveolar neutrophils play a critical role in particle-induced injury and toxicity in the lung of dust-exposed animals. Based on these results, we propose an adverse outcome pathway (AOP) for particle-associated lung disease that centers on the crucial role of alveolar neutrophil-derived oxidant species. A critical review of the toxicology literature on particle exposure and lung disease further supports a neutrophil-centric mechanism in the pathogenesis of lung disease and may explain previously reported animal species differences in responses to poorly soluble particles. Key findings from the toxicology literature indicate that (1) after exposures to the same dust at the same amount, rats have more alveolar neutrophils than hamsters; hamsters clear more particles from their lungs, consequently contributing to fewer neutrophils and less severe lung lesions; (2) rats exposed to nano-sized TiO(2) have more neutrophils and more severe lesions in their lungs than rats exposed to the same mass-concentration of micron-sized TiO(2); nano-sized dust has a greater number of particles and a larger total particle-cell contact surface area than the same mass of micron-sized dust, which triggers more alveolar epithelial cells (AECs) to synthesize and release more cytokines that recruit a greater number of neutrophils leading to more severe lesions. Thus, we postulate that, during chronic dust exposure, particle-inflicted AECs persistently release cytokines, which recruit neutrophils and activate them to produce oxidants resulting in a prolonged continuous source of endogenous oxidative stress that leads to lung toxicity. This neutrophil-driven lung pathogenesis explains why dust exposure induces more severe lesions in rats than hamsters; why, on a mass-dose basis, nano-sized dusts are more toxic than the micron-sized dusts; why lung lesions progress with time; and why dose-response curves of particle toxicity exhibit a hockey stick like shape with a threshold. The neutrophil centric AOP for particle-induced lung disease has implications for risk assessment of human exposures to dust particles and environmental particulate matter.

Most efforts to understand the biology of Vibrio cholerae have focused on a single group, the pandemic-generating lineage harbouring the strains responsible for all known cholera pandemics. Consequently, little is known about the diversity of this species in its native aquatic environment. To understand the differences in the V. cholerae populations inhabiting in regions with varying history of cholera cases and how that might influence the abundance of pandemic strains, a comparative analysis of population composition was performed. Little overlap was found in lineage compositions between those in Dhaka (cholera endemic) located in the Ganges delta, and of Falmouth (no known history of cholera), a small coastal town on the US East Coast. The most striking difference was the presence of a group of related lineages at high abundance in Dhaka which was completely absent from Falmouth. Phylogenomic analysis revealed that these lineages form a cluster at the base of the phylogeny of V. cholerae species, sufficiently differentiated genetically and phenotypically to form a novel species. Strains from this species have been anecdotally isolated from around the world and were isolated as early as 1916 from a British soldier in Egypt suffering from choleraic diarrhoea. In 1935 Gardner and Venkatraman unofficially referred to a member of this group as Vibrio paracholerae. In recognition of this earlier designation, we propose the name Vibrio paracholerae, sp. nov. for this bacterium. Genomic analysis suggests a link with human populations for this novel species and substantial interaction with its better-known sister species.Importance Cholera continues to remain a major public health threat around the globe. Understanding the ecology, evolution and environmental adaptation of the causative agent Vibrio cholerae and tracking the emergence of novel lineages with pathogenic potential are essential to combat the problem. In this study, we investigated the population dynamics of Vibrio cholerae in an inland locality which is known as endemic for cholera and compared with that of a cholera free coastal location. We found the consistent presence of the pandemic generating V. cholerae in cholera-endemic Dhaka and an exclusive presence of a lineage phylogenetically distinct from other V. cholerae. Our study suggests that this lineage represents a novel species having pathogenic potential and a human link to its environmental abundance. The possible association with human population, co-existence and interaction with toxigenic V. cholerae in the natural environment make this potential human pathogen an important subject for future studies.Competing Interest StatementThe authors have declared no competing interest.

