BACKGROUND: In 2016, Chile implemented a pilot project in two Santiago-area family health centers aimed at improving hypertension control using the HEARTS framework for cardiovascular disease (CVD) prevention. The core intervention replaced non-standardized, single-medication regimens with standardized treatment using fixed-dose combination pills. While prior studies demonstrate improved blood pressure control with fixed-dose combination pills, further evidence on cost-effectiveness is essential for scalability. METHODS: A 10-year outcomes-based Markov model was used to assess the benefits and costs of the HEARTS approach versus usual care from a societal perspective. Incremental program costs were estimated via activity-based costing, and incremental benefits from reductions in acute CVD events. The cost-effectiveness was quantified using incremental benefit-cost ratios (IBCR) and incremental cost per averted disability-adjusted life year (DALY). FINDINGS: While the HEARTS approach led to higher initial medication costs, averted CVD events generated net savings over time. The IBCR was estimated to exceed one by year 2 and reached 7.8 by year 10, showing that incremental benefits would exceed costs at an increasing rate over time. The cost per DALY averted in model year 10 was approximately $2,171, demonstrating high cost-effectiveness compared to the per-capita GDP threshold. INTERPRETATION: The HEARTS approach in Chile, which employs a standardized hypertension treatment protocol with fixed-dose combination pills, was estimated to be highly cost-effective compared to usual care. Over time, it progressively reduces the incidence of acute cardiovascular disease (CVD) events, resulting in substantial cost savings.

The ferret has been widely used to study both the pathogenicity and the transmissibility of respiratory viral infections, but little is known about how host-associated microbial communities alter disease susceptibility owing to the lack of a validated model. Here, we compared the safety of injectable versus oral broad-spectrum antibiotics and their efficacy in reducing culturable bacteria from the upper respiratory tract of ferrets before an influenza A virus challenge. Both injectable and oral antibiotic treatment led to drastic reductions in cultivable bacteria from nasal wash specimens when assessed after 7 days of ongoing treatment. Even when extended to 14 days, there were few adverse events noted and no clinically significant bloodwork changes. During challenge with either a high-dose or low-dose A(H1N1)pdm09 influenza A virus inoculum, all animals became productively infected and had generally similar viral titers and clinical measurements, regardless of antibiotic pretreatment. Collectively, these results support that both antibiotic regimens evaluated in laboratory ferrets can be utilized to further characterize host-microbial interactions in the context of respiratory viral infections and other pathogens, including a needle-free approach that may be suitable for studies of high-consequence pathogens in containment laboratory facilities.

BACKGROUND: The Nigeria Hypertension Control Initiative (NHCI) program, launched in 2020, integrates hypertension care into primary healthcare using the HEARTS technical package, which includes screening, health counselling, and standardized hypertension treatment protocols. This package has been piloted through NHCI in Kano and Ogun States and in the Federal Capital Territory (FCT) Abuja, as part of the Hypertension Treatment in Nigeria (HTN) project. OBJECTIVE: To assess the costs of scaling up the HEARTS hypertension control package and compare these costs with those of usual care. METHODS: Data on the costs of implementing the HEARTS program were collected from 15 purposively sampled primary health facilities in Kano, Ogun, and FCT Abuja between February and April 2024. Costs included training, medicines, provider time, and administrative expenses. We used the HEARTS costing tool, an Excel-based instrument, to collect and analyze the annual costs from a health system perspective, using an activity-based approach. RESULTS: The estimated annual cost of implementing HEARTS was USD 16 per adult primary care user (PCU), with variations across the three locations: USD 21 in Abuja, USD 11 in Kano, and USD 16 in Ogun. Average annual medication costs per patient treated under HEARTS also varied by location, amounting to USD 28 in Abuja, USD 27 in Ogun, and USD 16 in Kano. Under usual care, annual medication costs per patient were estimated at USD 32 in Kano and USD 16 in Ogun (data for Abuja were unavailable). Major cost drivers for the HEARTS package included provider time (49%) and medication (47%), compared to usual care, where medication alone accounted for 80% of costs. Implementing HEARTS requires a full-time equivalent of 0.45 doctors, 1.59 nurses, and 5.21 community health workers per 10,000 primary care users. CONCLUSIONS: In the Nigerian primary care setting, provider time costs and medication costs emerge as major considerations in scaling up hypertension services. Policy options could consider reducing follow-up visit frequency for well-controlled patients to decrease provider time costs. Additionally, medication costs may be reduced by prioritizing first-line treatments and volume-driven purchasing as program scale-up continues.

