Mapping HIV prevalence in sub-Saharan Africa between 2000 and 2017.

HIV/AIDS is a leading cause of disease burden in sub-Saharan Africa. Existing evidence has demonstrated that there is substantial local variation in the prevalence of HIV; however, subnational variation has not been investigated at a high spatial resolution across the continent. Here we explore within-country variation at a 5 × 5-km resolution in sub-Saharan Africa by estimating the prevalence of HIV among adults (aged 15-49 years) and the corresponding number of people living with HIV from 2000 to 2017. Our analysis reveals substantial within-country variation in the prevalence of HIV throughout sub-Saharan Africa and local differences in both the direction and rate of change in HIV prevalence between 2000 and 2017, highlighting the degree to which important local differences are masked when examining trends at the country level. These fine-scale estimates of HIV prevalence across space and time provide an important tool for precisely targeting the interventions that are necessary to bringing HIV infections under control in sub-Saharan Africa.

Frequency of HIV serodifferent couples within TB-affected households in a setting with a high burden of HIV-associated TB.

INTRODUCTION: Strong epidemiological links between human immunodeficiency virus (HIV) and tuberculosis (TB) may make household TB contact investigation an efficient strategy for HIV screening and finding individuals in serodifferent partnerships at risk of HIV and linking them to HIV prevention services. We aimed to compare the proportions of HIV serodifferent couples in TB-affected households and in the general population of Kampala, Uganda. METHODS: We included data from a cross-sectional trial of HIV counselling and testing (HCT) in the context of home-based TB evaluation in Kampala, Uganda in 2016-2017. After obtaining consent, community health workers visited the homes of participants with TB to screen contacts for TB and offer HCT to household members ≥ 15 years. We defined index participants and their spouses or parents as couples. Couples were classified as serodifferent if confirmed by self-reported HIV status or by HIV testing results. We used a two-sample test of proportions to compare the frequency of HIV serodifference among couples in the study to its prevalence among couples in Kampala in the 2011 Uganda AIDS Indicator Survey (UAIS). RESULTS: We included 323 index TB participants and 507 household contacts aged ≥ 18 years. Most index participants (55%) were male, while most (68%) adult contacts were female. There was ≥ 1 couple in 115/323 (35.6%) households, with most couples (98/115, 85.2%) including the index participant and spouse. The proportion of households with HIV-serodifferent couples was 18/323 (5.6%), giving a number-needed-to-screen of 18 households. The proportion of HIV serodifference among couples identified in the trial was significantly higher than among couples in the UAIS (15.7% vs. 8%, p = 0.039). The 18 serodifferent couples included 14 (77.8%) where the index participant was living with HIV and the spouse was HIV-negative, and 4 (22.2%) where the index partner was HIV-negative, while the spouse was living with HIV. CONCLUSIONS: The frequency of HIV serodifference among couples identified in TB-affected households was higher than in the general population. TB household contact investigation may be an efficient strategy for identifying people with substantial exposure to HIV and linking them to HIV prevention services.

Navigating the Storm of COVID-19 Literature Through Academic-Practice Partnership in Washington State: The COVID-19 Literature Situation Report.

CONTEXT: Shortly after the first COVID-19 case in the United States was identified in Washington, the Washington State Department of Health (WA DOH) determined that real-time knowledge of scientific findings related to SARS-CoV-2 was critical for an effective response. Epidemiologists at the WA DOH established the Daily Literature Situation Report (Lit Rep), within the agency's incident management team, to support public health and state leaders in evidence-based decision making. However, from January to May, the scale of the pandemic response and daily volume of emerging information grew beyond the capacity of the WA DOH epidemiology team tasked with gathering, reviewing, summarizing, and disseminating it daily. OBJECTIVE: To ensure public health leaders maintained awareness of the rapidly evolving scientific literature during the pandemic to support evidence-based practice. DESIGN: The WA DOH contracted the University of Washington (UW) Alliance for Pandemic Preparedness to assemble a team of faculty and students to continue producing the Lit Rep. MAIN OUTCOME: In addition to the daily Lit Rep, the UW team developed in-depth reports addressing questions from public health leadership and further evolved the methodology for the daily reports to support long-term sustainability and broader accessibility. RESULTS: Throughout its existence, the Lit Rep had summarized more than 4300 articles from more than 150 000 citations and had more than 5600 subscribers from public health practice, academia, and the general public, both domestic and international. CONCLUSIONS: The flexible Lit Rep model sets a standard for responding to emerging public health threats and communicating complex scientific information to government leaders, public health staff, and other interested parties. The WA DOH and the UW have exemplified how a mutually beneficial partnership can be established to support more effective public health practice based on real-time evidence both during a crisis and potentially for future public health challenges.