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. In 2020, the COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized hundreds of thousands of specific predictions from more than 50 different academic, industry, and independent research groups. This manuscript systematically evaluates 23 models that regularly submitted forecasts of reported weekly incident COVID-19 mortality counts in the US at the state and national level. One of these models was a multi-model ensemble that combined all available forecasts each week. The performance of individual models showed high variability across time, geospatial units, and forecast horizons. Half of the models evaluated showed better accuracy than a naïve baseline model. In combining the forecasts from all teams, the ensemble showed the best overall probabilistic accuracy of any model. Forecast accuracy degraded as models made predictions farther into the future, with probabilistic accuracy at a 20-week horizon more than 5 times worse than when predicting at a 1-week horizon. This project underscores the role that collaboration and active coordination between governmental public health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.Competing Interest StatementAV, MC, and APP report grants from Metabiota Inc outside the submitted work.Funding StatementFor teams that reported receiving funding for their work, we report the sources and disclosures below. CMU-TimeSeries: CDC Center of Excellence, gifts from Google and Facebook. CU-select: NSF DMS-2027369 and a gift from the Morris-Singer Foundation. COVIDhub: This work has been supported by the US Centers for Disease Control and Prevention (1U01IP001122) and the National Institutes of General Medical Sciences (R35GM119582). The content is solely the responsibility of the authors and does not necessarily represent the official views of CDC, NIGMS or the National Institutes of Health. Johannes Bracher was supported by the Helmholtz Foundation via the SIMCARD Information& Data Science Pilot Project. Tilmann Gneiting gratefully acknowledges support by the Klaus Tschira Foundation. DDS-NBDS: NSF III-1812699. EPIFORECASTS-ENSEMBLE1: Wellcome Trust (210758/Z/18/Z) GT_CHHS-COVID19: William W. George Endowment, Virginia C. and Joseph C. Mello Endowments, NSF DGE-1650044, NSF MRI 1828187, research cyberinfrastructure resources and services provided by the Partnership for an Advanced Computing Environment (PACE) at Georgia Tech, and the following benefactors at Georgia Tech: Andrea Laliberte, Joseph C. Mello, Richard Rick E. & Charlene Zalesky, and Claudia & Paul Raines GT-DeepCOVID: CDC MInD-Healthcare U01CK000531-Supplement. NSF (Expeditions CCF-1918770, CAREER IIS-2028586, RAPID IIS-2027862, Medium IIS-1955883, NRT DGE-1545362), CDC MInD program, ORNL and funds/computing resources from Georgia Tech and GTRI. IHME: This work was supported by the Bill & Melinda Gates Foundation, as well as funding from the state of Washington and the National Science Foundation (award no. FAIN: 2031096). IowaStateLW-STEM: Iowa State University Plant Sciences Institute Scholars Program, NSF DMS-1916204, NSF CCF-1934884, Laurence H. Baker Center for Bioinformatics and Biological Statistics. JHU_IDD-CovidSP: State of California, US Dept of Health and Human Services, US Dept of Homeland Security, US Office of Foreign Disaster Assistance, Johns Hopkins Health System, Office of the Dean at Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University Modeling and Policy Hub, Centers fo Disease Control and Prevention (5U01CK000538-03), University of Utah Immunology, Inflammation, & Infectious Disease Initiative (26798 Seed Grant). LANL-GrowthRate: LANL LDRD 20200700ER. MOBS-GLEAM_COVID: COVID Supplement CDC-HHS-6U01IP001137-01. NotreDame-mobility and NotreDame-FRED: NSF RAPID DEB 2027718 UA-EpiCovDA: NSF RAPID Grant # 2028401. UCSB-ACTS: NSF RAPID IIS 2029626. UCSD-NEU: Google Faculty Award, DARPA W31P4Q-21-C-0014, COVID Supplement CDC-HHS-6U01IP001137-01. UMass-MechBayes: NIGMS R35GM119582, NSF 1749854. UMich-RidgeTfReg: The University of Michigan Physics Department and the University of Michigan Office of Research.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:UMass-Amherst IRBAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data and code referred to in the manuscript are publicly available. https://github.com/reichlab/covid19-forecast-hub/ https://github.com/reichlab/covidEnsembles https://zoltardata.com/project/44

Neutralizing antibody plays a key role in protective immunity against COVID-19. As increasingly distinct variants circulate, debate continues regarding the value of adding novel variants to SARS-CoV-2 vaccines. In this study, we have analyzed live virus neutralization titers against WA1, Delta, BA.1, BA.2, and BA.5 in 187 hospitalized patients infected with Delta or Omicron strains. This information will be useful in selection of the SARS-CoV-2 strains to include in an updated vaccine. Our results show that unvaccinated Delta infected patients made a highly biased neutralizing antibody response towards the infecting Delta strain with slightly lower responses against the WA1 strain, but with strikingly lower titers against BA.1, BA.2, and BA.5. Delta infected patients that had been previously vaccinated with the WA1 containing COVID vaccine made equivalent responses to WA1 and Delta strains, but still had very low neutralizing antibody responses to Omicron strains. In striking contrast, both unvaccinated and vaccinated Omicron patients exhibited a more balanced ratio of Omicron virus neutralization compared to neutralization of ancestral strains. Interestingly, Omicron patients infected with BA.1 or BA.2 had detectable neutralizing antibody titers to BA.5, but these titers were lower than neutralization titers to BA.1 and BA.2. Taken together, these results suggest that inclusion of the Omicron BA.5 strain in a SARS-CoV-2 vaccine would be beneficial in protection against the widely circulating BA.5 variant. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