BACKGROUND: In 2020, a pilot program for hypertension control was initiated in primary care facilities in Lampang Province, Thailand. The program followed the framework of the HEARTS program for standardized hypertension treatment, but the financial costs of the program are not well understood. This study evaluates the costs of the HEARTS approach compared to usual care to inform future scale-up efforts of the program. METHODS: Cost data were collected and analyzed using the HEARTS costing tool, a Microsoft Excel-based tool that supports activity-based costing of the HEARTS program from the health system perspective. Three scenarios were considered: usual care, the HEARTS regimen using standardized hypertension treatment with single-agent pills, and a sub-scenario of the HEARTS regimen using single-pill dual-drug combination pills. Costs are estimated as annual costs from the health system perspective in all Lampang primary care facilities. RESULTS: For the usual care scenario, the HEARTS single-pill scenario, and the HEARTS combination-pill sub-scenario, the average annual medication cost per treated patient was USD 14.0 (THB 485), USD 13.8 (THB 479), and USD 14.3 (THB 497), respectively. Total program cost per primary care user was USD 13.6 (THB 472.7), THB USD 14.3 (494.5), and USD 14.4 (THB 499.9) across the three scenarios, respectively. The largest program cost driver (45-47% across the examined scenarios) was attributed to a comprehensive package of laboratory tests applied to all hypertension patients. Hypothetically, reducing test coverage from all hypertension patients (27% of primary care users) to 15% of primary care users (corresponding to the proportion of patients aged 65+) would reduce program cost per user from USD 14.3 to USD 12.0 in the HEARTS combination-pill scenario. CONCLUSIONS: Compared to usual care, HEARTS implementation costs include additional costs for staff training, which are balanced by lower medication expenditures using the HEARTS standardized regimen with single-agent pills. The HEARTS regimen using dual-drug combination pills was estimated to be slightly more costly due to the higher price of combination pills. Optimizing coverage of diagnostic tests and lowering the purchasing prices of combination-pill medicines are key areas for cost reduction in future scale-up efforts.

BACKGROUND: In 2021, the Philippines launched the Healthy Hearts demonstration project for delivering hypertension (HTN) services in seven Rural Health Units (RHUs) in District 1 of Iloilo Province, West Visayas Region. This study evaluates the provider time cost and medication cost of delivering these services under three medication procurement scenarios, projecting them to the district and province levels to inform scaling-up efforts. METHODS: A mixed-methods design was used for cost data collection, including key informant interviews (KII), focus group discussions (FGD), and secondary data sources. The HEARTS costing tool was adapted to analyze program costs per patient from the health system perspective. Three scenarios were assessed, depending on the procurement scheme of HTN medications: baseline local government procurement, pooled procurement through the Philippine Pharma Procurement Inc. (PPPI) national pooling mechanism, and private pharmacy outsourcing. We assessed annual provider labor costs and medication costs per patient for each scenario. RESULTS: The average provider cost per patient was considerably lower for patients with controlled HTN than for patients with uncontrolled HTN: USD 5 (range USD 3.4-6.1 across RHUs) vs. USD 32.9 (range USD 28.8-38.4)) due to the need for more frequent follow-up visits for the latter. Average medication costs per patient were estimated at USD 9.1 (range USD 7.2-11.5) using local procurement prices, USD 2.9 (range USD 2.3-3.7) using PPPI pooled procurement prices, and USD 23 (range USD 17.9-30.5) using private pharmacy outsourced prices. The higher medicine costs in the pharmacy outsourcing scenario were partially offset by lower provider costs (an average reduction of USD 1.5 per patient per year) due to reduced on-site dispensing time in this scenario. CONCLUSIONS: The findings from this study indicate two key opportunities for cost savings in HTN management in the Philippines' rural health units system: 1) enhancing the control of HTN, thereby reducing the need for follow-up visits and cutting down on provider time costs, and 2) utilizing pooled medication procurement mechanisms such as through the Philippine Pharma Procurement Inc. Provider time costs can also be partially reduced through outsourcing the dispensing of medications to private pharmacies, although doing so is currently associated with higher medication costs, further underscoring the utility of pooled procurement mechanisms for essential hypertension medicines.

