BACKGROUND& AIMS: The protection provided by rotavirus (RV) vaccines is highly heterogeneous amongst individuals. We hypothesized that microbiota composition might influence RV vaccine efficacy. METHODS: First, we examined the potential of segmented filamentous bacteria (SFB) colonization to influence RV vaccine efficacy in mice. Next, we probed the Influence of human microbiomes on RV vaccination via administering mice fecal microbial transplants (FMT) from children with robust or minimal RV vaccine responsiveness. Post-FMT, mice were subjected to RV vaccination followed by RV challenge. RESULTS: SFB colonization induced a phenotype that was reminiscent of RV vaccine failure, i.e. failure to generate RV antigens and, consequently, anti-RV antibodies following RV vaccination resulting in proneness to RV challenge after SFB levels diminished. FMT from children to mice recapitulated donor vaccination phenotype. Specifically, mice receiving FMT from high-responsive vaccinees copiously shed RV antigens and robustly generated anti-RV antibodies following RV vaccination. Concomitantly, such mice were impervious to RV challenge. In contrast, mice receiving FMT from children who had not responded to RV vaccination exhibited only modest responses to RV vaccination and, concomitantly, remained prone to RV challenge. Microbiome analysis ruled out a role for SFB but suggested involvement of Clostridium perfringens. Oral administration of cultured C. perfringens to gnotobiotic mice partially recapitulated the RV vaccine non-responder phenotype. Analysis of published microbiome data found C. perfringens abundance in children modestly associated with RV vaccine failure. CONCLUSION: Microbiota composition influences RV vaccine efficacy with C. perfringens being one, perhaps of many, potential contributing taxa.

BACKGROUND: Opioid use disorder (OUD) affects millions of individuals each year in the United States. Patient retention in medications for opioid use disorder (MOUD) treatment is suboptimal. This study examines and quantifies the associations between each additional month of buprenorphine or methadone use and nonprescribed opioid use. METHODS: Data were obtained from an 18-month longitudinal, observational cohort study of patients (age ≥ 18 years) treated for OUD. Patients completed a baseline self-reported questionnaire between March 2018 and December 2019 and were asked to complete follow-up questionnaires at approximately 3-, 6-, 12-, and 18-months post-baseline until May 2021. Patients treated with buprenorphine or methadone, without taking other MOUD at least 12 months prior to baseline, were included. Outcomes included past 30-day use of prescription opioids nonmedically, heroin, or illegally made fentanyl. A multivariable, multilevel regression model with a binomial distribution and a logit link was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: This study included 353 patients taking buprenorphine (mean [standard deviation, SD] age 39 [11] years; 226 [64%] female), and 785 patients taking methadone (mean [SD] age 42 [12] years; 392 [50%] female). Each additional month of MOUD treatment was associated with a 25% decrease in the odds of past 30-day nonprescribed opioid use for patients taking buprenorphine (aOR [95% CI] = 0.75 [0.68-0.83]), and a 17% decrease for patients taking methadone (aOR = 0.83 [0.79-0.87]). The COVID-19 pandemic (aOR = 9.29 [2.96-29.17]; aOR = 3.19 [1.74-5.86]) and MOUD adverse reaction experiences (aOR = 3.07 [1.11-8.48]; aOR = 2.51 [1.01-6.22]) were significantly associated with higher odds of nonprescribed opioid use among buprenorphine and methadone groups. CONCLUSION: Among patients treated with buprenorphine or methadone, with each additional treatment month since baseline, those who continued with treatment appeared to be more likely to report 17% to 25% decreased odds of past 30-day nonprescribed opioid use. Our findings can be used by clinicians in the shared decision-making process with patients, emphasizing the value of sustained retention in MOUD.

BACKGROUND: Although substance use rates among adolescents have decreased, drug overdose deaths among adolescents have increased since 2020, driven largely by illegally made fentanyl (IMF). This study explores substance use patterns and characteristics of adolescents who were assessed for substance use disorder (SUD) treatment to inform prevention and response strategies. METHODS: A convenience sample of adolescents aged 10-18 years assessed for SUD treatment from September 2017 to December 2021 was analyzed using the Comprehensive Health Assessment for Teens. The percentage of lifetime and past 30-day substance use was examined. Adolescent characteristics (e.g., demographics, history of overdoses or hospital visits due to drug/alcohol use) were analyzed by lifetime substances used. RESULTS: Among 5,377 assessments, most were male (58.7%), aged 16-18 years (50.5%), non-Hispanic White (43.1%), enrolled in school (87.3%), and living with their parent(s) (72.4%). The most commonly reported lifetime substances used were marijuana (68.0%), alcohol (54.2%), and prescription opioid misuse (13.6%). The most common past 30-day substance use combination was alcohol and marijuana (35.6%). The percentage of assessments indicating past-year overdoses or hospital visits due to drug/alcohol use was greatest among those who reported lifetime use of IMF (24.0%), followed by heroin (21.4%) and cocaine (15.3%). Overall, 2.3% reported lifetime IMF use and 0.6% thought IMF was causing them the most problems. CONCLUSIONS: Findings inform opportunities to address substance use and increased IMF-involved overdose among adolescents. Continued overdose prevention and response strategies such as evidence-based education campaigns, naloxone distribution and harm reduction efforts, and evidence-based SUD treatment expansion are needed.