Variation in Childhood Diarrheal Morbidity and Mortality in Africa, 2000-2015.

BACKGROUND: Diarrheal diseases are the third leading cause of disease and death in children younger than 5 years of age in Africa and were responsible for an estimated 30 million cases of severe diarrhea (95% credible interval, 27 million to 33 million) and 330,000 deaths (95% credible interval, 270,000 to 380,000) in 2015. The development of targeted approaches to address this burden has been hampered by a paucity of comprehensive, fine-scale estimates of diarrhea-related disease and death among and within countries. METHODS: We produced annual estimates of the prevalence and incidence of diarrhea and diarrhea-related mortality with high geographic detail (5 km2) across Africa from 2000 through 2015. Estimates were created with the use of Bayesian geostatistical techniques and were calibrated to the results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. RESULTS: The results revealed geographic inequality with regard to diarrhea risk in Africa. Of the estimated 330,000 childhood deaths that were attributable to diarrhea in 2015, more than 50% occurred in 55 of the 782 first-level administrative subdivisions (e.g., states). In 2015, mortality rates among first-level administrative subdivisions in Nigeria differed by up to a factor of 6. The case fatality rates were highly varied at the national level across Africa, with the highest values observed in Benin, Lesotho, Mali, Nigeria, and Sierra Leone. CONCLUSIONS: Our findings showed concentrated areas of diarrheal disease and diarrhea-related death in countries that had a consistently high burden as well as in countries that had considerable national-level reductions in diarrhea burden. (Funded by the Bill and Melinda Gates Foundation.).

Interferon-gamma release assay levels and risk of progression to active tuberculosis: a systematic review and dose-response meta-regression analysis.

BACKGROUND: Identifying and treating individuals with high risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease is critical for eliminating the disease. We aimed to conduct a systematic review and meta-regression analysis to quantify the dose-response relationship between interferon-gamma release assay (IGRA) levels and the risk of progression to active TB. METHODS: We searched PubMed and Embase from 1 January 2001 to 10 May 2020 for longitudinal studies that reported the risk of progression from latent to active TB as a function of baseline IGRA values. We used a novel Bayesian meta-regression method to pool effect sizes from included studies and generate a continuous dose-response risk curve. Our modeling framework enabled us to incorporate random effects across studies, and include data with different IGRA ranges across studies. The quality of included studies were assessed using the Newcastle-Ottawa scale (NOS). RESULTS: We included 34 studies representing 581,956 person-years of follow-up with a total of 788 incident cases of TB in the meta-regression analysis. Higher levels of interferon-gamma were associated with increased risk of progression to active tuberculosis. In the dose-response curve, the risk increased sharply between interferon-gamma levels 0 and 5 IU/ml, after which the risk continued to increase moderately but at a slower pace until reaching about 15 IU/ml where the risk levels off. Compared to 0 IU/ml, the relative risk of progression to active TB among those with interferon-gamma levels of 0.35, 1, 5, 10, 15, and 20 IU/ml were: 1.64 (1.28-2.08), 2.90 (2.02-3.88), 11.38 (6.64-16.38), 19.00 (13.08-26.90), 21.82 (14.65-32.57), and 22.31 (15.43-33.00), respectively. The dose-response relationship remains consistent when limiting the analysis to studies that scored highest in the NOS. CONCLUSION: The current practice of dichotomizing IGRA test results simplifies the TB infection disease continuum. Evaluating IGRA test results over a continuous scale could enable the identification of individuals at greatest risk of progression to active TB.

Xpert MTB/RIF and Xpert Ultra assays for screening for pulmonary tuberculosis and rifampicin resistance in adults, irrespective of signs or symptoms.