BACKGROUND: In 2016, Uganda introduced services for hypertension and diabetes in selected HIV clinics. We evaluated the costs associated with scaling up these services in HIV clinics in Mbarara and Ibanda districts, Uganda. METHODS: We estimated the annual costs of providing hypertension and diabetes services using an activity-based costing approach from the health system perspective in ten randomly selected HIV clinics in Mbarara and Ibanda districts. Cost inputs included 2023 data on costs of medications, health provider time, salaries, training costs, and monitoring costs. We determined the average annual cost and medication costs for hypertension and diabetes treatment per enrolled adult patient, stratified by type of health facility. RESULTS: The total annual cost of hypertension and diabetes management services in ten selected HIV clinics was estimated to be $413,850 (range: $8,386 - 186,973). The annual average clinic-level cost per enrolled patient was estimated at $14 (range: $7 - 31). Of the total annual cost, the cost of provider time for initial and follow-up visits represented the largest cost component in 5/10 clinics (mean: 37%, range [13-58%]). In 4/10 clinics, the major cost components were the costs of medication, diagnostic tests, and related supplies (mean: 37%, range [10-75%]). The average cost per enrolled adult patient was $11 at public facilities and $21 in private not-for-profit facilities. The average medication cost per patient for hypertension was $24 (range: $7 - 97) annually; $13 at public facilities and $50 at private not-for-profit facilities. For diabetes treatment, the average annual medication cost per patient was estimated at $14 (range: $6 - 35); $11 at public facilities and $22 at private not-for-profit facilities. CONCLUSION: Adding hypertension and diabetes management to routine HIV care might be feasible based on the estimated annual cost per patient. Hypertension and diabetes treatment was more costly in private not-for-profit facility-based clinics than at public facilities. This variation was primarily driven by higher medication procurement prices at private facilities, revealing a potential area for optimizing costs through improved procurement practices.

Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021-22 and 2022-23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021-22 and 12 out of 18 models in 2022-23. Averaging across all forecast targets, the FluSight ensemble is the 2(nd) most accurate model measured by WIS in 2021-22 and the 5(th) most accurate in the 2022-23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change.

Long-term follow-up of a cohort of unmarried girls who received one, two, or three doses of quadrivalent HPV vaccine, between 10 and 18 years of age, in an Indian multi-centric study allowed us to compare antibody responses between the younger and older age cohorts at 10-years post-vaccination, and study the impact of initiation of sexual activity and cervical HPV infections on antibody levels. Among the younger (10-14 years) recipients of a single dose, 97.7% and 98.2% had detectable binding antibody titers against HPV 16 and HPV 18 respectively at ten years post-vaccination. The proportions among those receiving a single dose at age 15-18 years were 92.3% and 94.2% against HPV 16 and HPV 18 respectively. Mean HPV 16 binding antibody titers were 2.1 folds (95%CI 1.4 to 3.3) higher in those vaccinated at ages 10-14 years, and 1.9 folds (95%CI 1.2 to 3.0) higher in those vaccinated at 15-18 years compared to mean titers seen in the unvaccinated women. Compared to previous timepoints of 36 or 48 months, binding antibodies against HPV 16 and neutralizing antibodies against both HPV 16 and HPV 18 were significantly higher at 10 years. This rise was more pronounced in participants vaccinated at 15-18 years. No association of marital status or cervical HPV infections was observed with the rise in titer. Durability of antibody response in single dose recipients correlated well with the high efficacy of a single dose against persistent HPV 16/18 infections irrespective of age at vaccination, as we reported earlier.

Ferrets represent an invaluable model for the study of influenza virus pathogenicity and transmissibility due to the ability of this species to recapitulate clinical symptoms of influenza infection present in humans. Ferrets are also employed for the study of bacterial pathogens that naturally infect humans at different anatomical sites, including the respiratory and gastrointestinal tracts. While viral and bacterial infection studies in isolation using animal models are important for furthering our understanding of pathogen biology and for the development of improved therapeutics, it is also critical to extend our knowledge to pathogen coinfections in vivo, to more closely examine interkingdom dynamics that may contribute to overall disease outcomes. Despite the increasing use of ferrets for studies with influenza virus, few reports have investigated influenza and bacterial coinfection challenges in ferrets. In this review, we discuss how ferrets have been employed to study a diverse range of both influenza viruses and bacterial species and summarize key studies that have utilized the ferret model for primary influenza virus challenge followed by secondary bacterial infection. These co-pathogenesis studies have provided critical insight into the dynamic interplay between these pathogens, underscoring the utility of ferrets as a model system for investigating influenza virus-bacteria interactions.

