Coronavirus disease-2019 precipitated the rapid deployment of novel therapeutics, which led to operational and logistical challenges for healthcare organizations. Four health systems participated in a qualitative study to abstract lessons learned, challenges, and promising practices from implementing neutralizing monoclonal antibody (nMAb) treatment programs. Lessons are summarized under three themes that serve as critical building blocks for health systems to rapidly deploy novel therapeutics during a pandemic: (1) clinical workflows, (2) data infrastructure and platforms, and (3) governance and policy. Health systems must be sufficiently agile to quickly scale programs and resources in times of uncertainty. Real-time monitoring of programs, policies, and processes can help support better planning and improve program effectiveness. The lessons and promising practices shared in this study can be applied by health systems for distribution of novel therapeutics beyond nMAbs and toward future pandemics and public health emergencies. © The Author(s), 2024. Published by Cambridge University Press.

Patterns of within-host influenza A virus (IAV) diversity and evolution have been described in natural human infections, but these patterns remain poorly characterized in non-human hosts. Elucidating these dynamics is important to better understand IAV biology and the evolutionary processes that govern spillover into humans. Here, we sampled an IAV outbreak in pigs during a week-long county fair to characterize viral diversity and evolution in this important reservoir host. Nasal wipes were collected on a daily basis from all pigs present at the fair, yielding up to 421 samples per day. Subtyping of PCR-positive samples revealed the co-circulation of H1N1 and H3N2 subtype swine IAVs. PCR-positive samples with robust Ct values were deep-sequenced, yielding 506 sequenced samples from a total of 253 pigs. Based on higher-depth re-sequenced data from a subset of these initially sequenced samples (260 samples from 168 pigs), we characterized patterns of within-host IAV genetic diversity and evolution. We find that IAV genetic diversity in single-subtype infected pigs is low, with the majority of intrahost Single Nucleotide Variants (iSNVs) present at frequencies of <10%. The ratio of the number of nonsynonymous to the number of synonymous iSNVs is significantly lower than under the neutral expectation, indicating that purifying selection shapes patterns of within-host viral diversity in swine. The dynamic turnover of iSNVs and their pronounced frequency changes further indicate that genetic drift also plays an important role in shaping IAV populations within pigs. Taken together, our results highlight similarities in patterns of IAV genetic diversity and evolution between humans and swine, including the role of stochastic processes in shaping within-host IAV dynamics.

BACKGROUND: Surgical voluntary medical male circumcision (VMMC) is a safe procedure; however, maintaining quality standards at scale, particularly during scale-up, is a challenge making ongoing quality management (QM) efforts essential. This study describes program quality measured by rates of adverse events (AEs) over four years of VMMC implementation in Namibia, compares AE rates over time, and discusses QM processes that contextualize AE trends and illustrate improvements in quality as the program matured. The International Training and Education Center for Health (I-TECH) assisted the Namibian Ministry of Health and Social Services (MoHSS) in expanding VMMC in three regions among boys and men over 10 years of age between January 2015 and September 2019. METHODS: A comprehensive package of QM strategies was implemented by multi-disciplinary onsite teams with support from national and international technical advisors. Retrospective routine MoHSS data from the VMMC register, client forms, and monthly AE reports were collected during implementation in the three regions to assess the impact of QM interventions on AEs and to calculate the proportion of clients who experienced AEs over time. The proportion of clients who experienced an AE over time was compared using a Cochran-Armitage test for trend. RESULTS: Between January 2015 and September 2019, 40,336 clients underwent VMMC and 593 (1.5%) clients experienced a post-operative AE in the three supported regions. The AE rate was highest in the first quarter of clinical service delivery in each region (January-March 2015 in Oshana and Zambezi, October-December 2017 in //Kharas) but declined over the implementation period as the program matured. This observed trend between program maturity and declining AE rates over time was significant (p < 0.001) when compared using a Cochran-Armitage test for trend. CONCLUSIONS: As the I-TECH-supported VMMC program matured, QM measures were introduced and routinized, and clinical quality improved over time with the rate of AEs decreasing significantly over the implementation period. Applying systematic and continuous QM processes and approaches across the continuum of VMMC services and considering local context can contribute to increased clinical safety. QM measures that are established in more mature program sites can be quickly adopted to respond to quality issues in program expansion sites.