Xylazine has been increasingly detected in illegally manufactured fentanyl (IMF) products and overdose deaths in the United States; most xylazine-involved overdose deaths involve IMF. A convenience sample of U.S. adults aged ≥18 years was identified from those evaluated for substance use treatment during July 2022-September 2023. Data were collected using the Addiction Severity Index-Multimedia Version clinical assessment tool. Among 43,947 adults, 6,415 (14.6%) reported IMF or heroin as their primary lifetime substance-use problem; 5,344 (12.2%) reported recent (i.e., past-30-day) IMF or heroin use. Among adults reporting IMF or heroin as their primary lifetime substance-use problem, 817 (12.7%) reported ever using xylazine. Among adults reporting recent IMF or heroin use, 443 (8.3%) reported recent xylazine use. Among adults reporting IMF or heroin use recently or as their primary lifetime substance-use problem, those reporting xylazine use reported a median of two past nonfatal overdoses from any drug compared with a median of one overdose among those who did not report xylazine use; as well, higher percentages of persons who reported xylazine use reported other recent substance use and polysubstance use. Provision of nonjudgmental care and services, including naloxone, wound care, and linkage to and retention of persons in effective substance use treatment, might reduce harms including overdose among persons reporting xylazine use.

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.

IMPORTANCE: Given the high number of opioid overdose deaths in the US and the complex epidemiology of opioid use disorder (OUD), systems models can serve as a tool to identify opportunities for public health interventions. OBJECTIVE: To estimate the projected 3-year association between public health interventions and opioid overdose-related outcomes among persons with OUD. DESIGN, SETTING, AND PARTICIPANTS: This decision analytical model used a simulation model of the estimated US population aged 12 years and older with OUD that was developed and analyzed between January 2019 and December 2023. The model was parameterized and calibrated using 2019 to 2020 data and used to estimate the relative change in outcomes associated with simulated public health interventions implemented between 2021 and 2023. MAIN OUTCOMES AND MEASURES: Projected OUD and medications for OUD (MOUD) prevalence in 2023 and number of nonfatal and fatal opioid-involved overdoses among persons with OUD between 2021 and 2023. RESULTS: In a baseline scenario assuming parameters calibrated using 2019 to 2020 data remained constant, the model projected more than 16 million persons with OUD not receiving MOUD treatment and nearly 1.7 million persons receiving MOUD treatment in 2023. Additionally, the model projected over 5 million nonfatal and over 145 000 fatal opioid-involved overdoses among persons with OUD between 2021 and 2023. When simulating combinations of interventions that involved reducing overdose rates by 50%, the model projected decreases of up to 35.2% in nonfatal and 36.6% in fatal opioid-involved overdoses among persons with OUD. Interventions specific to persons with OUD not currently receiving MOUD treatment demonstrated the greatest reduction in numbers of nonfatal and fatal overdoses. Combinations of interventions that increased MOUD initiation and decreased OUD recurrence were projected to reduce OUD prevalence by up to 23.4%, increase MOUD prevalence by up to 137.1%, and reduce nonfatal and fatal opioid-involved overdoses among persons with OUD by 6.7% and 3.5%, respectively. CONCLUSIONS AND RELEVANCE: In this decision analytical model study of persons with OUD, findings suggested that expansion of evidence-based interventions that directly reduce the risk of overdose fatality among persons with OUD, such as through harm reduction efforts, could engender the highest reductions in fatal overdoses in the short-term. Interventions aimed at increasing MOUD initiation and retention of persons in treatment projected considerable improvement in MOUD and OUD prevalence but could require a longer time horizon for substantial reductions in opioid-involved overdoses.

BACKGROUND: The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries. METHODS: Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5. RESULTS: Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5. CONCLUSION: This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified.