Designing studies for lipid-metabolism-related biomarker discovery is challenging because of the high prevalence of various statin and fibrate usage for lipid-lowering therapies. When the statin and fibrate use is determined based on self-reports, patient adherence to the prescribed statin dose regimen remains unknown. A potentially more accurate way to verify a patient's medication adherence is by direct analytical measurements. Current analytical methods are prohibitive because of the limited panel of drugs per test and large sample volume requirement that is not available from archived samples. A 4-min-long method was developed for the detection of seven statins and three fibrates using 10 µL of plasma analyzed via reverse-phase liquid chromatography and tandem mass spectrometry. The method was applied to the analysis of 941 archived plasma samples collected from patients before cardiac catheterization. When statin use was self-reported, statins were detected in 78.6% of the samples. In the case of self-reported atorvastatin use, the agreement with detection was 90.2%. However, when no statin use was reported, 42.4% of the samples had detectable levels of statins, with a similar range of concentrations as the samples from the self-reported statin users. The method is highly applicable in population studies designed for biomarker discovery or diet and lifestyle intervention studies, where the accuracy of statin or fibrate use may strongly affect the statistical evaluation of the biomarker data.

Objectives: To understand college and university student knowledge, attitudes, and behaviors (KAB) regarding COVID-19 prevention strategies. Methods: Thirteen colleges and universities volunteered to conduct an anonymous electronic survey in April 2021 to assess students' KAB about mask use and vaccination to prevent COVID-19. Results: Three-quarters of students indicated they "Always" wore a mask correctly when in public indoor places. Of those not yet vaccinated, 55% expressed concern about unknown side effects. Over half of students were unsure or believe they do not need to continue wearing masks after vaccination and older students more likely to be vaccinated. There was a significant inverse correlation between intention of getting vaccinated and intention to attend a large indoor party without a mask. Conclusions: Colleges and universities are important to community efforts to slow the COVID-19 pandemic. The KAB findings can inform approaches to increase overall mask use and vaccination uptake among young students.

Adeno-associated virus (AAV) based gene therapies are emerging strategies in Duchenne muscular dystrophy (DMD) treatment. Exposure to wild-type AAV can lead to development of neutralizing antibodies (NAb) and block AAV transduction, thereby limiting the delivery of AAV vector-based gene therapy. Therefore, it is imperative to check for the presence of AAV NAbs in a patient who is a candidate for gene therapy. We prospectively enrolled 101 genetically confirmed males with DMD (median age 11 years, 48% ambulatory, 59% on steroids) and performed AAV neutralization assays against AAV2, AAV8, AAV9, and AAVrh74 serotypes. Serotype analysis showed AAV9 (36%) and AAVrh74 (32%) seroprevalence was lower compared to AAV2 (56%) and AAV8 (47%). Interestingly, age was not correlated with NAb titer for any of the capsids. NAb responses were observed at a higher frequency in African American participants and at a lower frequency for Caucasian participants for all four serotypes. Further analysis showed no significant differences in NAb titers depending, regardless of serotype, on whether participants were taking steroids. Finally, we observed higher AAV8, AAV9, and AAVrh74 seroprevalence and significantly higher AAV2 and AAV8 NAb titers in participants that were ambulatory compared to the non-ambulatory participants. Overall, these data identify AAV9 and AAVrh74 as the two serotypes with lower preexisting NAbs in this study's cohort of 101 males with DMD, possibly showing their utility for future gene therapy applications to treat this cohort men with DMD.

Less than 99.99% of recorded cases of poliomyelitis have occurred since the Global Polio Eradication Initiative (GPEI) was established in 1988. By the end of 2021, only Afghanistan and Pakistan will still have endemic wild poliovirus (WPV). While Malawi reported a case of wild poliovirus type 1 (WPV1) with paralysis onset in 2021, just over a year after the WHO African Region (AFR) was proclaimed WPV-free, 31 nations reported incidences of circulating vaccine-derived poliovirus (cVDPV) between 2020 and 2021. Monitoring for acute flaccid paralysis (AFP) in people under the age of 15 is the main way to identify poliovirus transmission, and confirmation comes from testing stool samples at WHO-accredited labs. In all WHO regions in 2020, the COVID-19 pandemic had an impact on polio vaccination and surveillance; from January to September 2020, fewer AFP cases were reported, and there was a longer delay between collecting stools and labs receiving them than there had been during the same period in 2019. A significant increase from 2020, when only 23 (53%) of the priority countries attained the national targets for the two key surveillance performance metrics, was shown in 2021. High-performance surveillance is necessary to track the spread of the poliovirus. Gaps in surveillance indicators might be found, improvements could be made, and the overall sensitivity and promptness of poliovirus detection might be enhanced in order to successfully eradicate polio. The collection of adequate stool specimens8 from AFP patients, with a target of 80% adequate stool specimens, and the nonpolio AFP (NPAFP) rate, which is a rate of 2 per 100,000 people aged 15 years and considered sufficiently sensitive for detecting circulating poliovirus, are two key performance indicators used to assess the quality of AFP surveillance. 43 priority nations experiencing or at high risk of poliovirus transmission were the subject of an analysis of surveillance indicators as of 25 March 2022.