Reassortment among co-infecting influenza A viruses (IAVs) is an important source of viral diversity and can facilitate expansion into novel host species. Indeed, reassortment played a key role in the evolution of the last three pandemic IAVs. Observed patterns of reassortment within a coinfected host are likely to be shaped by several factors, including viral load, the extent of viral mixing within the host and the stringency of selection. These factors in turn are expected to vary among the diverse host species that IAV infects. To investigate host differences in IAV reassortment, here we examined reassortment of two distinct avian IAV within their natural host (mallards) and a mammalian model system (guinea pigs). Animals were co-inoculated with A/wildbird/California/187718-36/2008 (H3N8) and A/mallard/Colorado/P66F1-5/2008 (H4N6) viruses. Longitudinal samples were collected from the cloaca of mallards or the nasal tract of guinea pigs and viral genetic exchange was monitored by genotyping clonal isolates from these samples. Relative to those in guinea pigs, viral populations in mallards showed higher frequencies of reassortant genotypes and were characterized by higher genotype richness and diversity. In line with these observations, analysis of pairwise segment combinations revealed lower linkage disequilibrium in mallards as compared to guinea pigs. No clear longitudinal patterns in richness, diversity or linkage disequilibrium were present in either host. Our results reveal mallards to be a highly permissive host for IAV reassortment and suggest that reduced viral mixing limits avian IAV reassortment in a mammalian host.Competing Interest StatementThe authors have declared no competing interest.

For the first time, a complete genome of an RNA virus has been sequenced in its original form. Previously, RNA was sequenced by the chemical degradation of radiolabelled RNA, a difficult method that produced only short sequences. Instead, RNA has usually been sequenced indirectly by copying it into cDNA, which is often amplified to dsDNA by PCR and subsequently analyzed using a variety of DNA sequencing methods. We designed an adapter to short highly conserved termini of the influenza virus genome to target the (-) sense RNA into a protein nanopore on the Oxford Nanopore MinION sequencing platform. Utilizing this method and total RNA extracted from the allantoic fluid of infected chicken eggs, we demonstrate successful sequencing of the complete influenza virus genome with 100% nucleotide coverage, 99% consensus identity, and 99% of reads mapped to influenza. By utilizing the same methodology we can redesign the adapter in order to expand the targets to include viral mRNA and (+) sense cRNA, which are essential to the viral life cycle. This has the potential to identify and quantify splice variants and base modifications, which are not practically measurable with current methods.

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.

Recombination between SARS-CoV-2 virus variants can result in different viral properties (e.g., infectiousness or pathogenicity). In this report, we describe viruses with recombinant genomes containing signature mutations from Delta and Omicron variants. These genomes are the first evidence for a Delta-Omicron hybrid Spike protein in the United States. 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.

CDC has used national genomic surveillance since December 2020 to monitor SARS-CoV-2 variants that have emerged throughout the COVID-19 pandemic, including the Omicron variant. This report summarizes U.S. trends in variant proportions from national genomic surveillance during January 2022-May 2023. During this period, the Omicron variant remained predominant, with various descendant lineages reaching national predominance (>50% prevalence). During the first half of 2022, BA.1.1 reached predominance by the week ending January 8, 2022, followed by BA.2 (March 26), BA.2.12.1 (May 14), and BA.5 (July 2); the predominance of each variant coincided with surges in COVID-19 cases. The latter half of 2022 was characterized by the circulation of sublineages of BA.2, BA.4, and BA.5 (e.g., BQ.1 and BQ.1.1), some of which independently acquired similar spike protein substitutions associated with immune evasion. By the end of January 2023, XBB.1.5 became predominant. As of May 13, 2023, the most common circulating lineages were XBB.1.5 (61.5%), XBB.1.9.1 (10.0%), and XBB.1.16 (9.4%); XBB.1.16 and XBB.1.16.1 (2.4%), containing the K478R substitution, and XBB.2.3 (3.2%), containing the P521S substitution, had the fastest doubling times at that point. Analytic methods for estimating variant proportions have been updated as the availability of sequencing specimens has declined. The continued evolution of Omicron lineages highlights the importance of genomic surveillance to monitor emerging variants and help guide vaccine development and use of therapeutics.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

To detect new and changing SARS-CoV-2 variants, we investigated candidate Delta-Omicron recombinant genomes from Centers for Disease Control and Prevention national genomic surveillance. Laboratory and bioinformatic investigations identified and validated 9 genetically related SARS-CoV-2 viruses with a hybrid Delta-Omicron spike protein.