BACKGROUND: In 2020, Ethiopia launched the Ethiopia Hypertension Control Initiative (EHCI) program to improve hypertension care using the approach described in the WHO HEARTS technical package. OBJECTIVE: To estimate the costs of implementing the HEARTS program for hypertension control and cardiovascular disease (CVD) prevention in the primary care setting in Ethiopia for adult primary care users in the catchment area of five examined facilities. STUDY DESIGN: This study entails a program cost analysis using cross-sectional primary and secondary data. METHODS: Micro-costing facility surveys were used to assess activity costs related to training, counselling, screening, lab diagnosis, medications, monitoring, and start-up costs at five selected health facilities. Cost data were obtained from primary and secondary sources, and expert opinion. Annual costs from the health system perspective were estimated using the Excel-based HEARTS costing tool under two intervention scenarios - hypertension-only control and a CVD risk management program, which addresses diabetes and hypercholesterolemia in addition to hypertension. RESULTS: The estimated cost per adult primary care user was USD 5.3 for hypertension control and USD 19.3 for integrated CVD risk management. The estimated medication cost per person treated for hypertension was USD 9.0, whereas treating diabetes and high cholesterol would cost USD 15.4 and USD 15.3 per person treated, respectively. Medications were the major cost driver, accounting for 37% of the total cost in the hypertension control program. In the CVD risk management scenario, the proportions of medication and lab diagnostics of total costs were 18% and 64%, respectively. CONCLUSIONS: The results from this study can inform planning and budgeting for HEARTS scale-up to prevent CVD across Ethiopia.

Despite their importance for immunity against sexually transmitted infections (STIs), the composition of the female reproductive tract (FRT) memory CD4 T cell population in response to changes in the local tissue environment during the menstrual cycle remains poorly defined. Here we show that across humans, non-human primates (NHP), and mice, FRT CD4 T cells comprise distinct subsets corresponding to migratory memory (TMM) and resident memory (TRM) cells. TMM display tissue-itinerant trafficking characteristics, restricted FRT tissue distribution, with distinct transcriptional properties and effector responses to infection. CD4 T cell subset fluctuations synchronized with cycle-driven proinflammatory changes within the local tissue environment and oral administration of a CCR5 antagonist inhibited cycle phase-specific migratory T cell surveillance. This study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of memory T cell defense at the site of STI exposure. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Competition assays were conducted in vitro and in vivo to examine how the Delta (B.1.617.2) variant displaced the prototype Washington/1/2020 (WA/1) strain. While WA/1 virus exhibited a moderately increased proportion compared to that in the inoculum following co-infection in human respiratory cells, Delta variant possessed a substantial in vivo fitness advantage as this virus becoming predominant in both inoculated and contact animals. This work identifies critical traits of the Delta variant that likely played a role in it becoming a dominant variant and highlights the necessities of employing multiple model systems to assess the fitness of newly emerged SARS-CoV-2 variants.

Treatment as prevention (TasP) is an effective HIV prevention strategy. Our objectives were to explore TasP attitudes and beliefs among people with HIV (PWH) who are not engaged in care and to examine attitudes and beliefs by selected characteristics. We sampled PWH who had participated in the Medical Monitoring Project (MMP), a structured interview survey, from June 2018-May 2019 to participate in 60-minute semi-structured telephone interviews. We obtained sociodemographic and behavioral quantitative data from the MMP structured interview. We used applied thematic analysis to analyze the qualitative data and integrated the qualitative and quantitative data during analysis. Negative attitudes and beliefs, especially skepticism and mistrust, about TasP were pervasive. Only one participant who identified as female, was not sexually active, and had not heard of TasP held positive attitudes and beliefs about TasP. TasP messages should use clear and unambiguous language, address mistrust, and reach people who are not engaged in medical care.

Pathogenic recombination-activating gene 1 (RAG1) variants cause a phenotypic spectrum ranging from severe combined immunodeficiency (SCID) to combined immunodeficiency with granulomas and autoimmunity (CID-G/A), depending on residual recombinase activity.1-4 Our patient, a 12-year-old African American female with hypogammaglobulinemia and T-, B-cell lymphopenia, was diagnosed with CID at 5 years of age, with a history of recurrent herpes simplex virus (HSV) gingivostomatitis, bacterial pneumonia, and cutaneous abscess. She tolerated two doses of live measles–mumps–rubella (MMR) vaccine. She was referred to our facility for steroid-refractory sterile non-caseating cutaneous granulomas (Figure S1) affecting posterior thigh and midface, appearing at 9 years and with progressive lymphopenia (Figure 1A) concerning for a CID. Next-generation sequencing identified compound heterozygous pathogenic RAG1 variants, c.1187G>A, p.Arg396His and c.1566G>T, p.Trp522Cys (NM_000448.2). Residual recombinase activity is estimated at 40%–50% for RAG1-Trp522Cys and less than 5%–30% for RAG1-Arg396His.2, 5, 6