Aberrations in lipid and lipoprotein metabolic pathways can lead to numerous diseases, including cardiovascular disease, diabetes, neurological disorders, and cancer. The integration of quantitative lipid and lipoprotein profiling of human plasma may provide a powerful approach to inform early disease diagnosis and prevention. In this study, we leveraged data-driven quantitative targeted lipidomics and proteomics to identify specific molecular changes associated with different metabolic risk categories, including hyperlipidemic, hypercholesterolemic, hypertriglyceridemic, hyperglycemic, and normolipidemic conditions. Based on the quantitative characterization of serum samples from 146 individuals, we have determined individual lipid species and proteins that were significantly up- or down-regulated relative to the normolipidemic group. Then, we established protein-lipid topological networks for each metabolic category and linked dysregulated proteins and lipids with defined metabolic pathways. To evaluate the differentiating power of integrated lipidomics and proteomics data, we have built an artificial neural network model that simultaneously and accurately categorized the samples from each metabolic risk category based on the determined lipidomics and proteomics profiles. Together, our findings provide new insights into molecular changes associated with metabolic risk conditions, suggest new condition-specific associations between apolipoproteins and lipids, and may inform new biomarker discovery in lipid metabolism-associated disorders.

Humoral and cellular immune responses contribute to overall protective immunity against SARS-CoV-2 with neutralizing antibody playing a key role in preventing viral infection. This is evident from the large number of Omicron infections in vaccinated and convalescent patients since antibodies induced after vaccination or infection by the ancestral WA1 strain do not neutralize Omicron variants efficiently (1, 2). This has led to the FDA recommendation for inclusion of the Omicron variant in bivalent COVID-19 vaccines. However, issues have been raised about the value of adding Omicron to the vaccine based on data showing only modest differences between antibody responses after booster immunization with Omicron versus WA1 (3, 4). Also, a recent study has shown that booster responses to Omicron infection are impacted by previous SARS-CoV-2 infections (5). Thus, having additional information on the types of neutralizing antibody responses induced after infection with different SARS-CoV-2 variants will be helpful in addressing this important issue. Here we report live virus neutralization titers against WA1, Delta, BA.1, BA.2 and BA.5 variants in serum samples collected from hospitalized patients infected with SARS-COV-2 Delta or Omicron strains. Blood samples were collected from 187 patients hospitalized with acute COVID-19 between July 2021 - March 2022 at 8 U.S. hospitals (Supplemental Methods). 26% of these patients were immunocompromised, the details of which are given in Supplemental Table 1. The majority (69%) of these patients were sequence confirmed for Delta or Omicron infection and the remaining were classified according to calendar period of circulation. Patients were either unvaccinated (n=80) or vaccinated with COVID-19 mRNA vaccine (n=100) or adenovirus vector vaccine (n=7) before infection. Unvaccinated Delta infected patients made a highly biased neutralizing antibody response towards the infecting Delta strain with lower titers against WA1 (6-fold) and strikingly lower titers against BA.1 (60-fold) and BA.2 (22-fold) (Figure 1A). In vaccinated Delta patients the neutralization titers were similar between Delta and WA1 but were again much lower against BA.1 (17-fold) and BA.2 (9-fold) (Figure 1B). Thus, both unvaccinated and vaccinated Delta infected patients made significantly lower neutralizing antibody responses to Omicron (as determined by Wilcoxon rank sums test). A strikingly different pattern was seen in Omicron infected patients irrespective of their vaccination history with a more favorable neutralizing antibody response to BA.1 and BA.2. While BA.1 and BA.2 neutralizing titers were modestly lower in vaccinated compared to unvaccinated Omicron patients, there was a clear trend for a broader and more balanced antibody response with similar neutralization titers to Delta, BA.1, and BA.2 (Figures 1C, 1D). Importantly, the ratio of BA.1 to WA1 neutralizing titers was significantly higher in Omicron patients compared to Delta patients in both unvaccinated (19-fold) and vaccinated (11-fold) patients (Figure 1E, 1F). This analysis of the ratio between neutralizing antibody to Omicron versus WA1 within a given individual nicely documents that Omicron infection favors Omicron specific antibody responses. These Omicron neutralizing antibodies could have emerged from either de novo naïve B cells or from cross-reactive memory B cells. Given the importance of the currently dominant BA.5 strain we then tested neutralization against BA.5. Note that our samples were collected prior to dominance of BA.5 and most of our patients were infected with BA.1 (Supplemental Table 1). In the subset of Omicron patient samples that we analyzed, there was detectable neutralization of BA.5 but it was lower than for BA.1. and BA.2 in both vaccinated and unvaccinated patients (Figure 1G, 1H, Supplemental Figure 1). This reduced neutralization activity against BA.5 in patients infected with BA.1 suggests that it is better to have BA.5 than BA.1 in the vaccine. In summary, our results show that Omicron infection of unvaccinated or vaccinated patients induces a more proportional and balanced neutralizing antibody response to Omicron variants supporting the recent decision to include Omicron in the bivalent SARS-CoV-2 vaccine. However, it remains to be seen how these findings from infection will translate to vaccination. Our results are from hospitalized patients with high levels of infected cells and antigen that would have efficiently induced a primary response to Omicron in addition to selectively recruiting Omicron reactive memory B cells. It is possible that a single immunization with the Omicron bivalent vaccine may not be sufficient and that two doses may be needed to give the desired antibody response (6). Future studies should address this issue, and it will also be interesting to see how the bivalent vaccine works in people who have already been infected with an Omicron strain.