Post-translational modification of host and viral proteins by ubiquitin and ubiquitin-like proteins plays a key role in a host's ability to mount an effective immune response. Avian species lack a ubiquitin-like protein found in mammals and other non-avian reptiles; interferon stimulated gene product 15 (ISG15). ISG15 serves as a messenger molecule and can be conjugated to both host and viral proteins leading them to be stabilized, degraded, or sequestered. Structurally, ISG15 is comprised of a tandem ubiquitin-like domain (Ubl), which serves as the motif for post-translational modification. The 2'-5' oligoadenylate synthetase-like proteins (OASL) also encode two Ubl domains in series near its C-terminus which binds OASL to retinoic acid inducible gene-I (RIG-I). This protein-protein interaction increases the sensitivity of RIG-I and results in an enhanced production of type 1 interferons and a robust immune response. Unlike human and other mammalian OASL homologues, avian OASLs terminate their tandem Ubl domains with the same LRLRGG motif found in ubiquitin and ISG15, a motif required for their conjugation to proteins. Chickens, however, lack RIG-I, raising the question of structural and functional characteristics of chicken OASL (chOASL). By investigating chOASL, the evolutionary history of viruses with deubiquitinases can be explored and drivers of species specificity for these viruses may be uncovered. Here we show that the chOASL tandem Ubl domains shares structural characteristics with mammalian ISG15, and that chOASL can oligomerize and conjugate to itself. In addition, the ISG15-like features of avian OASLs and how they impact interactions with viral deubiquitinases and deISGylases are explored.

BACKGROUND: Human respiratory syncytial virus (RSV) is one of the leading causes of respiratory infections, especially in infants and young children. Previous RSV sequencing studies have primarily focused on partial sequencing of G gene (200-300 nucleotides) for genotype characterization or diagnostics. However, the genotype assignment with G gene has not recapitulated the phylogenetic signal of other genes, and there is no consensus on RSV genotype definition. METHODS: We conducted maximum likelihood phylogenetic analysis with 10 RSV individual genes and whole-genome sequence (WGS) that are published in GenBank. RSV genotypes were determined by using phylogenetic analysis and pair-wise node distances. RESULTS: In this study, we first statistically examined the phylogenetic incongruence, rate variation for each RSV gene sequence and WGS. We then proposed a new RSV genotyping system based on a comparative analysis of WGS and the temporal distribution of strains. We also provide an RSV classification tool to perform RSV genotype assignment and a publicly accessible up-to-date instance of Nextstrain where the phylogenetic relationship of all genotypes can be explored. CONCLUSIONS: This revised RSV genotyping system will provide important information for disease surveillance, epidemiology, and vaccine development.

INTRODUCTION: Monitoring clinical safety of voluntary medical male circumcision (VMMC) is critical to minimize risk as VMMC programs for HIV prevention are scaled. This cross-sectional analysis describes the adverse event (AE) profile of a large-scale, routine VMMC program and identifies factors associated with the development, severity, and timing of AEs to provide recommendations for program quality improvement. MATERIALS AND METHODS: From 2015-2018 there were 28,990 circumcisions performed in International Training and Education Center for Health (I-TECH) supported regions of Namibia in collaboration with the Ministry of Health and Social Services. Two routine follow-up visits after VMMC were scheduled to identify clients with AEs. Summary statistics were used to describe characteristics of all VMMC clients and the subset who experienced an AE. We used chi-square tests to evaluate associations between AE timing, patient age, and other patient and AE characteristics. We used a logistic regression model to explore associations between patient characteristics and AE severity. RESULTS: Of the 498 clients with AEs (AE rate of 1.7%), 40 (8%) occurred ≤2 days, 262 (53%) occurred 3-7 days, 161 (32%) between day 8 and 14, and 35 (7%) were ≥15 days post-VMMC. Early AEs (on or before day 2) tended to be severe and categorized as bleeding, while infections were the most common AEs occurring later (p<0.001). Younger clients (aged 10-14 years) experienced more infections, whereas older clients experienced more bleeding (p<0.001). CONCLUSIONS: Almost 40% of AEs occurred after the second follow-up visit, of which 179 (91%) were infections. Improvements in pre-surgical and post-surgical counselling and post-operative educational materials encouraging clients to seek care at any time, adoption of alternative follow-up methods, and the addition of a third follow-up visit may improve outcomes for patients. Enhancing post-surgical counselling and emphasizing wound care for younger VMMC clients and their caregivers could help mitigate elevated risk of infection.

