Background: The Health Resources and Services Administration's Ryan White HIV/AIDS Program provides services to more than half of all people diagnosed with HIV in the United States. We present and validate a mathematical model that can be used to estimate the long-term public health and cost impact of the federal program. Methods: We developed a stochastic, agent-based model that reflects the current HIV epidemic in the United States. The model simulates everyone's progression along the HIV care continuum, using 2 network-based mechanisms for HIV transmission: injection drug use and sexual contact. To test the validity of the model, we calculated HIV incidence, mortality, life expectancy, and lifetime care costs and compared the results with external benchmarks. Results: The estimated HIV incidence rate for men who have sex with men (502 per 100,000 person years), mortality rate of all people diagnosed with HIV (1663 per 100,000 person years), average life expectancy for individuals with low CD4 counts not on antiretroviral therapy (1.52–3.78 years), and lifetime costs ($362,385) all met our validity criterion of within 15% of external benchmarks. Conclusions: The model represents a complex HIV care delivery system rather than a single intervention, which required developing solutions to several challenges, such as calculating need for and receipt of multiple services and estimating their impact on care retention and viral suppression. Our strategies to address these methodological challenges produced a valid model for assessing the cost-effectiveness of the Ryan White HIV/AIDS Program.

Background: With an annual budget of more than $2 billion, the Health Resources and Services Administration's Ryan White HIV/AIDS Program (RWHAP) is the third largest source of public funding for HIV care and treatment in the United States, yet little analysis has been done to quantify the long-term public health and economic impacts of the federal program. Methods: Using an agent-based, stochastic model, we estimated health care costs and outcomes over a 50-year period in the presence of the RWHAP relative to those expected to prevail if the comprehensive and integrated system of medical and support services funded by the RWHAP were not available. We made a conservative assumption that, in the absence of the RWHAP, only uninsured clients would lose access to these medical and support services. Results: The model predicts that the proportion of people with HIV who are virally suppressed would be 25.2 percentage points higher in the presence of the RWHAP (82.6 percent versus 57.4 percent without the RWHAP). The number of new HIV infections would be 18 percent (190,197) lower, the number of deaths among people with HIV would be 31 percent (267,886) lower, the number of quality-adjusted life years would be 2.7 percent (5.6 million) higher, and the cumulative health care costs would be 25 percent ($165 billion) higher in the presence of the RWHAP relative to the counterfactual. Based on these results, the RWHAP has an incremental cost-effectiveness ratio of $29,573 per quality-adjusted life year gained compared with the non-RWHAP scenario. Sensitivity analysis indicates that the probability of transmitting HIV via male-to-male sexual contact and the cost of antiretroviral medications have the largest effect on the cost-effectiveness of the program. Conclusions: The RWHAP would be considered very cost-effective when using standard guidelines of less than the per capita gross domestic product of the United States. The results suggest that the RWHAP plays a critical and cost-effective role in the United States' public health response to the HIV epidemic.

Opioid misuse takes an enormous toll on the health and economy of the U.S., costing 130 lives per day, and an estimated 157 billion dollars per year. Mitigating the epidemic requires better information on the mix of drugs being used in a community and when and where drug use concentrates. Many widely used data sources, such as national population surveys, have a two-year lag before the data are available, and underestimate the prevalence of drug use because they rely on self-reported information about a stigmatized behavior. For rural populations, the data gap is compounded by privacy policies that suppress key information (for example, opioid-related death rates) in small populations. Municipal wastewater testing is an innovative approach to assessing community-level drug use that can provide near real-time, cost-effective, and unbiased measures of drug use. Importantly, wastewater-based data cannot reveal who is using a particular drug, mitigating privacy concerns. The methodology is routinely used across Europe and Australia as part of a holistic multi-indicator monitoring and alert system. When combined with geospatial mapping and advanced analytics, wastewater-based data can help locate geographic hotspots of use and provide an early warning for new substances entering into a community. We conducted a pilot study to compare temporal trends in estimates of per-capita drug use between wastewater-based data and other local data sources in two municipalities (one urban, one rural) in Montana. In the first phase of our study (Bishop et al. 2020, manuscript is in submission to Sci Total Environ), we optimized testing to estimate per-capita drug use in wastewater in an urban and rural municipality. Here, we report the value of these data for public health officials to predict rather than react to changes in drug use patterns. We also illustrate how rural populations can use the methodology to assess the impacts of local law enforcement efforts and evaluate the effectiveness of programs, such as the prescription take-back program, to improve public health and safety.

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Neural tube defects (NTDs) are a group of severe congenital malformations caused by a failure of neural tube closure during early embryonic development. Although extensively investigated, the genetic etiology of NTDs remains poorly understood. FKBP8 is critical for proper mammalian neural tube closure. Fkbp8−/− mouse embryos showed posterior NTDs consistent with a diagnosis of spina bifida (SB). To date, no publication has reported any association between FKBP8 and human NTDs. Using Sanger sequencing on genomic DNA samples from 472 SB and 565 control samples, we identified 5 rare (MAF < =0.001) deleterious variants in SB patients, while no rare deleterious variant was identified in the controls (p = 0.0191). p.Glu140* affected FKBP8 localization to the mitochondria and created a truncated form of the FKBP8 protein, thus impairing its interaction with BCL2 and ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein levels. p.Lys315Asn further increased the cellular apoptosis. RNA sequencing on anterior and posterior tissues isolated from Fkbp8−/− and wildtype mice at E9.5 and E10.5 showed that Fkbp8−/− embryos have an abnormal expression profile within tissues harvested at posterior sites, thus leading to a posterior NTD. Moreover, we found that Fkbp8 knockout mouse embryos have abnormal expression of Wnt3a and Nkx2.9 during the early stage of neural tube development, perhaps also contributing to caudal specific NTDs. These findings provide evidence that functional variants of FKBP8 are risk factors for SB, which may involve a novel mechanism by which Fkbp8 mutations specifically cause SB in mice.