During a COVID-19 outbreak in a prison in Zambia from December 14 to 19, 2021, a case-control study was done to measure vaccine effectiveness (VE) against infection and symptomatic infection, when the Omicron variant was the dominant circulating variant. Among 382 participants, 74.1% were fully vaccinated, and the median time since full vaccination was 54 days. There were no hospitalizations or deaths. COVID-19 VE against any SARS-CoV-2 infection was 64.8%, and VE against symptomatic SARS-CoV-2 infection was 72.9%. COVID-19 vaccination helped protect incarcerated persons against SARS-CoV-2 infection during an outbreak while Omicron was the dominant variant in Zambia. These findings provide important local evidence that might be used to increase COVID-19 vaccination in Zambia and other countries in Africa.

Throughout the rapid and intense changes that adolescents experience, their parents retain important influence over how they interact with the complex factors that shape their development. How parents care for their adolescent children has a deep and lasting impact on their well-being and development. Yet, parents often require support to meet their own and their adolescent children’s needs, which can be achieved through parenting support programmes. Parenting support programmes are delivered to parents of younger children across different contexts and populations, but the benefit of these programmes for parents of adolescents is not well-recognised or prioritised. Given the clear need for these interventions during adolescence and the substantial evidence for effectiveness in this age group, it is time to move the field forward. Increased resources to support parents of adolescents would maximise adolescents’ developmental potential and promote their well-being. We highlight four pressing areas for action: including parents of adolescents in parenting initiatives; involving parents in adolescent programming; strengthening efforts to address poverty and inequality, violence, and gender inequality; and engaging in strategic research to intensify the impact of programming. © 2022 Informa UK Limited, trading as Taylor & Francis Group.

Since the Global Polio Eradication Initiative (GPEI) was established in 1988, the number of reported poliomyelitis cases worldwide has declined by approximately 99.99%. By the end of 2021, wild poliovirus (WPV) remained endemic in only two countries (Pakistan and Afghanistan). However, a WPV type 1 (WPV1) case with paralysis onset in 2021, was reported by Malawi a year after the World Health Organization (WHO) African Region (AFR) was certified as WPV-free and circulating vaccine-derived poliovirus (cVDPV) cases were reported from 31 countries during 2020-2021 (1,2). cVDPVs are oral poliovirus vaccine-derived viruses that can emerge after prolonged circulation in populations with low immunity and cause paralysis. The primary means of detecting poliovirus transmission is through surveillance for acute flaccid paralysis (AFP) among persons aged <15 years, with confirmation through stool specimen testing by WHO-accredited laboratories, supplemented by systematic sampling of sewage and testing for the presence of poliovirus (environmental surveillance). The COVID-19 pandemic caused disruptions in polio vaccination and surveillance activities across WHO regions in 2020; during January-September 2020, the number of reported cases of AFP declined and the interval between stool collection and receipt by laboratories increased compared with the same period in 2019 (3). This report summarizes surveillance performance indicators for 2020 and 2021 in 43 priority countries* and updates previous reports (4). In 2021, a total of 32 (74%) priority countries(†) met two key surveillance performance indicator targets nationally, an improvement from 2020 when only 23 (53%) met both targets; however, substantial national and subnational gaps persist. High-performing poliovirus surveillance is critical to tracking poliovirus transmission. Frequent monitoring of surveillance indicators could help identify gaps, guide improvements, and enhance the overall sensitivity and timelines of poliovirus detection to successfully achieve polio eradication.

The COVID-19 pandemic has made it clear that epidemic models play an important role in how governments and the public respond to infectious disease crises. Early in the pandemic, models were used to estimate the true number of infections. Later, they estimated key parameters, generated short-term forecasts of outbreak trends, and quantified possible effects of interventions on the unfolding epidemic.1,2 In contrast to the coordinating role played by major national or international agencies in weather-related emergencies, pandemic modeling efforts were initially scattered across many research institutions. Differences in modeling approaches led to contrasting results, contributing to confusion in public perception of the pandemic. Efforts to coordinate modeling efforts in so-called hubs have provided governments, healthcare agencies, and the public with assessments and forecasts that reflect the consensus in the modeling community.36 This has been achieved by openly synthesizing uncertainties across different modeling approaches and facilitating comparisons between them.