BACKGROUND: Mosquito larval control through the use of insecticides is the most common strategy for suppressing West Nile virus (WNV) vector populations in Connecticut (CT), United States. To evaluate the ability of larval control to reduce entomological risk metrics associated with WNV, we performed WNV surveillance and assessments of municipal larvicide application programs in Milford and Stratford, CT in 2019 and 2020. Each town treated catch basins and non-basin habitats (Milford only) with biopesticide products during both WNV transmission seasons. Adult mosquitoes were collected weekly with gravid and CO(2) -baited light traps and tested for WNV; larvae and pupae were sampled weekly from basins within 500 m of trapping sites, and Culex pipiens larval mortality was determined with lab bioassays of catch basin water samples. RESULTS: Declines in 4th instar larvae and pupae were observed in catch basins up to 2-weeks post-treatment, and we detected a positive relationship between adult female Cx. pipiens collections in gravid traps and pupal abundance in basins. We also detected a significant difference in total light trap collections between the two towns. Despite these findings, Cx. pipiens adult collections and WNV mosquito infection prevalence in gravid traps were similar between towns. CONCLUSION: Larvicide applications reduced pupal abundance and the prevalence of host-seeking adults with no detectable impact on entomological risk metrics for WNV. Further research is needed to better determine the level of mosquito larval control required to reduce WNV transmission risk. This article is protected by copyright. All rights reserved.

Eastern equine encephalitis virus (EEEV) is an arbovirus endemic to the eastern United States. Human cases are rare but can be serious. The primary enzootic vector is Culiseta melanura (Coquillett) (Diptera: Culicidae), an ornithophagic mosquito. We conducted an aerial application of a granular methoprene formulation in Hockomock Swamp (Massachusetts), which represents a focus of EEEV transmission. Water collected from inside and outside Cs. melanura crypts was evaluated in bioassays of early fourth instar Cs. melanura larvae using treated and untreated water. Adult eclosion rates were 36% significantly lower in treated compared with untreated water (P < 0.05). Eclosion rates for water collected from inside crypts were significantly higher (62%) than rates from outside crypts (30%) (P < 0.05), indicating higher efficacy outside crypts. We tested whether reduced methoprene efficacy inside the crypts was due to reduced chemical penetration into this habitat. Chemical water analyses confirmed that methoprene concentrations were lower inside the crypts (0.1 ± 0.05 ppb) compared to water from outside crypts (1.79 ± 0.41 ppb). The susceptibility of Cs. melanura to methoprene was also determined to allow for comparison against concentrations observed in water collected from the field (LC-95: 1.95 ± 0.5 ppb). Overall, methoprene-treated water prevented mosquito development for up to 4 wk, but with a reduction in efficacy between 4- and 6-wk post-application. Our results suggest that aerial methoprene applications can effectively treat open water in wetlands but may not provide efficacious control of Cs. melanura due to an inability to penetrate larval habitats.

Reassortment among co-infecting influenza A viruses (IAVs) is an important source of viral diversity and can facilitate expansion into novel host species. Indeed, reassortment played a key role in the evolution of the last three pandemic IAVs. Observed patterns of reassortment within a coinfected host are likely to be shaped by several factors, including viral load, the extent of viral mixing within the host and the stringency of selection. These factors in turn are expected to vary among the diverse host species that IAV infects. To investigate host differences in IAV reassortment, here we examined reassortment of two distinct avian IAVs within their natural host (mallards) and a mammalian model system (guinea pigs). Animals were co-inoculated with A/wildbird/California/187718-36/2008 (H3N8) and A/mallard/Colorado/P66F1-5/2008 (H4N6) viruses. Longitudinal samples were collected from the cloaca of mallards or the nasal tract of guinea pigs and viral genetic exchange was monitored by genotyping clonal isolates from these samples. Relative to those in guinea pigs, viral populations in mallards showed higher frequencies of reassortant genotypes and were characterized by higher genotype richness and diversity. In line with these observations, analysis of pairwise segment combinations revealed lower linkage disequilibrium in mallards as compared to guinea pigs. No clear longitudinal patterns in richness, diversity or linkage disequilibrium were present in either host. Our results reveal mallards to be a highly permissive host for IAV reassortment and suggest that reduced viral mixing limits avian IAV reassortment in a mammalian host.