BACKGROUND: Tuberculosis is a leading cause of infectious disease-related death and is one of the top 10 causes of death worldwide. The World Health Organization (WHO) recommends the use of specific rapid molecular tests, including Xpert MTB/RIF or Xpert Ultra, as initial diagnostic tests for the detection of tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. However, the WHO estimates that nearly one-third of all active tuberculosis cases go undiagnosed and unreported. We were interested in whether a single test, Xpert MTB/RIF or Xpert Ultra, could be useful as a screening test to close this diagnostic gap and improve tuberculosis case detection. OBJECTIVES: To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for screening for pulmonary tuberculosis in adults, irrespective of signs or symptoms of pulmonary tuberculosis in high-risk groups and in the general population. Screening "irrespective of signs or symptoms" refers to screening of people who have not been assessed for the presence of tuberculosis symptoms (e.g. cough). To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for detecting rifampicin resistance in adults screened for tuberculosis, irrespective of signs and symptoms of pulmonary tuberculosis in high-risk groups and in the general population. SEARCH METHODS: We searched 12 databases including the Cochrane Infectious Diseases Group Specialized Register, MEDLINE and Embase, on 19 March 2020 without language restrictions. We also reviewed reference lists of included articles and related Cochrane Reviews, and contacted researchers in the field to identify additional studies. SELECTION CRITERIA: Cross-sectional and cohort studies in which adults (15 years and older) in high-risk groups (e.g. people living with HIV, household contacts of people with tuberculosis) or in the general population were screened for pulmonary tuberculosis using Xpert MTB/RIF or Xpert Ultra. For tuberculosis detection, the reference standard was culture. For rifampicin resistance detection, the reference standards were culture-based drug susceptibility testing and line probe assays. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardized form and assessed risk of bias and applicability using QUADAS-2. We used a bivariate random-effects model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs) separately for tuberculosis detection and rifampicin resistance detection. We estimated all models using a Bayesian approach. For tuberculosis detection, we first estimated screening accuracy in distinct high-risk groups, including people living with HIV, household contacts, people residing in prisons, and miners, and then in several high-risk groups combined. MAIN RESULTS: We included a total of 21 studies: 18 studies (13,114 participants) evaluated Xpert MTB/RIF as a screening test for pulmonary tuberculosis and one study (571 participants) evaluated both Xpert MTB/RIF and Xpert Ultra. Three studies (159 participants) evaluated Xpert MTB/RIF for rifampicin resistance. Fifteen studies (75%) were conducted in high tuberculosis burden and 16 (80%) in high TB/HIV-burden countries. We judged most studies to have low risk of bias in all four QUADAS-2 domains and low concern for applicability. Xpert MTB/RIF and Xpert Ultra as screening tests for pulmonary tuberculosis In people living with HIV (12 studies), Xpert MTB/RIF pooled sensitivity and specificity (95% CrI) were 61.8% (53.6 to 69.9) (602 participants; moderate-certainty evidence) and 98.8% (98.0 to 99.4) (4173 participants; high-certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 40 would be Xpert MTB/RIF-positive; of these, 9 (22%) would not have tuberculosis (false-positives); and 960 would be Xpert MTB/RIF-negative; of these, 19 (2%) would have tuberculosis (false-negatives). In people living with HIV (1 study), Xpert Ultra sensitivity and specificity (95% CI) were 69% (57 to 80) (68 participants; very low-certainty evidence) and 98% (97 to 99) (503 participants; moderate-certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 53 would be Xpert Ultra-positive; of these, 19 (36%) would not have tuberculosis (false-positives); and 947 would be Xpert Ultra-negative; of these, 16 (2%) would have tuberculosis (false-negatives). In non-hospitalized people in high-risk groups (5 studies), Xpert MTB/RIF pooled sensitivity and specificity were 69.4% (47.7 to 86.2) (337 participants, low-certainty evidence) and 98.8% (97.2 to 99.5) (8619 participants, moderate-certainty evidence). Of 1000 people where 10 have tuberculosis on culture, 19 would be Xpert MTB/RIF-positive; of these, 12 (63%) would not have tuberculosis (false-positives); and 981 would be Xpert MTB/RIF-negative; of these, 3 (0%) would have tuberculosis (false-negatives). We did not identify any studies using Xpert MTB/RIF or Xpert Ultra for screening in the general population. Xpert MTB/RIF as a screening test for rifampicin resistance Xpert MTB/RIF sensitivity was 81% and 100% (2 studies, 20 participants; very low-certainty evidence), and specificity was 94% to 100%, (3 studies, 139 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Of the high-risks groups evaluated, Xpert MTB/RIF applied as a screening test was accurate for tuberculosis in high tuberculosis burden settings. Sensitivity and specificity were similar in people living with HIV and non-hospitalized people in high-risk groups. In people living with HIV, Xpert Ultra sensitivity was slightly higher than that of Xpert MTB/RIF and specificity similar. As there was only one study of Xpert Ultra in this analysis, results should be interpreted with caution. There were no studies that evaluated the tests in people with diabetes mellitus and other groups considered at high-risk for tuberculosis, or in the general population.

Progress toward eliminating TB and HIV deaths in Brazil, 2001-2015: a spatial assessment.