We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.

SignificanceThis paper compares the probabilistic accuracy of short-term forecasts of reported deaths due to COVID-19 during the first year and a half of the pandemic in the United States. Results show high variation in accuracy between and within stand-alone models and more consistent accuracy from an ensemble model that combined forecasts from all eligible models. This demonstrates that an ensemble model provided a reliable and comparatively accurate means of forecasting deaths during the COVID-19 pandemic that exceeded the performance of all of the models that contributed to it. This work strengthens the evidence base for synthesizing multiple models to support public-health action.

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced following infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health (NIH) established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants potentially impacting transmission, virulence, and resistance to convalescent and vaccine-induced immunity. The SAVE program serves as a critical data-generating component of the United States Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines, and therapeutics and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity, and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models, and pivotal findings facilitated by this collaborative approach and identify future challenges. This program serves as a template for the response against rapidly evolving pandemic pathogens by monitoring viral evolution in the human population to identify variants that could erode the effectiveness of countermeasures.

Humans will set foot on the Moon again soon. The lunar dust (LD) is potentially reactive and could pose an inhalation hazard to lunar explorers. We elucidated LD toxicity and investigated the toxicological impact of particle surface reactivity (SR) using three LDs, quartz, and TiO(2). We first isolated the respirable-size-fraction of an Apollo-14 regolith and ground two coarser samples to produce fine LDs with increased SR. SR measurements of these five respirable-sized dusts, determined by their in-vitro ability to generate hydroxyl radicals (OH), showed that ground LDs>unground LDTiO(2) quartz. Rats were each intratracheally instilled with 0, 1, 2.5, or 7.5mg of a test dust. Toxicity biomarkers and histopathology were assessed up to 13weeks after the bolus instillation. All dusts caused dose-dependent-increases in pulmonary lesions and toxicity biomarkers. The three LDs, which possessed mineral compositions/properties similar to Arizona volcanic ash, were moderately toxic. Despite a 14-fold OH difference among these three LDs, their toxicities were indistinguishable. Quartz produced the lowest OH amount but showed the greatest toxicity. Our results showed no correlation between the toxicity of mineral dusts and their ability to generate free radicals. We also showed that the amounts of oxidants per neutrophil increased with doses, time and the cytotoxicity of the dusts in the lung, which supports our postulation that dust-elicited neutrophilia is the major persistent source of oxidative stress. These results and the discussion of the crucial roles of the short-lived, continuously replenished neutrophils in dust-induced pathogenesis are presented.

During November 19-21, 2021, an indoor convention (event) in New York City (NYC), was attended by approximately 53,000 persons from 52 U.S. jurisdictions and 30 foreign countries. In-person registration for the event began on November 18, 2021. The venue was equipped with high efficiency particulate air (HEPA) filtration, and attendees were required to wear a mask indoors and have documented receipt of at least 1 dose of a COVID-19 vaccine.* On December 2, 2021, the Minnesota Department of Health reported the first case of community-acquired COVID-19 in the United States caused by the SARS-CoV-2 B.1.1.529 (Omicron) variant in a person who had attended the event (1). CDC collaborated with state and local health departments to assess event-associated COVID-19 cases and potential exposures among U.S.-based attendees using data from COVID-19 surveillance systems and an anonymous online attendee survey. Among 34,541 attendees with available contact information, surveillance data identified test results for 4,560, including 119 (2.6%) persons from 16 jurisdictions with positive SARS-CoV-2 test results. Most (4,041 [95.2%]), survey respondents reported always wearing a mask while indoors at the event. Compared with test-negative respondents, test-positive respondents were more likely to report attending bars, karaoke, or nightclubs, and eating or drinking indoors near others for at least 15 minutes. Among 4,560 attendees who received testing, evidence of widespread transmission during the event was not identified. Genomic sequencing of 20 specimens identified the SARS-CoV-2 B.1.617.2 (Delta) variant (AY.25 and AY.103 sublineages) in 15 (75%) cases, and the Omicron variant (BA.1 sublineage) in five (25%) cases. These findings reinforce the importance of implementing multiple, simultaneous prevention measures, such as ensuring up-to-date vaccination, mask use, physical distancing, and improved ventilation in limiting SARS-CoV-2 transmission, during large, indoor events.(†).