BACKGROUND: Pre-existing antibodies to influenza, shaped by early infection and subsequent exposures, may impact responses to influenza vaccination. METHODS: We enrolled 72 children (7-17 years) in 2015-16, all received inactivated influenza vaccines. Forty-one were also vaccinated in 2014-15 with 12 became infected with A(H3N2) in 2014-15. Thirty-one children did not have documented influenza exposures in the prior 5 seasons. Sera were collected pre- and post-vaccination in both seasons. We constructed antibody landscapes using hemagglutination inhibition antibody titers against 16 A(H3N2) viruses representative of major antigenic clusters that circulated between 1968 and 2015. RESULTS: The breadth of the antibody landscapes increased with age. Vaccine-induced antibody responses correlated with boosting of titers to previously encountered antigens. Post-vaccination titers were highest against vaccine antigens rather than the historic A(H3N2) viruses previously encountered. Pre-vaccination titers to the vaccine were the strongest predictors of post-vaccination titers. Responses to vaccine antigens did not differ by likely priming virus. Influenza A(H3N2) infected children in 2014-15 had narrower antibody landscapes than those uninfected, but prior season infection status had little effect on antibody landscapes following 2015-16 vaccination. CONCLUSIONS: A(H3N2) antibody landscapes in children were largely determined by age-related immune priming, rather than recent vaccination or infection.

Mycobacterium tuberculosis complex (MTBC) is divided into several major phylogenetic lineages, with differential distribution globally. Using population-based data collected over a three year period, we performed 24-locus Mycobacterial Interspersed Repeat Unit - Variable Number Tandem Repeat (MIRU-VNTR) genotyping on all culture isolates from two districts of the country that differ in tuberculosis (TB) incidence (Gaborone, the capital, and Ghanzi in the Western Kalahari). The study objective was to characterize the molecular epidemiology of TB in these districts. Overall phylogenetic diversity mirrored that reported from neighboring Republic of South Africa, but differences in the two districts were marked. All four major lineages of M. tuberculosis were found in Gaborone, but only three of the four major lineages were found in Ghanzi. Strain diversity was lower in Ghanzi, with a large proportion (38%) of all isolates having an identical MIRU-VNTR result, compared to 6% of all isolates in Gaborone with the same MIRU-VNTR result. This study demonstrates localized differences in strain diversity by two districts in Botswana, and contributes to a growing characterization of MTBC diversity globally.

HIV pre-exposure prophylaxis (PrEP) is a highly effective prevention method. It is an attractive self-initiated approach to reduce the spread of HIV amongst female sex workers (FSW). PrEP, however, has not yet achieved its potential to reduce HIV infections partially due to a general lack of awareness from women who may benefit. Aims of this cross-sectional study of 1,466 FSW in China were to understand: levels of awareness of and willingness to use PrEP among female sex workers (FSW) in China, and factors contributing to willingness to use PrEP. We found that awareness (10.2%) and willingness (35.5%) to use PrEP were low in our survey areas. Low PrEP willingness is likely reflective of the overall poor knowledge and understanding of HIV risk and prevention. FSW that demonstrated greater HIV knowledge through having been tested or having greater decision-making involvement in condom use were more willing to use PrEP. Study findings may be used to inform future HIV prevention activities, including possible use of PrEP among FSW at higher risk of incident HIV infection in China.