BACKGROUND: Brazil has high burdens of tuberculosis (TB) and HIV, as previously estimated for the 26 states and the Federal District, as well as high levels of inequality in social and health indicators. We improved the geographic detail of burden estimation by modelling deaths due to TB and HIV and TB case fatality ratios for the more than 5400 municipalities in Brazil. METHODS: This ecological study used vital registration data from the national mortality information system and TB case notifications from the national communicable disease notification system from 2001 to 2015. Mortality due to TB and HIV was modelled separately by cause and sex using a Bayesian spatially explicit mixed effects regression model. TB incidence was modelled using the same approach. Results were calibrated to the Global Burden of Disease Study 2016. Case fatality ratios were calculated for TB. RESULTS: There was substantial inequality in TB and HIV mortality rates within the nation and within states. National-level TB mortality in people without HIV infection declined by nearly 50% during 2001 to 2015, but HIV mortality declined by just over 20% for males and 10% for females. TB and HIV mortality rates for municipalities in the 90th percentile nationally were more than three times rates in the 10th percentile, with nearly 70% of the worst-performing municipalities for male TB mortality and more than 75% for female mortality in 2001 also in the worst decile in 2015. The same municipality ranking metric for HIV was observed to be between 55% and 61%. Within states, the TB mortality rate ratios by sex for municipalities in the worst decile versus the best decile varied from 1.4 to 2.9, and HIV varied from 1.4 to 4.2. The World Health Organization target case fatality rate for TB of less than 10% was achieved in 9.6% of municipalities for males versus 38.4% for females in 2001 and improved to 38.4% and 56.6% of municipalities for males versus females, respectively, by 2014. CONCLUSIONS: Mortality rates in municipalities within the same state exhibited nearly as much relative variation as within the nation as a whole. Monitoring the mortality burden at this level of geographic detail is critical for guiding precision public health responses.

Global variation in bacterial strains that cause tuberculosis disease: a systematic review and meta-analysis.

BACKGROUND: The host, microbial, and environmental factors that contribute to variation in tuberculosis (TB) disease are incompletely understood. Accumulating evidence suggests that one driver of geographic variation in TB disease is the local ecology of mycobacterial genotypes or strains, and there is a need for a comprehensive and systematic synthesis of these data. The objectives of this study were to (1) map the global distribution of genotypes that cause TB disease and (2) examine whether any epidemiologically relevant clinical characteristics were associated with those genotypes. METHODS: We performed a systematic review of PubMed and Scopus to create a comprehensive dataset of human TB molecular epidemiology studies that used representative sampling techniques. The methods were developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We extracted and synthesized data from studies that reported prevalence of bacterial genotypes and from studies that reported clinical characteristics associated with those genotypes. RESULTS: The results of this study are twofold. First, we identified 206 studies for inclusion in the study, representing over 200,000 bacterial isolates collected over 27 years in 85 countries. We mapped the genotypes and found that, consistent with previously published maps, Euro-American lineage 4 and East Asian lineage 2 strains are widespread, and West African lineages 5 and 6 strains are geographically restricted. Second, 30 studies also reported transmission chains and 4 reported treatment failure associated with genotypes. We performed a meta-analysis and found substantial heterogeneity across studies. However, based on the data available, we found that lineage 2 strains may be associated with increased risk of transmission chains, while lineages 5 and 6 strains may be associated with reduced risk, compared with lineage 4 strains. CONCLUSIONS: This study provides the most comprehensive systematic analysis of the evidence for diversity in bacterial strains that cause TB disease. The results show both geographic and epidemiological differences between strains, which could inform our understanding of the global burden of TB. Our findings also highlight the challenges of collecting the clinical data required to inform TB diagnosis and treatment. We urge future national TB programs and research efforts to prioritize and reinforce clinical data collection in study designs and results dissemination.

Impact of Vaccination and Nonpharmaceutical Interventions With Possible COVID-19 Viral Evolutions Using an Agent-Based Simulation.

Introduction: The COVID-19 pandemic continues with highly contagious variants and waning immunity. As the virus keeps evolving to be more infectious and immune evasive, some question whether the COVID-19 pandemic can be managed through sustainable public health measures. Methods: We developed an agent-based simulation to explore the impact of COVID-19 mutations, periodic vaccinations, and nonpharmaceutical interventions on reducing COVID-19 deaths. The model is calibrated to the greater Seattle area by observing local epidemic data. We perform scenario analyses on viral mutations that change infectiousness, disease severity, and immune evasiveness from previous infections and vaccination every 6 months. The simulation is run until the end of year 2023. Results: Variants with increased infectivity or increased immune evasion dominate previous strains. With enhanced immune protection from a pancoronavirus vaccine, the most optimistic periodic vaccination rate reduces average total deaths by 44.6% compared with the most pessimistic periodic vaccination rate. A strict threshold nonpharmaceutical intervention policy reduces average total deaths by 71.3% compared with an open society, whereas a moderate nonpharmaceutical intervention policy results in a 33.6% reduction. Conclusions: Our findings highlight the potential benefits of pancoronavirus vaccines that offer enhanced and longer-lasting immunity. We emphasize the crucial role of nonpharmaceutical interventions in reducing COVID-19 deaths regardless of virus mutation scenarios. Owing to highly immune evasive and contagious SARS-CoV-2 variants, most scenarios in this study fail to reduce the mortality of COVID-19 to the level of influenza and pneumonia. However, our findings indicate that periodic vaccinations and a threshold nonpharmaceutical intervention policy may succeed in achieving this goal. This indicates the need for caution and vigilance in managing a continuing COVID-19 epidemic.