BACKGROUND: Medications for Opioid Use Disorder (MOUD) are an effective method to treat persons with opioid use disorder (OUD). Longer treatment times are associated with better health outcomes, yet treatment retention rates remain low. This study aimed to assess patient characteristics and experiences associated with retention in treatment. METHODS: Data were from an observational cohort study of OUD treatments. Among persons receiving buprenorphine or methadone, log-binomial regression models assessed the relationship between patient characteristics and experiences and three retention outcomes: retention in any OUD treatment, retention in the index treatment (OUD treatment being administered at the time when patients were screened for study eligibility), and 6-month retention in the index treatment. RESULTS: Individuals being treated with methadone at the start of the study compared to those treated with buprenorphine were more likely to remain in their same index treatment at the 18-month follow-up (aPR = 1.35; 95 % CI = 1.11-1.65), and to have remained on their index treatment for 6-months or longer (aPR = 1.22; 95 % CI = 1.14-1.32), but were not significantly more likely to remain in any OUD treatment overall. Individuals residing five miles or less from treatment were more likely to have been retained in any OUD treatment (aPR = 1.06; 95 % CI = 1.00-1.12), to remain in their index treatment at the 18-month follow-up (aPR = 1.21; 95 % CI = 1.08-1.36), and to have remained in their index treatment for 6 months or more (aPR = 1.08; 95 % CI = 1.02-1.13). Individuals without health insurance were less likely to be retained in any OUD treatment (aPR = 0.86; 95 % CI = 0.78-0.95). CONCLUSION: The prevalence of retention in any OUD treatment was higher for individuals residing five miles or less from treatment. These findings expand on previous studies that have shown distance to and location of treatment sites can impact treatment access and retention. Lack of health insurance was also associated with lower retention in any OUD treatment in this study. Given the high burden associated with overdose deaths, it is important to understand and address barriers to retention in treatment.

Substance use often begins during adolescence, placing youths at risk for fatal overdose and substance use disorders (SUD) in adulthood. Understanding the motivations reported by adolescents for using alcohol, marijuana, and other drugs and the persons with whom they use these substances could guide strategies to prevent or reduce substance use and its related consequences among adolescents. A cross-sectional study was conducted among adolescents being assessed for SUD treatment in the United States during 2014-2022, to examine self-reported motivations for using substances and the persons with whom substances were used. The most commonly reported motivation for substance use was "to feel mellow, calm, or relaxed" (73%), with other stress-related motivations among the top reasons, including "to stop worrying about a problem or to forget bad memories" (44%) and "to help with depression or anxiety" (40%); one half (50%) reported using substances "to have fun or experiment." The majority of adolescents reported using substances with friends (81%) or using alone (50%). These findings suggest that interventions related to reducing stress and addressing mental health concerns might reduce these leading motivations for substance use among adolescents. Education for adolescents about harm reduction strategies, including the danger of using drugs while alone and how to recognize and respond to an overdose, can reduce the risk for fatal overdose.

Rotavirus group A (RVA) is the most common cause of severe childhood diarrhea worldwide. The introduction of rotavirus vaccination programs has contributed to a reduction in hospitalizations and mortality caused by RVA. From 2016 to 21, we conducted surveillance to monitor RVA prevalence and genotype distribution in Nam Dinh and Thua Thien Hue (TT Hue) provinces where a pilot Rotavin-M1 vaccine (Vietnam) implementation took place from 2017 to 20. Out of 6626 stool samples, RVA was detected in 2164 (32.6%) by ELISA. RT-PCR using type-specific primers were used to determine the G and P genotypes of RVA-positive specimens. Whole genome sequences of a subset of 52 specimens randomly selected from 2016 to 21 were mapped using next-generation sequencing. From 2016 to 21, the G9, G3 and G8 strains dominated, with detected frequencies of 39%, 23%, and 19%, respectively; of which, the most common genotypes identified were G9P[8], G3P[8] and G8P[8]. G1 strains re-emerged in Nam Dinh and TT Hue (29.5% and 11.9%, respectively) from 2020 to 2021. G3 prevalence decreased from 74% to 20% in TT Hue and from 21% to 13% in Nam Dinh province between 2017 and 2021. The G3 strains consisted of 52% human typical G3 (hG3) and 47% equine-like G3 (eG3). Full genome analysis showed substantial diversity among the circulating G3 strains with different backgrounds relating to equine and feline viruses. G9 prevalence decreased sharply from 2016 to 2021 in both provinces. G8 strains peaked during 2019-2020 in Nam Dinh and TT Hue provinces (68% and 46%, respectively). Most G8 and G9 strains had no genetic differences over the surveillance period with very high nucleotide similarities of 99.2-99.9% and 99.1-99.7%, respectively. The G1 strains were not derived from the RVA vaccine. Changes in the genotype distribution and substantial diversity among circulating strains were detected throughout the surveillance period and differed between the two provinces. Determining vaccine effectiveness against circulating strains over time will be important to ensure that observed changes are due to natural secular variation and not from vaccine pressure.