BACKGROUND: Electronic health information systems (HIS) are critical components of national health systems, and have been identified as a key element in the development and strengthening of health systems globally. Novel approaches are needed to effectively and efficiently train health care workers on the use of HIS. One such approach is the use of digital eLearning programs, either alone or blended with face-to-face learning activities. METHODS: We developed a novel blended eLearning course based on an in-person HIS training package previously developed by the United States Centers for Disease Control and Prevention. We then conducted a pilot implementation of the eLearning course in Namibia and Tanzania. RESULTS: The blended eLearning pilot program enrolled 131 people, 72 (55%) from Namibia and 59 (45%) from Tanzania. The majority of enrollees were female (n = 88, 67%) and were nurses (n=66, 50%). Of the 131 people who participated in the in-person orientation, 95 (73%) completed some or all of the eLearning modules. Across all three modules, the mean score on the post-test was significantly greater than on the pre-test (p<0.001). When comparing results from previous in-person workshops and the blended eLearning course, we found that participants experienced strong learning gains in both, although learning gains were somewhat greater in the in-person course. Blended eLearning course participants reported good to very good satisfaction with the overall content of the course and with the eLearning modules (3.5 and 3.6 out of 5-point Likert scale). We estimate that the total cost per participant is 2.2-3.4 times greater for the in-person course (estimated cost USD $980) than for the blended eLearning course (estimated cost USD $287-$437). CONCLUSION: A blended eLearning course is an effective method with which to train healthcare workers in the basic features of HIS, and the cost is up to 3.4 times less expensive than for an in-person course with similar content.

The prevalence of human immunodeficiency virus (HIV) infection in China is low overall (0.06%) (1); however, it is substantially higher (8.0%) among men who have sex with men (MSM) (2), and the stigmatization of same-sex behaviors in China presents challenges for HIV prevention and treatment efforts. In 2015, Blued, a Beijing-based media company that operates an online dating application popular among Chinese MSM, launched an ongoing HIV testing campaign that combined its push-notification(dagger) platform and geolocation capabilities to encourage HIV testing among MSM in Beijing. To assess trends in use of HIV testing services, Blued and CDC's China HIV program examined testing at six Blued-operated Beijing HIV testing centers from 2 years before the campaign launch in 2015 through December 31, 2017. A sharp increase in HIV testing followed the launch of Blued's online campaign, indicating that leveraging social media platforms and their geolocation-based text messaging functionality might be useful in increasing HIV testing among MSM, particularly those aged </=35 years.

For the first time, a coding complete genome of an RNA virus has been sequenced in its original form. Previously, RNA was sequenced by the chemical degradation of radiolabeled RNA, a difficult method that produced only short sequences. Instead, RNA has usually been sequenced indirectly by copying it into cDNA, which is often amplified to dsDNA by PCR and subsequently analyzed using a variety of DNA sequencing methods. We designed an adapter to short highly conserved termini of the influenza A virus genome to target the (-) sense RNA into a protein nanopore on the Oxford Nanopore MinION sequencing platform. Utilizing this method with total RNA extracted from the allantoic fluid of influenza rA/Puerto Rico/8/1934 (H1N1) virus infected chicken eggs (EID50 6.8 x 10(9)), we demonstrate successful sequencing of the coding complete influenza A virus genome with 100% nucleotide coverage, 99% consensus identity, and 99% of reads mapped to influenza A virus. By utilizing the same methodology one can redesign the adapter in order to expand the targets to include viral mRNA and (+) sense cRNA, which are essential to the viral life cycle, or other pathogens. This approach also has the potential to identify and quantify splice variants and base modifications, which are not practically measurable with current methods.

The effects of maternal tenofovir use on infant bone mineral content (BMC) and bone mineral density (BMD) were evaluated in a pilot study of HIV/Hepatitis B-coinfected pregnant women in China. BMD and BMC were assessed at age 6 months of life in 14 tenofovir-exposed and 13 unexposed infants. Trends toward lower BMC and BMD were observed in infants exposed to maternal tenofovir but were not statistically significant.

Highly pathogenic avian influenza (HPAI) A(H5N1) viruses pose a significant economic burden to the poultry industry worldwide and have pandemic potential. Poultry vaccination against HPAI A(H5N1) viruses has been an important component of HPAI control measures and has been performed in Vietnam since 2005. To systematically assess antigenic matching of current vaccines to circulating field variants, we produced a panel of chicken and ferret antisera raised against historical and contemporary Vietnamese reference viruses representing clade variants that were detected between 2001 and 2014. The antisera were used for hemagglutination inhibition (HI) assays to generate data sets for analysis by antigenic cartography, allowing for a direct comparison of results from chicken or ferret antisera. HI antigenic maps, developed with antisera from both hosts, revealed varying patterns of antigenic relationships and clustering of viruses that were dependent on the clade of viruses analyzed. Antigenic relationships between existing poultry vaccines and circulating field viruses were also aligned with in vivo protection profiles determined by previously reported vaccine challenge studies. Our results establish the feasibility and utility of HPAI A(H5N1) antigenic characterization using chicken antisera and support further experimental and modeling studies to investigate quantitative relationships between genetic variation, antigenic drift and correlates of poultry vaccine protection in vivo.