Modeled estimates of HIV-serodifferent couples in tuberculosis-affected households in four sub-Saharan African countries.

Household-based tuberculosis (TB) contact evaluation may be an efficient strategy to reach people who could benefit from oral pre-exposure prophylaxis (PrEP) because of the epidemiological links between HIV and TB. This study estimated the number of HIV serodifferent couples in TB-affected households and potential HIV acquisitions averted through their PrEP use in 4 TB-HIV high-burden countries. We conducted a model-based analysis set in Ethiopia, Kenya, South Africa, and Uganda using parameters from population-based household surveys, systematic literature review and meta-analyses, and estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. We parameterized the nonlinear relationship between the proportion of serodifferent couples among people living with HIV and population-level HIV prevalence using Markov chain Monte Carlo methods. We integrated all parameters in a mathematical model and propagated uncertainty using a Monte Carlo approach. We estimated the HIV prevalence among adults aged 15-49 living in TB-affected households to be higher than in the general population in all 4 countries. The proportion of serodifferent couples among all couples in TB-affected households was also higher than in the general population (South Africa: 20.7% vs. 15.7%, Kenya: 15.7% vs. 5.7%, Uganda: 14.5% vs. 6.0%, Ethiopia: 4.1% vs. 0.8%). We estimated that up to 1,799 (95% UI: 1,256-2,341) HIV acquisitions in South Africa could be prevented annually by PrEP use in serodifferent couples in TB-affected households, 918 (95% UI: 409-1,450) in Kenya, 686 (95% UI: 505-871) in Uganda, and 408 (95% UI: 298-522) in Ethiopia. As couples in TB-affected households are more likely to be serodifferent than couples in the general population, offering PrEP during household TB contact evaluation may prevent a substantial number of HIV acquisitions.

Preventing tuberculosis with community-based care in an HIV-endemic setting: a modelling analysis.

INTRODUCTION: Antiretroviral therapy (ART) and tuberculosis preventive treatment (TPT) both prevent tuberculosis (TB) disease and deaths among people living with HIV. Differentiated care models, including community-based care, can increase the uptake of ART and TPT to prevent TB in settings with a high burden of HIV-associated TB, particularly among men. METHODS: We developed a gender-stratified dynamic model of TB and HIV transmission and disease progression among 100,000 adults ages 15-59 in KwaZulu-Natal, South Africa. We drew model parameters from a community-based ART initiation and resupply trial in sub-Saharan Africa (Delivery Optimization for Antiretroviral Therapy, DO ART) and other scientific literature. We simulated the impacts of community-based ART and TPT care programmes during 2018-2027, assuming that community-based ART and TPT care were scaled up to similar levels as in the DO ART trial (i.e. ART coverage increasing from 49% to 82% among men and from 69% to 83% among women) and sustained for 10 years. We projected the number of TB cases, deaths and disability-adjusted life years (DALYs) averted relative to standard, clinic-based care. We calculated programme costs and incremental cost-effectiveness ratios from the provider perspective. RESULTS: If community-based ART care could be implemented with similar effectiveness to the DO ART trial, increased ART coverage could reduce TB incidence by 27.0% (range 21.3%-34.1%) and TB mortality by 34.6% (range 24.8%-42.2%) after 10 years. Increasing both ART and TPT uptake through community-based ART with TPT care could reduce TB incidence by 29.7% (range 23.9%-36.0%) and TB mortality by 36.0% (range 26.9%-43.8%). Community-based ART with TPT care reduced gender disparities in TB mortality rates, with a projected 54 more deaths annually among men than women (range 11-103) after 10 years of community-based care versus 109 (range 41-182) in standard care. Over 10 years, the mean cost per DALY averted by community-based ART with TPT care was $846 USD (range $709-$1012). CONCLUSIONS: By substantially increasing coverage of ART and TPT, community-based care for people living with HIV could reduce TB incidence and mortality in settings with high burdens of HIV-associated TB and reduce TB gender disparities.