BACKGROUND: The recent World Health Organization recommendation supporting single-dose of HPV vaccine will significantly reduce programmatic cost, mitigate the supply shortage, and simplify logistics, thus allowing more low- and middle-income countries to introduce the vaccine. From a programmatic perspective the durability of protection offered by a single-dose will be a key consideration. The primary objectives of the present study were to determine whether recipients of a single-dose of quadrivalent HPV vaccine had sustained immune response against targeted HPV types (HPV 6,11,16,18) at 10 years post-vaccination and whether this response was superior to the natural antibody titres observed in unvaccinated women. METHODS: Participants received at age 10-18 years either one, two or three doses of the quadrivalent HPV vaccine. Serology samples were obtained at different timepoints up to 10 years after vaccination from a convenience sample of vaccinated participants and from age-matched unvaccinated women at one timepoint. The evolution of the binding and neutralizing antibody response was presented by dose received. 10-year durability of immune responses induced by a single-dose was compared to that after three doses of the vaccine and in unvaccinated married women. RESULTS: The dynamics of antibody response among the single-dose recipients observed over 120 months show stabilized levels 18 months after vaccination for all four HPV types. Although the HPV type-specific (binding or neutralizing) antibody titres after a single-dose were significantly inferior to those after three doses of the vaccine (lower bounds of GMT ratios < 0.5), they were all significantly higher than those observed in unvaccinated women following natural infections (GMT ratios: 2.05 to 4.04-fold higher). The results correlate well with the high vaccine efficacy of single-dose against persistent HPV 16/18 infections reported by us earlier at 10-years post-vaccination. CONCLUSION: Our study demonstrates the high and durable immune response in single-dose recipients of HPV vaccine at 10-years post vaccination.

Herpes zoster is a localized skin infection caused by reactivation of latent varicella-zoster virus. Tissue-resident T cells likely control skin infections. Zoster provides a unique opportunity to determine if focal reinfection of human skin boosts local or disseminated antigen-specific tissue-resident T cells. Here, we show virus-specific T cells are retained over one year in serial samples of rash site and contralateral unaffected skin of individuals recovered from zoster. Consistent with zoster resolution, viral DNA is largely undetectable on skin from day 90 and virus-specific B and T cells decline in blood. In skin, there is selective infiltration and long-term persistence of varicella-zoster virus-specific T cells in the rash site relative to the contralateral site. The skin T cell infiltrates express the canonical tissue-resident T cell markers CD69 and CD103. These findings show that zoster promotes spatially-restricted long-term retention of antigen-specific tissue-resident T cells in previously infected skin.

BACKGROUND: Differentiated care strategies are rapidly becoming the norm for HIV care delivery globally. Building upon an interest in tailoring antiretroviral therapy (ART) delivery for client-centered needs, the Ministry of Health and Population in Haiti formally endorsed multiple-month dispenses (MMD) in the 2016 national ART guidelines This study explores heterogeneity in retention in care with MMD for specific Haitian populations living with HIV and evaluates if a targeted algorithm for optimal ART prescription intervals is warranted in Haiti. METHODS: This study included ART-naïve individuals who started ART on or after January 1st, 2017 in Haiti. To identify subgroups in which to explore heterogeneity of retention, we implemented a double-lasso regression method to determine which individual characteristics would define the subgroups. Characteristics evaluated for potential subgroup definition included: sex, age category, WHO clinical stage, and body mass index category. We employed instrumental variable models to estimate the causal effect of increasing ART dispensing length on ART retention, by client subgroup. The outcome of interest was retention in care after one year in treatment. We then estimated the marginal effect of a 30-day increase to ART dispensing length to retention in care for each of these subgroups. RESULTS: There was evidence for heterogeneity in the effect of extending ART dispensing intervals on retention by WHO clinical stage. We observed significant improvements to retention in care at one year with a 30-day increase in ART dispense length for all subgroups defined by WHO clinical stages 1-4. The effects ranged from a 14.7% increase (95% CI: 12.4-17.0) to the likelihood of retention for people with HIV in WHO stage 1 to a 21.6% increase (95% CI: 18.7-24.5) to the likelihood of retention for those in WHO stage 3. CONCLUSIONS: All the subgroups defined by WHO clinical stage experienced a benefit of extending ART intervals to retention in care at one year. Though the effect did differ slightly by WHO stage, the effects went in the same direction and were of similar magnitude. Therefore, a standardized recommendation for MMD among those living with HIV and new on ART is appropriate for Haiti treatment guidelines.