Folate is a source of one-carbons necessary for DNA methylation, a critical epigenetic modification necessary for genomic structure and function. The use of supplemental folic acid is widespread however; the potential influence on DNA methylation is unclear. We measured global DNA methylation using DNA extracted from samples from a population-based, double-blind randomized trial of folic acid supplementation (100, 400, 4000 µg per day) taken for 6 months; including a 3 month post-supplementation sample. We observed no changes in global DNA methylation in response to up to 4,000 µg/day for 6 months supplementation in DNA extracted from uncoagulated blood (approximates circulating blood). However, when DNA methylation was determined in coagulated samples from the same individuals at the same time, significant time, dose, and MTHFR genotype-dependent changes were observed. The baseline level of DNA methylation was the same for uncoagulated and coagulated samples; marked differences between sample types were observed only after intervention. In DNA from coagulated blood, DNA methylation decreased (-14%; P<0.001) after 1 month of supplementation and 3 months after supplement withdrawal, methylation decreased an additional 23% (P<0.001) with significant variation among individuals (max+17%; min-94%). Decreases in methylation of ≥25% (vs. <25%) after discontinuation of supplementation were strongly associated with genotype: MTHFR CC vs. TT (adjusted odds ratio [aOR] 12.9, 95%CI 6.4, 26.0). The unexpected difference in DNA methylation between DNA extracted from coagulated and uncoagulated samples in response to folic acid supplementation is an important finding for evaluating use of folic acid and investigating the potential effects of folic acid supplementation on coagulation.

This study examines mean yearly out-of-pocket cost for naloxone dispensed from retail pharmacies by payer between 2018 and 2022 and by prescription characteristics and payer in 2022. | eng

OBJECTIVE: Opioid use disorder (OUD) affects approximately 5.6 million people in the United States annually, yet rates of the use of effective medication for OUD (MOUD) treatment are low. We conducted an observational cohort study from August 2017 through May 2021, the MOUD Study, to better understand treatment engagement and factors that may influence treatment experiences and outcomes. In this article, we describe the study design, data collected, and treatment outcomes. METHODS: We recruited adult patients receiving OUD treatment at US outpatient facilities for the MOUD Study. We collected patient-level data at 5 time points (baseline to 18 months) via self-administered questionnaires and health record data. We collected facility-level data via questionnaires administered to facility directors at 2 time points. Across 16 states, 62 OUD treatment facilities participated, and 1974 patients enrolled in the study. We summarized descriptive data on the characteristics of patients and OUD treatment facilities and selected treatment outcomes. RESULTS: Approximately half of the 62 facilities were private, nonprofit organizations; 62% focused primarily on substance use treatment; and 20% also offered mental health services. Most participants were receiving methadone (61%) or buprenorphine (32%) and were predominately non-Hispanic White (68%), aged 25-44 years (62%), and female (54%). Compared with patient-reported estimates at baseline, 18-month estimates suggested that rates of abstinence increased (55% to 77%), and rates of opioid-related overdoses (7% to 2%), emergency department visits (9% to 4%), and arrests (15% to 7%) decreased. CONCLUSIONS: Our results demonstrated the benefits of treatment retention not only on abstinence from opioid use but also on other quality-of-life metrics, with data collected during an extended period. The MOUD Study produced rich, multilevel data that can lay the foundation for an evidence base to inform OUD treatment and support improvement of care and patient outcomes.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

BACKGROUND: Syringe services programs (SSPs) are community-based prevention programs that provide a range of harm reduction services to persons who inject drugs. Despite their benefits, SSP laws vary across the United States. Little is known regarding how legislation surrounding SSPs may have influenced HIV transmission over the COVID-19 pandemic, a period in which drug use increased. This study examined associations between state SSP laws and HIV transmission among the Medicaid population before and after the COVID-19 pandemic. METHODS: State-by-month counts of new HIV diagnoses among the Medicaid population were produced using administrative claims data from the Transformed Medicaid Statistical Information System from 2019 to 2020. Data on SSP laws were collected from the Prescription Drug Abuse Policy System. Associations between state SSP laws and HIV transmission before and after the start of the COVID-19 pandemic were evaluated using an event study design, controlling for the implementation of COVID-19 nonpharmaceutical interventions and state and time fixed effects. RESULTS: State laws allowing the operation of SSPs were associated with 0.54 (P = 0.044) to 1.18 (P = 0.001) fewer new monthly HIV diagnoses per 100,000 Medicaid enrollees relative to states without such laws in place during the 9 months after the start of the COVID-19 pandemic. The largest effects manifested for population subgroups disproportionately affected by HIV, such as male and non-Hispanic Black Medicaid enrollees. CONCLUSION: Less restrictive laws on SSPs may have helped mitigate HIV transmission among the Medicaid population throughout the COVID-19 pandemic. Policymakers can consider implementing less restrictive SSP laws to mitigate HIV transmission resulting from future increases in injection drug use. DISCLAIMER: The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