OBJECTIVE: To examine the relationship between combination antiretroviral therapy (cART) and preterm delivery (PTD) or low delivery weight among pregnant Chinese women with HIV. METHODS: The present retrospective cross-sectional medical chart review enrolled pregnant women with HIV who delivered at five tertiary hospitals in China between January 1, 2009, and December 31, 2014. Generalized linear mixed modeling was used to explore PTD (<37 weeks of pregnancy) and low delivery weight (<2500 g) risk factors. RESULTS: Among 731 mother-neonate pairs, 93 (12.7%) mothers had PTD and 133 (18.2%) neonates had low delivery weight. Use of cART pre-conception or its initiation in the first trimester was associated with PTD (adjusted odds ratio [aOR] 2.82; P=0.002) and low delivery weight (aOR 1.92; P=0.026). First-trimester cART initiation was associated with PTD for lopinavir/ritonavir (aOR 2.59; P=0.006) and nevirapine (aOR, 2.64; P=0.003) regimens compared with later; the same was not true for efavirenz-based cART (P=0.197). Low maternal body mass index (</=23.5) before delivery was independently associated with an increased likelihood of low delivery weight (aOR 1.60; P=0.038) but not PTD. CONCLUSION: Early use of cART was associated with increased likelihood of PTD and low delivery weight. Efavirenz-based cART appear to be favorable for women with HIV regardless of the timing of cART initiation. Good nutritional status is essential to prevent low delivery weight. This article is protected by copyright. All rights reserved.

Following cessation of continuous Ebola virus (EBOV) transmission within Western Africa, sporadic EBOV disease (EVD) cases continued to re-emerge beyond the viral incubation period. Epidemiological and genomic evidence strongly suggests that this represented transmission from EVD survivors. To investigate whether persistent infections are characterized by ongoing viral replication, we sequenced EBOV from the semen of nine EVD survivors and a subset of corresponding acute specimens. EBOV evolutionary rates during persistence were either similar to or reduced relative to acute infection rates. Active EBOV replication/transcription continued during convalescence, but decreased over time, consistent with viral persistence rather than viral latency. Patterns of genetic divergence suggest a moderate relaxation of selective constraints within the sGP carboxy-terminal tail during persistent infections, but do not support widespread diversifying selection. Altogether, our data illustrate that EBOV persistence in semen, urine, and aqueous humor is not a quiescent or latent infection.

The chief concerns for antiretroviral therapy (ART) programs considering removal of CD4(+) cell count thresholds for treatment are the increased incidence of ART-related adverse events. A nationwide observational cohort study was conducted among patients who initiated ART in 2012. We divided the eligible patients into three groups: an early ART group with a baseline CD4(+) cell count of 500 cells/μL or greater, a standard ART group with a baseline CD4(+) cell count between 350 and 499 cells/μL, and a late ART group with a baseline CD4(+) cell count between 200 and 349 cells/μL. These patients were followed up to December 31, 2014 and observed for three outcomes: virological failure, treatment nonretention, or time to death. Patients who met the eligibility criteria numbered at 26,752. Out of all study participants, 20,827 participants were in late ART group, 4336 were in standard ART group, and 1589 were in early ART group. Patients in late ART group were more likely to become virally suppressed 12 and 24 months after treatment initiation than patients in early ART group [adjusted odds ratio (aOR) 0.81; 95% CI, 0.69-0.95 and aOR, 0.78; 95% CI, 0.65-0.94]. Treatment nonretention was also less likely to occur among patients in late ART group than early ART group 12 months after treatment initiation (aOR, 0.85; 95% CI, 0.75-0.96). Compared with early ART group, neither standard ART group nor late ART group had a statistically significant difference in the time-to-death analysis. Late ART initiates were more likely to be virally suppressed and retained on treatment than early ART initiates. The importance of treatment retention and adherence should be emphasized for high CD4(+) patients newly initiated to ART therapy through education and counseling programs.