Background: Multi-month dispensing (MMD) for antiretroviral therapy (ART) is a promising care strategy to improve HIV treatment adherence. The effectiveness of MMD in routine settings has not yet been evaluated within a causal inference framework. We analyzed data from a robust clinical data system to evaluate MMD in Haiti. Method(s): We assessed 1-year retention in care among 21,880 ART-naive HIV-positive persons who started ART on or after January 1, 2017, up until November 1, 2018. We used an instrumental variable analysis to estimate the causal impact of MMD. This approach was used to address potential selection into specific dispensing intervals because MMD is not randomly applied to individuals. Finding(s): We found that extending ART dispensing intervals increased the probability of retention at 12 months after ART initiation, with up to a 24.2%-point increase (95%CI: 21.9, 26.5) in the likelihood of retention with extending dispenses by 30 days for those receiving one-month dispenses. We observed statistically significant gains to retention with MMD with up to an approximately 4-month supply of ART; +5.1%-points (95%CI: 2.4,7.8). Increasing dispensing lengths for those already receiving >=5-month supply of ART had a potentially negative effect on retention. Interpretation(s): MMD for ART is an effective service delivery strategy that improves care retention for new ART recipients. There is a potentially negative effect of increasing prescription lengths for those new ART recipients already receiving longer ART supplies, though more research is needed to characterize this effect given medication supplies of this length are not common for newer ART recipients. Copyright © 2021 The Author(s)

BACKGROUND: Pediatric tuberculosis (TB), human immunodeficiency virus (HIV), and TB-HIV co-infection are health problems with evidence-based diagnostic and treatment algorithms that can reduce morbidity and mortality. Implementation and operational barriers affect adherence to guidelines in many resource-constrained settings, negatively affecting patient outcomes. This study aimed to assess performance in the pediatric HIV and TB care cascades in Mozambique. METHODS: A retrospective analysis of routine PEPFAR site-level HIV and TB data from 2012 to 2016 was performed. Patients 0-14 years of age were included. Descriptive statistics were used to report trends in TB and HIV indicators. Linear regression was done to assess associations of site-level variables with performance in the pediatric TB and HIV care cascades using 2016 data. RESULTS: Routine HIV testing and cotrimoxazole initiation for co-infected children in the TB program were nearly optimal at 99% and 96% in 2016, respectively. Antiretroviral therapy (ART) initiation was lower at 87%, but steadily improved from 2012 to 2016. From the HIV program, TB screening at the last consultation rose steadily over the study period, reaching 82% in 2016. The percentage of newly enrolled children who received either TB treatment or isoniazid preventive treatment (IPT) also steadily improved in all provinces, but in 2016 was only at 42% nationally. Larger volume sites were significantly more likely to complete the pediatric HIV and TB care cascades in 2016 (p value range 0.05 to < 0.001). CONCLUSIONS: Mozambique has made significant strides in improving the pediatric care cascades for children with TB and HIV, but there were missed opportunities for TB diagnosis and prevention, with IPT utilization being particularly problematic. Strengthened TB/HIV programming that continues to focus on pediatric ART scale-up while improving delivery of TB preventive therapy, either with IPT or newer rifapentine-based regimens for age-eligible children, is needed.

INTRODUCTION: Whether existing serological assays are sufficiently robust to measure the lower antibody levels expected following single-dose HPV vaccination is unknown. METHODS: We evaluated seven assays measuring HPV-16/18 immunological responses overall and by number of doses in 530 serum samples from participants receiving varying doses of Cervarix or Gardasil up to 36-months post-vaccination. Serum was evaluated by simplex (HPV-16 ELISA, HPV-18 ELISA), multiplex (LIA-4, VLP-MIA, M9ELISA, GST-L1), and high-throughput pseudovirion-based neutralization assays (HT-PBNA), and results were compared to the gold standard HPV-16/18 secreted alkaline phosphatase neutralization assay (SEAP-NA). Reproducibility was assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Percent agreement, Pearson correlation, and weighted-kappa were used to assess validity. Determinants of seronegativity were evaluated by chi-squared test. RESULTS: HPV-16: Seropositivity range was 97.1-99.5% for single dose and 98.8-99.8% overall. CV range was 4.0-18.0% for single dose and 2.9-19.5% overall. ICC range was 0.77-0.99 for single dose and 0.74-0.99 overall. Correlation with SEAP-NA range was 0.43-0.85 for single dose and 0.51-0.90 overall. Weighted-kappa range was 0.34-0.82 for single dose and 0.45-0.84 overall. HPV-18: Seropositivity range was 63.9-94.7% for single dose and 86.2-97.9% overall. CV range was 8.1-18.2% for single dose and 4.6-18.6% overall. ICC range was 0.75-0.99 for single dose and 0.83-0.99 overall. Correlation with SEAP-NA range was 0.31-0.99 for single dose and 0.27-0.96 overall. Weighted-kappa range was 0.35-0.83 for single dose and 0.45-0.84 overall. HPV-16 seronegativity was <5% for all assays. HPV-18 seronegativity range was 5.5-17.3%. For LIA-4 and GST-L1 where the proportion of seronegativity was >10%, the strongest correlates of seronegativity were receiving a single vaccine dose and receiving Gardasil. CONCLUSIONS: These results support the utility of existing serological assays to monitor antibody responses following single-dose HPV vaccination.