BACKGROUND: Nonmedical use (NMU) of prescription psychotherapeutic drugs (PPD) may increase risk for significant morbidity and mortality in the overdose crisis. OBJECTIVE: This study examines sources of PPD using real-world data from adolescents and adults reporting past 30-day NMU of PPDs. METHODS: A convenience sample of individuals aged ≥10 years assessed for substance use disorders (SUD) treatment was analyzed using the 2014-2022 National Addictions Vigilance Intervention and Prevention Program datasets. PPD include prescription opioids, prescription tranquilizers/sedatives, and prescription stimulants. RESULTS: Overall, among assessments of adolescents aged 10-18 years (N = 1991) and young adults aged 19-24 years (N = 15,166), "family/friend" (46.08-47.41 %) and "dealer" (33.82-42.71 %) were the most common sources. Among assessments of adults aged ≥25 years (N = 89,225), "own prescription" was the most common source and increased in frequency as age increased. Across all age groups, "family/friend" was the most frequent source for all drug classes (41.96-48.76 %) except for nonmedically used buprenorphine/methadone, for which "own prescription" was the most common source (51.85 %) among adults. CONCLUSIONS: Our study demonstrates heterogeneity in sources of nonmedically used PPD across age groups. Tailored prevention strategies for different age groups and improving timely access to medical care to ensure proper treatment of chronic medical conditions including SUD are needed.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2). While evolutionarily conserved, ACE2 receptors differ across various species and differential interactions with Spike (S) glycoproteins of SARS-CoV-2 viruses impact species specificity. Reverse zoonoses led to SARS-CoV-2 outbreaks on multiple American mink (Mustela vison) farms during the pandemic and gave rise to mink-associated S substitutions known for transmissibility between mink and zoonotic transmission to humans. In this study, we used bio-layer interferometry (BLI) to discern the differences in binding affinity between multiple human and mink-derived S glycoproteins of SARS-CoV-2 and their respective ACE2 receptors. Further, we conducted a structural analysis of a mink variant S glycoprotein and American mink ACE2 (mvACE2) using cryo-electron microscopy (cryo-EM), revealing four distinct conformations. We discovered a novel intermediary conformation where the mvACE2 receptor is bound to the receptor-binding domain (RBD) of the S glycoprotein in a "down" position, approximately 34° lower than previously reported "up" RBD. Finally, we compared residue interactions in the S-ACE2 complex interface of S glycoprotein conformations with varying RBD orientations. These findings provide valuable insights into the molecular mechanisms of SARS-CoV-2 entry.

Poor social and economic circumstances affect the health of individuals throughout the life cycle. The purpose of the study was to examine whether state-level and individual-level socioeconomic factors are associated with mentally or physically unhealthy days in the general U.S. population of adults. The Behavioral Risk Factor Surveillance System and the American Community Survey in 2016 were used to examine state-level social determinants of health and the number of self-reported mentally unhealthy days in the last 30 days using Zero-Inflated Negative Binomial (ZINB) regression models. Men, older individuals, minorities, persons with higher educational attainment levels, persons who were employed, persons who were married, or with a partner, and persons with one or zero chronic condition were more likely to report excessive zeros for responses to the mentally, and physically unhealthy days. The negative binomial regression results indicated that higher state-level poverty rates, higher income inequity, lower median income, and higher unemployment rates were related to the higher number of reported mentally, and physically unhealthy days. Persons with higher educational attainment, and who were employed reported lower mentally, and physically unhealthy days. The findings show significant relationships between socioeconomic contexts and general health status. Health planners and policymakers may use the results to allocate resources and guide public policies and programs. © The Author(s) 2023.

In April 2023, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by one new family, 14 new genera, and 140 new species. Two genera and 538 species were renamed. One species was moved, and four were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.

Coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses is inevitable as the COVID-19 pandemic continues. This study aimed to evaluate cell lines commonly used in virus diagnosis and isolation for their susceptibility to SARS-CoV-2. While multiple kidney cell lines from monkeys were susceptible and permissive to SARS-CoV-2, many cell types derived from human, dog, mink, cat, mouse, or chicken were not. Analysis of MDCK cells, which are most commonly used for surveillance and study of influenza viruses, demonstrated that they were insusceptible to SARS-CoV-2 and that the cellular barrier to productive infection was due to low expression level of the angiotensin converting enzyme 2 (ACE2) receptor and lower receptor affinity to SARS-CoV-2 spike, which could be overcome by over-expression of canine ACE2 in trans. Moreover, SARS-CoV-2 cell tropism did not appear to be affected by a D614G mutation in the spike protein.Competing Interest StatementThe authors have declared no competing interest.