Preventing tuberculosis with community-based care in an HIV-endemic setting: a modeling analysis.

Introduction: Antiretroviral therapy (ART) and TB preventive treatment (TPT) both prevent tuberculosis (TB) disease and deaths among people living with HIV. Differentiated care models, including community-based care, can increase uptake of ART and TPT to prevent TB in settings with a high burden of HIV-associated TB, particularly among men. Methods: We developed a gender-stratified dynamic model of TB and HIV transmission and disease progression among 100,000 adults ages 15-59 in KwaZulu-Natal, South Africa. We drew model parameters from a community-based ART initiation and resupply trial in sub-Saharan Africa (Delivery Optimization for Antiretroviral Therapy, DO ART) and other scientific literature. We simulated the impacts of community-based ART and TPT care programs during 2018-2027, assuming that community-based ART and TPT care were scaled up to similar levels as in the DO ART trial (i.e., ART coverage increasing from 49% to 82% among men and from 69% to 83% among women) and sustained for ten years. We projected the number of TB cases, deaths, and disability-adjusted life years (DALYs) averted relative to standard, clinic-based care. We calculated program costs and incremental cost-effectiveness ratios from the provider perspective. Results: If community-based ART care could be implemented with similar effectiveness to the DO ART trial, increased ART coverage could reduce TB incidence by 27.0% (range 21.3% - 34.1%) and TB mortality by 36.0% (range 26.9% - 43.8%) after ten years. Increasing both ART and TPT uptake through community-based ART with TPT care could reduce TB incidence by 29.7% (range 23.9% - 36.0%) and TB mortality by 36.0% (range 26.9% - 43.8%). Community-based ART with TPT care reduced gender disparities in TB mortality rates by reducing TB mortality among men by a projected 39.8% (range 32.2% - 46.3%) and by 30.9% (range 25.3% - 36.5%) among women. Over ten years, the mean cost per DALY averted by community-based ART with TPT care was $846 USD (range $709 - $1,012). Conclusions: By substantially increasing coverage of ART and TPT, community-based care for people living with HIV could reduce TB incidence and mortality in settings with high burdens of HIV-associated TB and reduce TB gender disparities.

Early Outcomes of SARS-CoV-2 Infection in a Multisite Prospective Cohort of Inpatient Veterans.

Background: Over 870 000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have occurred among Veterans Health Administration users, and 24 000 have resulted in death. We examined early outcomes of SARS-CoV-2 infection in hospitalized veterans. Methods: In an ongoing, prospective cohort study, we enrolled veterans age ≥18 tested for SARS-CoV-2 and hospitalized at 15 Department of Veterans Affairs medical centers between February 2021 and June 2022. We estimated adjusted odds ratios (aORs), adjusted incidence rate ratios (aIRRs), and adjusted hazard ratios (aHRs) for maximum illness severity within 30 days of study entry (defined using the 4-category VA Severity Index for coronavirus disease 2019 [COVID-19]), as well as length of hospitalization and rehospitalization within 60 days, in relationship with demographic characteristics, Charlson comorbidity index (CCI), COVID-19 vaccination, and calendar period of enrollment. Results: The 542 participants included 329 (61%) who completed a primary vaccine series (with or without booster; "vaccinated"), 292 (54%) enrolled as SARS-CoV-2-positive, and 503 (93%) men, with a mean age of 64.4 years. High CCI scores (≥5) occurred in 61 (44%) vaccinated and 29 (19%) unvaccinated SARS-CoV-2-positive participants. Severe illness or death occurred in 29 (21%; 6% died) vaccinated and 31 (20%; 2% died) unvaccinated SARS-CoV-2-positive participants. SARS-CoV-2-positive inpatients per unit increase in CCI had greater multivariable-adjusted odds of severe illness (aOR, 1.21; 95% CI, 1.01-1.45), more hospitalization days (aIRR, 1.06; 95% CI, 1.03-1.10), and rehospitalization (aHR, 1.07; 95% CI, 1.01-1.12). Conclusions: In a cohort of hospitalized US veterans with SARS-CoV-2 infection, those with a higher CCI had more severe COVID-19 illness, more hospital days, and rehospitalization, after adjusting for vaccination status, age, sex, and calendar period.

Estimated Health Outcomes and Costs of COVID-19 Prophylaxis With Monoclonal Antibodies Among Unvaccinated Household Contacts in the US.