Cancer Informatics for Cancer Centers (CI4CC) is a grassroots, nonprofit 501c3 organization intended to provide a focused national forum for engagement of senior cancer informatics leaders, primarily aimed at academic cancer centers anywhere in the world but with a special emphasis on the 70 National Cancer Institute-funded cancer centers. Although each of the participating cancer centers is structured differently, and leaders' titles vary, we know firsthand there are similarities in both the issues we face and the solutions we achieve. As a consortium, we have initiated a dedicated listserv, an open-initiatives program, and targeted biannual face-to-face meetings. These meetings are a place to review our priorities and initiatives, providing a forum for discussion of the strategic and pragmatic issues we, as informatics leaders, individually face at our respective institutions and cancer centers. Here we provide a brief history of the CI4CC organization and meeting highlights from the latest CI4CC meeting that took place in Napa, California from October 14-16, 2019. The focus of this meeting was "intersections between informatics, data science, and population science." We conclude with a discussion on "hot topics" on the horizon for cancer informatics.

A long-acting injectable formulation of the HIV integrase inhibitor cabotegravir (CAB-LA) is currently in clinical development for PrEP. Although the long plasma half-life of CAB-LA is an important attribute for PrEP, it also raises concerns about drug resistance emergence if someone becomes infected with HIV, or if PrEP is initiated during undiagnosed acute infection. Here we use a macaque model of SHIV infection to model risks of drug resistance to CAB-LA PrEP. Six macaques infected with SHIV received CAB-LA before seroconversion. We show integrase mutations G118R, E92G/Q, or G140R in plasma from 3/6 macaques as early as day 57, and identify G118R and E92Q in viruses from vaginal and rectal fluids. G118R and G140R confer > 800-fold resistance to CAB and cross-resistance to all licensed integrase inhibitors. Our results emphasize the need for appropriate HIV testing strategies before and possibly shortly after initiating CAB LA PrEP to exclude acute infection.

OBJECTIVE: Loose-fitting powered air-purifying respirators (PAPRs) are increasingly being used in healthcare. NIOSH has previously used advanced manikin headforms to develop methods to evaluate filtering facepiece respirator fit; research has now begun to develop methods to evaluate PAPR performance using headforms. This preliminary study investigated the performance of PAPRs at different work rates to support development of a manikin-based test method. METHODS: Manikin penetration factors (mPF) of three models of loose-fitting PAPRs were measured at four different work rates (REST: 11 Lpm, LOW: 25 Lpm, MODERATE: 48 Lpm, and HIGH: 88 Lpm) using a medium-sized NIOSH static advanced headform mounted onto a torso. In-mask differential pressure was monitored throughout each test. Two condensation particle counters were used to measure the sodium chloride aerosol concentrations in the test chamber and also inside the PAPR facepiece over a 2-minute sample period. Two test system configurations were evaluated for returning air to the headform in the exhalation cycle (filtered and unfiltered). Geometric mean (GM) and 5th percentile mPFs for each model/work rate combination were computed. Analysis of variance tests were used to assess the variables affecting mPF. RESULTS: PAPR model, work rate, and test configuration significantly affected PAPR performance. PAPR airflow rates for the three models were approximately 185, 210, and 235 Lpm. All models achieved GM mPFs and 5(th) percentile mPFs greater than their designated Occupational Safety and Health Administration assigned protection factors despite negative minimum pressures observed for some work rate/model combinations. CONCLUSIONS: PAPR model, work rate, and test configuration affect PAPR performance. Advanced headforms have potential for assessing PAPR performance once test methods can be matured. A manikin-based inward leakage test method for PAPRs can be further developed using the knowledge gained from this study. Future studies should vary PAPR airflow rate to better understand the effects on performance. Additional future research is needed to evaluate the correlation of PAPR performance using advanced headforms to the performance measured with human subjects.