We present a small molecule chemotype, identified by an orthogonal drug screen, exhibiting nanomolar activity against members of all the six viral families causing most human respiratory viral disease, with a demonstrated barrier to resistance development. Antiviral activity is shown in mammalian cells, including human primary bronchial epithelial cells cultured to an air-liquid interface and infected with SARS-CoV-2. In animals, efficacy of early compounds in the lead series is shown by survival (for a coronavirus) and viral load (for a paramyxovirus). The drug target is shown to include a subset of the protein 14-3-3 within a transient host multi-protein complex containing components implicated in viral lifecycles and in innate immunity. This multi-protein complex is modified upon viral infection and largely restored by drug treatment. Our findings suggest a new clinical therapeutic strategy for early treatment upon upper respiratory viral infection to prevent progression to lower respiratory tract or systemic disease. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

Human-aided invasion of alien species across the world sometimes leads to economic, health or environmental burdens. During invasion process, species encounter new environments and partially escape some ecological constrains they faced in their native range, while they face new ones. The Asian tiger mosquito Aedes albopictus is one of the most iconic invasive species that was introduced in every inhabited continent over a short period of time due to international trade. It has also been shown to be infected by a prevalent and yet disregarded gregarine entomoparasite Ascogregarina taiwanensis. In this study, we aimed at deciphering the global dynamics of As. taiwanensis infection in natural Ae. albopictus populations and we further explored factors shaping its distribution. We showed that Ae. albopictus populations are highly colonized by several As. taiwanesis genotypes but recently introduced ones are escaping the parasite. We further performed experiments to explain such pattern. First, we hypothesized that founder effects (i.e. population establishment by a small number of individuals) may influence the parasite dynamics. This was confirmed since experimental increase in mosquitoes' density improves the parasite horizontal transmission to larvae. Furthermore, Ae. albopictus larvae do not exhibit density dependent prophylaxis to control the parasite meaning that infection is not mitigated when larval density increases. Secondly, we hypothesized that unparasitized mosquitoes were more prompt to found new populations through active flight dispersal. This was, however, unlikely since parasitized mosquitoes tend to be more active than their unparasitized relatives. Finally, we hypothesized that mosquito passive dispersal (i.e. often mediated by human-aided transportation of dried eggs) affects the parasite infectiveness. Our results support this hypothesis since parasite infection decreases over time when dry eggs are stored. This study highlights the importance of global trade on parasitism escape in one of the most invasive vector species on earth. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

The early Omicron lineage variants evolved and gave rise to diverging lineages that fueled the COVID-19 pandemic in 2022. Bivalent mRNA vaccines, designed to broaden protection against circulating and future variants, were authorized by the U.S. Food and Drug Administration (FDA) in August 2022 and recommended by the U.S. Centers for Disease Control and Prevention (CDC) in September 2022. The impact of bivalent vaccination on eliciting neutralizing antibodies against homologous BA.4/BA.5 viruses as well as emerging heterologous viruses needs to be analyzed. In this study, we analyze the neutralizing activity of sera collected after a third dose of vaccination (2-6 weeks post monovalent booster) or a fourth dose of vaccination (2-7 weeks post bivalent booster) against 10 predominant/recent Omicron lineage viruses including BA.1, BA.2, BA.5, BA.2.75, BA.2.75.2, BN.1, BQ.1, BQ.1.1, XBB, and XBB.1. The bivalent booster vaccination enhanced neutralizing antibody titers against all Omicron lineage viruses tested, including a 10-fold increase in neutralization of BQ.1 and BQ.1.1 viruses that predominated in the U.S. during the last two months of 2022. Overall, the data indicate the bivalent vaccine booster strengthens protection against Omicron lineage variants that evolved from BA.5 and BA.2 progenitors. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