Importance: The COVID-19 pandemic has led to more than 900 000 deaths in the US and continues to disrupt lives even as effective vaccines are available. Objective: To estimate the health outcomes and net cost of implementing postexposure prophylaxis (PEP) with monoclonal antibodies (mAbs) against household exposure to COVID-19. Design, Setting, and Participants: This study is a decision analytical model of results from a randomized clinical trial of casirivimab with imdevimab administered as subcutaneous injections to unvaccinated, SARS-CoV-2-negative household contacts of people with confirmed COVID-19 with complementary data on household demographic structure, vaccine coverage, and confirmed COVID-19 case counts. The study used US data from May 2021 for a simulated population of US individuals of all ages within low-transmission or high-transmission scenarios. Exposures: Age, sex, race, ethnicity, and COVID-19 vaccination status. Main Outcome or Measures: Symptomatic infection, hospitalization, death, and net payer cost of monoclonal antibody PEP for COVID-19. Results: In a month of transmission intensity similar to that of May 2021, a mAb PEP program reaching 50% of exposed, unvaccinated household members aged 50 years and older was estimated to avert 1820 symptomatic infections (95% uncertainty interval [UI], 1220-2454 symptomatic infections), 528 hospitalizations (95% UI, 354-724 hospitalizations), and 84 deaths (95% UI, 55-116 deaths) in a low-transmission scenario and 4834 symptomatic infections (95% UI, 3375-6257 symptomatic infections), 1404 hospitalizations (95% UI, 974-1827 hospitalizations), and 223 deaths (95% UI, 152-299 deaths) in a high-transmission scenario. Without mAb PEP, the estimated cost of hospitalizations due to COVID-19 infections from household exposure in the lower transmission scenario was $149 million (95% UI, $115-$196 million), whereas the estimated hospitalization cost in the higher transmission scenario was $400 million (95% UI, $312-$508 million). In the lower transmission scenario, mAb PEP administered to 50% of eligible contacts aged 80 years and older was estimated to have 82% probability of saving costs, but was not associated with cost savings at age thresholds of 50 years and older or 20 years and older. In contrast, in the high-transmission scenario, mAb PEP administered to 50% of eligible household contacts had estimated cost savings in 100% of simulations at the 80-year age threshold, 96% of simulations at the 50-year threshold, and 2% of simulations at the 20-year thresholds. Conclusions and Relevance: In this modeling study of a simulated US population, a mAb PEP for COVID-19 program was estimated to improve health outcomes and reduce costs. In the setting of a susceptible variant of SARS-CoV-2, health system and public health actors would have an opportunity to improve health and reduce net payer costs through COVID-19 PEP with mAbs.

TB Hackathon: Development and Comparison of Five Models to Predict Subnational Tuberculosis Prevalence in Pakistan.

Pakistan's national tuberculosis control programme (NTP) is among the many programmes worldwide that value the importance of subnational tuberculosis (TB) burden estimates to support disease control efforts, but do not have reliable estimates. A hackathon was thus organised to solicit the development and comparison of several models for small area estimation of TB. The TB hackathon was launched in April 2019. Participating teams were requested to produce district-level estimates of bacteriologically positive TB prevalence among adults (over 15 years of age) for 2018. The NTP provided case-based data from their 2010-2011 TB prevalence survey, along with data relating to TB screening, testing and treatment for the period between 2010-2011 and 2018. Five teams submitted district-level TB prevalence estimates, methodological details and programming code. Although the geographical distribution of TB prevalence varied considerably across models, we identified several districts with consistently low notification-to-prevalence ratios. The hackathon highlighted the challenges of generating granular spatiotemporal TB prevalence forecasts based on a cross-sectional prevalence survey data and other data sources. Nevertheless, it provided a range of approaches to subnational disease modelling. The NTP's use and plans for these outputs shows that, limitations notwithstanding, they can be valuable for programme planning.

Estimating the population at high risk for tuberculosis through household exposure in high-incidence countries: a model-based analysis.