Whole genome sequences of representative highly pathogenic avian influenza A(H5) viruses from Vietnam were generated, comprising samples from poultry outbreaks and active market surveillance collected from January 2012 to August 2015. Six hemagglutinin gene clades were characterized. Clade 1.1.2 was predominant in southern Mekong provinces throughout 2012 and 2013, but gradually disappeared and was not detected after April 2014. Clade 2.3.2.1c viruses spread rapidly during 2012 and were detected in the south and center of the country. A number of clade 1.1.2 and 2.3.2.1c inter-clade reassortant viruses were detected with different combinations of internal genes derived from 2.3.2.1a and 2.3.2.1b viruses indicating extensive co-circulation. Although reassortment generated genetic diversity at the genotype level, there was relatively little genetic drift within the individual gene segments suggesting genetic stasis over recent years. Antigenically, clade 1.1.2, 2.3.2.1a, 2.3.2.1b, 2.3.2.1c viruses remained related to earlier viruses and WHO recommended pre-pandemic vaccine strains representing these clades. Clade 7.2 viruses, although only detected in small numbers, were the exception as indicated by introduction of a genetically and antigenically diverse strain in 2013. Clade 2.3.4.4 viruses (H5N1 and H5N6) were likely introduced in April 2014 and appeared to gain dominance across northern and central regions. Antigenic analyses of clade 2.3.4.4 viruses compared to existing clade 2.3.4 candidate vaccine viruses (CVV) indicated the need for an updated vaccine virus. A/Sichuan/26221/2014 (H5N6), was developed and ferret antisera generated against this virus was demonstrated to inhibit some but not all clade 2.3.4.4 viruses suggesting consideration of alternative clade 2.3.4.4 CVVs. IMPORTANCE: Highly pathogenic avian influenza (HPAI) A(H5) viruses have circulated continuously in Vietnam since 2003 resulting in hundreds of poultry outbreaks and sporadic human infections. Despite significant reduction in the number of human infections in recent years, poultry outbreaks continue to occur and the virus continues to diversify. Vaccination of poultry has been used as a means to control spread and impact of the virus but due to the diversity and changing distribution of antigenically distinct viruses, the utility of vaccines in the face of mismatched circulating strains remains questionable. This study assesses the putative amino acid changes in viruses leading to antigenic variability, underscoring the complexity of vaccine selection for both veterinary and public health purposes. Given the overlapping geographic distribution of multiple, antigenically distinct clades of HPAI A(H5) viruses in Vietnam, the vaccine efficacy of bivalent poultry vaccine formulations should be tested in the future.

The primary aim of the Million Hearts initiative is to prevent 1 million cardiovascular events over 5 years. Concordant with the Million Hearts' focus on achieving more than 70% performance in the "ABCS" of aspirin for those at risk, blood pressure control, cholesterol management, and smoking cessation, we outline the cardiovascular events that would be prevented and a road map to achieve more than 70% participation in cardiac rehabilitation (CR)/secondary prevention programs by the year 2022. Cardiac rehabilitation is a class Ia recommendation of the American Heart Association and the American College of Cardiology after myocardial infarction or coronary revascularization, promotes the ABCS along with lifestyle counseling and exercise, and is associated with decreased total mortality, cardiac mortality, and rehospitalizations. However, current participation rates for CR in the United States generally range from only 20% to 30%. This road map focuses on interventions, such as electronic medical record-based prompts and staffing liaisons that increase referrals of appropriate patients to CR, increase enrollment of appropriate individuals into CR, and increase adherence to longer-term CR. We also calculate that increasing CR participation from 20% to 70% would save 25,000 lives and prevent 180,000 hospitalizations annually in the United States.

BACKGROUND: There is limited information on HBV-antiviral therapy among HIV/HBV co-infected pregnant women. METHODS: Phase II randomized controlled trial of a regimen containing tenofovir (TDF) /lamivudine (3TC), versus 3TC, in HIV/HBV co-infected pregnant women in China. The HBV virological response was compared in study arms (Clinical Trials registration: #NCT01125696). RESULTS: Median decline of HBV DNA was 2.60 log10 copies/ml in the TDF-3TC arm; 2.24 log10 copies/ml in the 3TC arm (p=0.41). All women achieved delivery HBV DNA levels <6 log10 copies/ml. CONCLUSIONS: Initiation of either regimen led to achieving HBV DNA levels below the threshold associated with perinatal HBV transmission.