Rotaviruses (RVs) preferentially replicate in the small intestine, frequently cause severe diarrheal disease, and following enteric infection generally induce variable levels of protective systemic and mucosal immune responses in humans and other animals. Rhesus rotavirus (RRV) is a simian RV that was previously used as a human RV vaccine and has been extensively studied in mice. Although RRV replicates poorly in the suckling mouse intestine, infection induces a robust and protective antibody response. The recent availability of plasmid-based RV reverse genetics systems has enabled the generation of recombinant RVs expressing foreign proteins. However, recombinant RVs have not yet been experimentally tested as potential vaccine vectors to immunize against other gastrointestinal pathogens in vivo. This is a missed opportunity because several live-attenuated RV vaccines are already widely administered to infants and young children worldwide. To explore the feasibility of using RV as a dual vaccine vector, we rescued a replication-competent recombinant RRV harboring bicistronic gene segment 7 that encodes both the native RV NSP3 protein and a human norovirus (HuNoV) VP1 protein from the predominant genotype GII.4 (rRRV-HuNoV-VP1). The rRRV-HuNoV-VP1 expressed HuNoV VP1 in infected cells in vitro and importantly, elicited both systemic and local antibody responses to HuNoV following oral infection of suckling mice. Serum IgG and fecal IgA from infected suckling mice bound to and neutralized both RV and HuNoV. These findings have encouraging practical implications for the design of RV-based next-generation multivalent enteric vaccines to target HuNoV and other human enteric pathogens while providing immunity to RV. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence of many new variant lineages that have exacerbated the COVID-19 pandemic. Some of those variants were designated as variants of concern/interest (VOC/VOI) by national or international authorities based on many factors including their potential impact on vaccines. To ascertain and rank the risk of VOCs and VOIs, we analyzed their ability to escape from vaccine-induced antibodies. The variants showed differential reductions in neutralization and replication titers by post-vaccination sera. Although the Omicron variant showed the most escape from neutralization, sera collected after a third dose of vaccine (booster sera) retained moderate neutralizing activity against that variant. Therefore, vaccination remains the most effective strategy to combat the COVID-19 pandemic.

Endocrine disrupting chemicals (EDCs) can adversely affect human health and are ubiquitously found in everyday products. We examined temporal trends in urinary concentrations of EDCs and their replacements. Urinary concentrations of 11 environmental phenols, 15 phthalate metabolites, phthalate replacements such as two di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) metabolites, and triclocarban were quantified using isotope-dilution tandem mass spectrometry. This prospective ecological study included 996 male and 819 female patients who were predominantly White/Caucasian (83 %) with an average age of 35 years and a BMI of 25.5 kg/m(2) seeking fertility treatment in Boston, MA, USA. Patients provided a total of 6483 urine samples (median = 2, range = 1-30 samples per patient) between 2000 and 2017. Over the study period, we observed significant decreases (% per year) in urinary concentrations of traditional phenols, parabens, and phthalates such as bisphenol A (β: -6.3, 95 % CI: -7.2, -5.4), benzophenone-3 (β: -6.5, 95 % CI: -1.1, -18.9), parabens ((β range:-5.4 to -14.2), triclosan (β: -18.8, 95 % CI: -24, -13.6), dichlorophenols (2.4-dichlorophenol β: -6.6, 95 % CI: -8.8, -4.3); 2,5-dichlorophenol β: -13.6, 95 % CI: -17, -10.3), di(2-ethylhexyl) phthalate metabolites (β range: -11.9 to -22.0), and other phthalate metabolites including mono-ethyl, mono-n-butyl, and mono-methyl phthalate (β range: -0.3 to -11.5). In contrast, we found significant increases in urinary concentrations of environmental phenol replacements including bisphenol S (β: 3.9, 95 % CI: 2.7, 7.6) and bisphenol F (β: 6, 95 % CI: 1.8, 10.3), DINCH metabolites (cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester [MHiNCH] β: 20, 95 % CI: 17.8, 22.2; monocarboxyisooctyl phthalate [MCOCH] β: 16.2, 95 % CI: 14, 18.4), and newer phthalate replacements such as mono-3-carboxypropyl phthalate, monobenzyl phthalate, mono-2-ethyl-5-carboxypentyl phthalate and di-isobutyl phthalate metabolites (β range = 5.3 to 45.1), over time. Urinary MHBP concentrations remained stable over the study period. While the majority of biomarkers measured declined over time, concentrations of several increased, particularly replacement chemicals that are studied.

Background: Half of diarrhea hospitalizations in children aged <5 years in Vietnam are due to rotavirus. Following introduction of a locally developed and licensed oral rotavirus vaccine, Rotavin-M1, into the routine immunization program in two Vietnamese provinces, Nam Dinh and TT Hue, we describe changes in rotavirus positivity among children hospitalized for diarrhea and calculate vaccine effectiveness against moderate-to-severe rotavirus hospitalizations. Methods: Active rotavirus surveillance among children <5 years began in December 2016 at sentinel hospitals in districts where rotavirus vaccine was introduced in December 2017. To estimate reductions in rotavirus detection, we calculated risk ratios comparing rotavirus positivity pre- and post-vaccine introduction. We used a test-negative case–control design to calculate vaccine effectiveness. Findings: From December 2016 to May 2021, 7228 children <5 years hospitalized for diarrhea were enrolled. Following introduction, Rotavin-M1 coverage was 77% (1066/1377) in Nam Dinh and 42% (203/489) in TT Hue. In Nam Dinh, rotavirus positivity among children <5 years significantly declined by 40.6% (95% CI: 34.8%–45.8%) during the three-year post-vaccine introduction period. In TT Hue, no change in rotavirus positivity was observed. Among children aged 6–23 months, a 2-dose series of Rotavin-M1 was 57% (95% CI: 39%–70%) effective against moderate-to-severe rotavirus hospitalizations. Interpretation: Higher vaccination coverage in Nam Dinh than TT Hue likely contributed to substantial declines in rotavirus positivity observed in Nam Dinh following rotavirus vaccine introduction. Robust vaccine effectiveness was observed through the second year of life. National rotavirus vaccine introduction with high coverage may have substantial impact on reducing rotavirus disease burden in Vietnam. Funding: Bill and Melinda Gates Foundation. © 2023