Zika virus (ZIKV) is a mosquito-borne flavivirus that has rapidly extended its geographic range around the world. Its association with abnormal fetal brain development, sexual transmission, and lack of a preventive vaccine have constituted a global health concern. Designing a safe and effective vaccine requires significant caution due to overlapping geographical distribution of ZIKV with dengue virus (DENV) and other flaviviruses, possibly resulting in more severe disease manifestations in flavivirus immune vaccinees such as Antibody-Dependent Enhancement (ADE, a phenomenon involved in pathogenesis of DENV, and a risk associated with ZIKV vaccines using the envelope proteins as immunogens). Here, we describe the development of an alternative vaccine strategy encompassing the expression of ZIKV non-structural-1 (NS1) protein from a clinically proven safe, Modified Vaccinia Ankara (MVA) vector, thus averting the potential risk of ADE associated with structural protein-based ZIKV vaccines. A single intramuscular immunization of immunocompetent mice with the MVA-ZIKV-NS1 vaccine candidate provided robust humoral and cellular responses, and afforded 100% protection against a lethal intracerebral dose of ZIKV (strain MR766). This is the first report of (i) a ZIKV vaccine based on the NS1 protein and (ii) single dose protection against ZIKV using an immunocompetent lethal mouse challenge model.

BACKGROUND: The quality of variable number of tandem repeats (VNTR) typing of Mycobacterium tuberculosis was first investigated in 2009 in 37 laboratories worldwide. The results revealed an inter- and intra-laboratory reproducibility of respectively 60% and 72%. These data spurred an improvement in laboratory-specific assays and global standardisation of VNTR typing. OBJECTIVE: To measure the effects of the technical improvements and increased standardisation, a test panel consisting of 30 M. tuberculosis complex DNA samples was distributed for VNTR typing in 41 participating laboratories from 36 countries. RESULTS: The inter- and intra-laboratory reproducibility increased overall to respectively 78% and 88%. The 33 laboratories that participated in both the first and second proficiency studies improved their inter- and intra-laboratory reproducibility from 62% and 72% to respectively 79% and 88%. The largest improvement in reproducibility was detected in 10 laboratories that use an in-house polymerase chain reaction technique and perform amplicon sizing using gel electrophoresis. Detailed error analysis revealed a reduction in the number of systematic errors, sample exchange events and non-amplifiable loci. CONCLUSION: This second worldwide proficiency study indicates a substantial increase in the reproducibility of VNTR typing of M. tuberculosis. This will contribute to a more meaningful interpretation of molecular epidemiological and phylogenetic studies on the M. tuberculosis complex.

Although infections with "natural" West Nile virus (WNV) and the chimeric W956IC WNV infectious clone virus produce comparable peak virus yields in type I interferon (IFN) response-deficient BHK cells, W956IC infection produces higher levels of "unprotected" viral RNA at early times after infection. Analysis of infections with these two viruses in IFN-competent cells showed that W956IC activated NF-kappaB, induced higher levels of IFN-beta, and produced lower virus yields than WNV strain Eg101. IPS-1 was required for both increased induction of IFN-beta and decreased yields of W956IC. In Eg101-infected cells, phospho-STAT1/STAT2 nuclear translocation was blocked at all times analyzed, while some phospho-STAT1/STAT2 nuclear translocation was still detected at 8 h after infection in W956IC-infected mouse embryonic fibroblasts (MEFs), and early viral protein levels were lower in these cells. A set of additional chimeras was made by replacing various W956IC gene regions with the Eg101 equivalents. As reported previously, for three of these chimeras, the low early RNA phenotype of Eg101 was restored in BHK cells. Analysis of infections with two of these chimeric viruses in MEFs detected lower early viral RNA levels, higher early viral protein levels, lower early IFN-beta levels, and higher virus yields similar to those seen after Eg101 infection. The data suggest that replicase protein interactions directly or indirectly regulate genome switching between replication and translation at early times in favor of translation to minimize NF-kappaB activation and IFN induction by decreasing the amount of unprotected viral RNA, to produce sufficient viral protein to block canonical type I IFN signaling, and to efficiently remodel cell membranes for exponential genome amplification.

Serotype G9 strains have been detected sporadically and in localized outbreaks in various African countries, including South Africa, Botswana, Malawi, Kenya, Cameroon, Nigeria, Ghana, Guinea-Bissau, Libya, and Mauritius. Serotype G9 strains were analyzed to investigate genogroup characteristics, including subgroup specificity, electropherotype, and P and G genotypes. In addition, the antigenic composition of the South African G9 strains was assessed. African G9 strains were associated with both DS-1-like characteristics and Wa-like characteristics, indicating the predisposition of G9 strains to frequently reassort. Despite these reassortment events, serotype G9 strains appear to maintain antigenic character in the outer capsid protein, as evident with the reaction of the South African G9 strains with the G9-specific monoclonal antibody F45:1. Phylogenetic analysis clustered African G9 strains geographically, regardless of genogroup characteristics, into 1 lineage (IIId). Two groups of G9 strains, originating in India and Japan, were identified in this lineage. Continuous surveillance of circulating rotavirus strains in Africa is vital to prepare for future vaccine implementation on a continent that clearly needs such preventative medicines.