BACKGROUND: Household contacts of people with pulmonary tuberculosis (TB) have greater risk of developing TB. Recent guidelines conditionally recommended TB preventive treatment (TPT) for household contacts of any age living in TB high-incidence countries, expanding earlier guidance to provide TPT to household contacts under five. The all-age population of household contacts has not been estimated. METHODS: Our model-based estimation included 20 countries with >80% of incident TB globally in 2019. We developed country-specific distributions of household composition by age and sex using bootstrap resampling from health surveys and census data. We incorporated age-, sex-, year-, and location-specific estimates of pulmonary TB incidence from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 to estimate the population in each country sharing a household with someone with incident pulmonary TB, and quantified uncertainty using a Monte Carlo approach. FINDINGS: We estimate that 38 million [95% uncertainty interval (UI) 33- 43 million] individuals lived in a household with someone with incident pulmonary TB in 2019 in these 20 countries. Children under five made up 12% of the population with household exposure, while adults were 65%. Zimbabwe, Mozambique, Zambia, and Pakistan had the highest proportion of the population with household exposure, while India had the highest number of contacts (11·4 million, 95% UI 9·7-13·4 million). INTERPRETATION: Expanding TPT evaluation to household contacts of all ages in high-incidence countries could include a population more than 7-times larger than the under-5 contacts previously prioritized. This would substantially increase the impact of household contact investigation on reducing TB morbidity and mortality. FUNDING: JMR is supported by the National Institute of Allergy and Infectious Diseases (K01 AI138620). This research was funded in part by a 2020 developmental grant from the University of Washington / Fred Hutch Center for AIDS Research, an NIH funded program under award number AI027757 which is supported by the following NIH Institutes and Centers: NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NIA, NIGMS, NIDDK. This work was funded in part by the National Science Foundation (DMS-1839116).

Isoniazid preventive therapy plus antiretroviral therapy for the prevention of tuberculosis: a systematic review and meta-analysis of individual participant data.

BACKGROUND: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. METHODS: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. FINDINGS: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per µL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. INTERPRETATION: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. FUNDING: National Institutes of Health and National Institute of Allergy and Infectious Diseases.

The DM domain protein MAB-3 promotes sex-specific neurogenesis in C. elegans by regulating bHLH proteins.

Sexual dimorphism in the nervous system is required for sexual behavior and reproduction in many metazoan species. However, little is known of how sex determination pathways impose sex specificity on nervous system development. In C. elegans, the conserved sexual regulator MAB-3 controls several aspects of male development, including formation of V rays, male-specific sense organs required for mating. Here we show that MAB-3 promotes expression of the proneural protein LIN-32 in V ray precursors by transcriptional repression of ref-1, a member of the Hes family of neurogenic factors. Mutations in ref-1 restore lin-32::gfp expression and normal V ray development to mab-3 mutants, suggesting that ref-1 is the primary target of MAB-3 in the V ray lineage. Proteins related to MAB-3 (DM domain proteins) control sexual differentiation in diverse metazoans. We therefore suggest that regulation of Hes genes by DM domain proteins may be a general mechanism for specifying sex-specific neurons.

Bringing a health systems modelling approach to complex evaluations: multicountry applications in HIV, TB and malaria.

INTRODUCTION: Understanding how to deliver interventions more effectively is a growing emphasis in Global Health. Simultaneously, health system strengthening is a key component to improving delivery. As a result, it is challenging to evaluate programme implementation while reflecting real-world complexity. We present our experience in using a health systems modelling approach as part of a mixed-methods evaluation and describe applications of these models. METHODS: We developed a framework for how health systems translate financial inputs into health outcomes, with in-country and international experts. We collated available data to measure framework indicators and developed models for malaria in Democratic Republic of the Congo (DRC), and tuberculosis in Guatemala and Senegal using Bayesian structural equation modelling. We conducted several postmodelling analyses: measuring efficiency, assessing bottlenecks, understanding mediation, analysing the cascade of care and measuring subnational effectiveness. RESULTS: The DRC model indicated a strong relationship between shipment of commodities and utilisation thereof. In Guatemala, the strongest model coefficients were more evenly distributed. Results in Senegal varied most, but pathways related to community care had the strongest relationships. In DRC, we used model results to estimate the end-to-end cost of delivering commodities. In Guatemala, we used model results to identify potential bottlenecks and understand mediation. In Senegal, we used model results to identify potential weak links in the cascade of care, and explore subnationally. CONCLUSION: This study demonstrates a complementary modelling approach to traditional evaluation methods. Although these models have limitations, they can be applied in a variety of ways to gain greater insight into implementation and functioning of health service delivery.

Polycomb group regulation of Hox gene expression in C. elegans.

Polycomb group (PcG) chromatin proteins regulate homeotic genes in both animals and plants. In Drosophila and vertebrates, PcG proteins form complexes and maintain early patterns of Hox gene repression, ensuring fidelity of developmental patterning. PcG proteins in C. elegans form a complex and mediate transcriptional silencing in the germline, but no role for the C. elegans PcG homologs in somatic Hox gene regulation has been demonstrated. Surprisingly, we find that the PcG homologs MES-2 [E(Z)] and MES-6 (ESC), along with MES-3, a protein without known homologs, do repress Hox expression in C. elegans. mes mutations cause anteroposterior transformations and disrupt Hox-dependent neuroblast migration. Thus, as in Drosophila, vertebrates, and plants, C. elegans PcG proteins regulate key developmental patterning genes to establish positional identity.