In Colorado, excessive alcohol use* contributed to $5 billion in economic costs in 2010 (1) and >1,800 deaths annually during 2011-2015 (2). The most common pattern of excessive drinking is binge drinking (consumption of four or more drinks on an occasion for women or five or more drinks for men) (3), which is associated with increased likelihood of using other substances, including marijuana (4). Retail (i.e., nonmedical) marijuana sales began in Colorado on January 1, 2014. The Colorado Department of Public Health and Environment (CDPHE) and CDC used data from Colorado's 2015-2019 Behavioral Risk Factor Surveillance System (BRFSS) to examine current use of marijuana (including hashish) by drinking patterns among 45,991 persons aged ≥18 years who responded to questions about alcohol and marijuana use. The age-standardized, weighted prevalence of current marijuana use among persons who reported binge drinking (34.4%) was significantly higher than the prevalence among current non-binge drinkers (14.8%) and nondrinkers (9.9%). Evidence-based strategies recommended by the Community Preventive Services Task Force to reduce excessive alcohol use and tobacco use (e.g., increasing prices or reducing access) can reduce alcohol- and tobacco-related harms. Similar strategies might be effective in reducing marijuana use and its potential harms as well.

The evolution of herbicide-resistant weed species is a serious threat for weed control. Therefore, we need an improved understanding of how gene regulation confers herbicide resistance in order to slow the evolution of resistance. The present study analyzed differentially expressed genes after glyphosate treatment on a glyphosate-resistant Tennessee ecotype (TNR) of horseweed (Conyza canadensis), compared to a susceptible biotype (TNS). A read size of 100.2 M was sequenced on the Illumina platform and subjected to de novo assembly, resulting in 77,072 gene-level contigs, of which 32,493 were uniquely annotated by a BlastX alignment of protein sequence similarity. The most differentially expressed genes were enriched in the gene ontology (GO) term of the transmembrane transport protein. In addition, fifteen upregulated genes were identified in TNR after glyphosate treatment but were not detected in TNS. Ten of these upregulated genes were transmembrane transporter or kinase receptor proteins. Therefore, a combination of changes in gene expression among transmembrane receptor and kinase receptor proteins may be important for endowing non-target-site glyphosate-resistant C. canadensis.

Understanding COVID-19 vaccine acceptability among clients and staff of homeless shelters can inform public health efforts focused on communicating with and educating this population about COVID-19 vaccines and thus improve vaccine uptake. The objective of this study was to assess COVID-19 vaccine acceptability and uptake among people in homeless shelters in Detroit, Michigan. A cross-sectional study was conducted from February 9 to 23, 2021. Seventeen homeless shelters were surveyed: seven male-only, three male/female, and seven women and family shelters. All clients and staff aged ≥18 years and able to complete a verbal survey in English or with a translator were eligible to participate; of the 168 individuals approached, 26 declined, leaving a total sample of 106 clients and 36 staff participating in the study. The median client and staff ages were 44 and 54 years, respectively. Most participants (>80%) identified as non-Hispanic Black or African American. Sixty-one (57.5%) clients and 27 (75.5%) staff had already received or planned to receive a COVID-19 vaccination. Twelve (11.3%) clients and four (11.1%) staff were unsure, and 33 (31.1%) clients and five (13.9%) staff did not plan to get vaccinated. Reasons for hesitancy were concerns over side effects (29 clients [64.4%] and seven staff [77.8%]) and unknown long-term health impacts (26 clients [57.8%] and six staff [66.7%]). More than half of the clients had already received or planned to receive the vaccine. Continuing efforts such as vaccine education for hesitant clients and staff and having accessible vaccine events for this population may improve acceptability and uptake.

BACKGROUND: Although a human adenovirus (HAdV) vaccine is available for military use, officers-in-training are not routinely vaccinated. We describe an HAdV-associated respiratory outbreak among unvaccinated cadets at the U.S. Coast Guard Academy and its impact on cadet training. METHODS: We defined a case as a cadet with new onset cough or sore throat during August 1-October 4, 2019. We reviewed medical records and distributed a questionnaire to identify cases and to estimate impact on cadet training. We performed real-time PCR testing on patient and environmental samples and whole genome sequencing on a subset of positive patient samples. RESULTS: Among the 1,072 cadets, 378 (35%) cases were identified by medical records (n=230) or additionally by the questionnaire (n=148). Of the 230 cases identified from medical records, 138 (60%) were male and 226 (98%) had no underlying conditions. From questionnaire responses, 113/228 (50%) cases reported duty restrictions. Of cases with respiratory specimens, 36/50 (72%) were HAdV positive; all 14 sequenced specimens were HAdV-4a1. Sixteen (89%) of 18 environmental specimens from the cadet dormitory were HAdV-positive. CONCLUSIONS: The HAdV-4-associated outbreak infected a substantial number of cadets and significantly impacted cadet training. Routine vaccination could prevent HAdV respiratory outbreaks in this population.