Background: Half of diarrhea hospitalizations in children aged <5 years in Vietnam are due to rotavirus. Following introduction of a locally developed and licensed oral rotavirus vaccine, Rotavin-M1, into the routine immunization program in two Vietnamese provinces, Nam Dinh and TT Hue, we describe changes in rotavirus positivity among children hospitalized for diarrhea and calculate vaccine effectiveness against moderate-to-severe rotavirus hospitalizations. Methods: Active rotavirus surveillance among children <5 years began in December 2016 at sentinel hospitals in districts where rotavirus vaccine was introduced in December 2017. To estimate reductions in rotavirus detection, we calculated risk ratios comparing rotavirus positivity pre- and post-vaccine introduction. We used a test-negative casecontrol design to calculate vaccine effectiveness. Findings: From December 2016 to May 2021, 7228 children <5 years hospitalized for diarrhea were enrolled. Following introduction, Rotavin-M1 coverage was 77% (1066/1377) in Nam Dinh and 42% (203/489) in TT Hue. In Nam Dinh, rotavirus positivity among children <5 years significantly declined by 40.6% (95% CI: 34.8%45.8%) during the three-year post-vaccine introduction period. In TT Hue, no change in rotavirus positivity was observed. Among children aged 623 months, a 2-dose series of Rotavin-M1 was 57% (95% CI: 39%70%) effective against moderate-to-severe rotavirus hospitalizations. Interpretation: Higher vaccination coverage in Nam Dinh than TT Hue likely contributed to substantial declines in rotavirus positivity observed in Nam Dinh following rotavirus vaccine introduction. Robust vaccine effectiveness was observed through the second year of life. National rotavirus vaccine introduction with high coverage may have substantial impact on reducing rotavirus disease burden in Vietnam. Funding: Bill and Melinda Gates Foundation. 2023

During the evolution of SARS-CoV-2 in humans a D614G substitution in the spike (S) protein emerged and became the predominant circulating variant (S-614G) of the COVID-19 pandemic (1) . However, whether the increasing prevalence of the S-614G variant represents a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains elusive. Here, we generated isogenic SARS-CoV-2 variants and demonstrate that the S-614G variant has (i) enhanced binding to human ACE2, (ii) increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a novel human ACE2 knock-in mouse model, and (iii) markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Collectively, our data show that while the S-614G substitution results in subtle increases in binding and replication in vitro , it provides a real competitive advantage in vivo , particularly during the transmission bottle neck, providing an explanation for the global predominance of S-614G variant among the SARS-CoV-2 viruses currently circulating.

Can a change in venues sampled in syphilis serosurveys influence prevalence estimates among men who have sex with men (MSM), and has this contributed to spurious trends of decline in the past decade? In this issue of The Lancet Global Health, Ting-Ting Jiang and colleagues in their Correspondence pose this question and note evidence from China that HIV prevalence evaluated among MSM at public bathhouses and saunas is consistently higher than among MSM recruited through internet sites.1 This difference in testing venues could extend to syphilis, although such a difference was not apparent in our recent global systematic review and meta-analysis of syphilis prevalence among MSM published in The Lancet Global Health.2 In our study, the pooled prevalence estimate of syphilis among studies that recruited MSM at venues including bathhouses and saunas, clubs, and one-off public events was 6·1% (95% CI 3·7–9·1; 13 229 MSM; 29 data points). When taking into account MSM studies that used a variety of convenience sampling methods, including internet advertising, the pooled prevalence estimate was 8·7% (95% CI 7·6–9·9%; 109 065 MSM; 64 data points). Neither of these subgroup estimates were meaningfully different from our overall pooled estimate of 7·5% (95% CI 7·0–8·0; 606 232 MSM; 345 data points). However, a prevalence data compilation and trend estimation of syphilis in Yunnan province, China did find prevalence among MSM (or female sex workers) to be systematically lower in routine annual surveillance surveys and higher in research studies.3 The venues involved might have contributed to this difference, although neither dataset (nor their weighted sum) showed a statistically significant upward or downward prevalence trend over 2010–17; these findings do highlight the importance of inferring time trends only within series of methodologically comparable samples.