Most efforts to understand the biology of Vibrio cholerae have focused on a single group, the pandemic-generating lineage harbouring the strains responsible for all known cholera pandemics. Consequently, little is known about the diversity of this species in its native aquatic environment. To understand the differences in the V. cholerae populations inhabiting regions with a history of cholera cases and those lacking such a history, a comparative analysis of population composition was performed. Little overlap was found in lineage compositions between those in Dhaka (cholera endemic) located in the Ganges delta, and of Falmouth (no known history of cholera), a small coastal town on the United States east coast. The most striking difference was the presence of a group of related lineages at high abundance in Dhaka which was completely absent from Falmouth. Phylogenomic analysis revealed that these lineages form a cluster at the base of the phylogeny for the V. cholerae species, sufficiently differentiated genetically and phenotypically to form a novel species. A retrospective search revealed that strains from this species have been anecdotally found from around the world and were isolated as early as 1916 from a British soldier in Egypt suffering from choleraic diarrhoea. In 1935 Gardner and Venkatraman unofficially referred to a member of this group as Vibrio paracholerae. In recognition of this earlier designation, we propose the name Vibrio paracholerae sp. nov. for this bacterium. Genomic analysis suggests a link with human populations for this novel species and substantial interaction with its better-known sister species. Importance Cholera continues to remain a major public health threat around the globe. Understanding the ecology, evolution, and environmental adaptation of the causative agent Vibrio cholerae and tracking the emergence of novel lineages with pathogenic potential are essential to combat the problem. In this study, we investigated the population dynamics of Vibrio cholerae in an inland locality which is known as endemic for cholera and compared with that of a cholera free coastal location. We found the consistent presence of the pandemic generating V. cholerae in cholera-endemic Dhaka and an exclusive presence of a lineage phylogenetically distinct from other V. cholerae. Our study suggests that this lineage represents a novel species having pathogenic potential and a human link to its environmental abundance. The possible association with human population, co-existence and interaction with toxigenic V. cholerae in the natural environment make this potential human pathogen an important subject for future studies.

In 2020, a total of 92 tuberculosis (TB) cases were reported in Seattle and King County, Washington, 5% fewer than the median of 97 (range = 94 –132) reported during the same period 2015–2019 and 30% fewer than 132 cases reported in 2019. Interviews and chart reviews were completed as part of a public health investigation. This activity was reviewed by Centers for Disease Control and Prevention (CDC) and was conducted consistent with applicable federal law and CDC policy. Results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests performed prior to TB diagnosis were available to TB public health officials for 40 (43%) patients with TB: 3 had a positive result; 37 had negative results, with 12 having been tested twice or more. We were not able to verify SARS-CoV-2 testing status or results prior to TB diagnosis for 52 TB cases. We attempted to reach out to all pulmonary TB cases diagnosed in March 2020 or later and were able to interview 29 patients by telephone or in person about how pandemic coronavirus disease 2019 (COVID-19) affected their medical care. Four of them stated that their TB diagnosis had been delayed because of pandemic-related problems. Of these, 3 waited to seek care because of fear of contracting COVID-19, and one, patient 1, was told that she probably had COVID-19 by at least 2 healthcare providers. The stories of the following 3 patients who had prolonged respiratory illnesses with fever illustrate the delays in TB diagnosis during the COVID-19 pandemic.

When the Global Polio Eradication Initiative (GPEI) was established in 1988, an estimated 350,000 poliomyelitis cases were reported worldwide. In 2020, 140 wild poliovirus (WPV) cases were confirmed, representing a 99.99% reduction since 1988. WPV type 1 transmission remains endemic in only two countries (Pakistan and Afghanistan), but outbreaks of circulating vaccine-derived poliovirus (cVDPV) occurred in 33 countries during 2019-2020 (1,2). Poliovirus transmission is detected primarily through syndromic surveillance for acute flaccid paralysis (AFP) among children aged <15 years, with confirmation by laboratory testing of stool specimens. Environmental surveillance supplements AFP surveillance and plays an increasingly important role in detecting poliovirus transmission. Within 2 weeks of COVID-19 being declared a global pandemic (3), GPEI recommended continuing surveillance activities with caution and paused all polio supplementary immunization activities (4). This report summarizes surveillance performance indicators for 2019 and 2020 in 42 priority countries at high risk for poliovirus transmission and updates previous reports (5). In 2020, 48% of priority countries* in the African Region, 90% in the Eastern Mediterranean Region, and 40% in other regions met AFP surveillance performance indicators nationally. The number of priority countries rose from 40 in 2019 to 42 in 2020.(†) Analysis of 2019-2020 AFP surveillance data from 42 countries at high risk for poliovirus transmission indicates that national and subnational nonpolio AFP rates and stool specimen adequacy declined in many priority countries, particularly in the African Region, suggesting a decline in surveillance sensitivity and quality. The findings in this report can be used to guide improvements to restore a sensitive surveillance system that can track poliovirus transmission and provide evidence of interruption of transmission.