Greater Covid-19 vaccine uptake among enrollees offered health and social needs case management: Results from a randomized trial.

OBJECTIVE: To investigate Covid-19 vaccination as a potential secondary public health benefit of case management for Medicaid beneficiaries with health and social needs. DATA SOURCES AND STUDY SETTING: The CommunityConnect case management program for Medicaid beneficiaries is run by Contra Costa Health, a county safety net health system in California. Program enrollment data were merged with comprehensive county vaccination records. STUDY DESIGN: Individuals with elevated risk of hospital and emergency department use were randomized each month to a case management intervention or usual care. Interdisciplinary case managers offered coaching, community referrals, healthcare connections, and other support based on enrollee interest and need. Using survival analysis with intent-to-treat assignment, we assessed rates of first-dose Covid-19 vaccination from December 2020 to September 2021. In exploratory sub-analyses we also examined effect heterogeneity by gender, race/ethnicity, age, and primary language. DATA COLLECTION AND EXTRACTION METHODS: Data were extracted from county and program records as of September 2021, totaling 12,866 interventions and 25,761 control enrollments. PRINCIPAL FINDINGS: Approximately 58% of enrollees were female and 41% were under age 35. Enrollees were 23% White, 12% Asian/Pacific Islander, 20% Black/African American, and 36% Hispanic/Latino, and 10% other/unknown. Approximately 35% of the intervention group engaged with their case manager. Approximately 56% of all intervention and control enrollees were vaccinated after 9 months of analysis time. Intervention enrollees had a higher vaccination rate compared to control enrollees (adjusted hazard ratio [aHR]: 1.06; 95% confidence interval [CI]: 1.02-1.10). In sub-analyses, the intervention was associated with stronger likelihood of vaccination among males and individuals under age 35. CONCLUSIONS: Case management infrastructure modestly improved Covid-19 vaccine uptake in a population of Medicaid beneficiaries that over-represents social groups with barriers to early Covid-19 vaccination. Amidst mixed evidence on vaccination-specific incentives, leveraging trusted case managers and existing case management programs may be a valuable prevention strategy.

Effect of Social Needs Case Management on Hospital Use Among Adult Medicaid Beneficiaries : A Randomized Study.

BACKGROUND: Case management programs assisting patients with social needs may improve health and avoid unnecessary health care use, but little is known about their effectiveness. OBJECTIVE: This large-scale study assessed the population-level impact of a case management program designed to address patients' social needs. DESIGN: Single-site randomized encouragement design with administrative enrollment from an eligible population and intention-to-treat analysis. Study participants were enrolled between August 2017 and December 2018 and followed for 1 year. (ClinicalTrials.gov: NCT04000074). SETTING: Contra Costa County, an economically and culturally diverse community in the San Francisco Bay Area. PARTICIPANTS: 57 972 randomized enrollments of adult Medicaid patients at elevated risk for health care use (top 15%) to the intervention or control group. INTERVENTION: Enrollees were offered 12 months of social needs case management, which provided more intensive services to patients with higher demonstrated needs. MEASUREMENTS: Medical use was measured via emergency department (ED) visits and inpatient admissions, some of which were classified as avoidable. RESULTS: Participants in the intervention group visited the ED at ratios of 0.96 (95% CI, 0.91 to 1.00) for all visits and 0.97 (CI, 0.92 to 1.03) for avoidable visits relative to the control group. The intervention group was hospitalized at ratios of 0.89 (CI, 0.81 to 0.98) for all admissions and 0.72 (CI, 0.55 to 0.88) for avoidable admissions. LIMITATIONS: Only 40% of the intervention group engaged with the program. The program was in continual development during the trial period. CONCLUSION: Although social needs case management programs may reduce health care use, these savings may not cover full program costs. More work is needed to identify ways to increase patient uptake and define characteristics of successful programs. PRIMARY FUNDING SOURCE: Contra Costa Health Services via the Medicaid waiver program.

The association of county-level socioeconomic factors with individual tobacco and alcohol use: a longitudinal study of U.S. adults.

BACKGROUND: Place-based factors have been implicated as root causes of socioeconomic disparities in risky health behaviors such as tobacco and alcohol use. Yet few studies examine the effects of county-level socioeconomic characteristics, despite the fact that social and public health policies are often implemented at the county level. In this study, we tested the hypothesis that county-level socioeconomic disadvantage was associated with individual tobacco and alcohol use. METHODS: The sample included a panel of participants from the National Longitudinal Survey of Youth (N = 9302). The primary predictors were three time-varying measures of socioeconomic disadvantage in an individual's county of residence: educational attainment, percent unemployment, and per capita income. We first conducted traditional ordinary least squares (OLS) models, both unadjusted and adjusted for individual-level covariates. We then conducted fixed effects (FE) models to adjust for confounding by unmeasured time-invariant individual-level factors. RESULTS: OLS and FE models yielded contrasting results: higher county-level per capita income was associated with decreased drinking in OLS models and increased drinking in FE models, while decreased county-level educational attainment was associated with decreased smoking in OLS models and more cigarettes per day in FE models. The findings from FE models suggest that OLS models were confounded by unobserved time-invariant characteristics. Notably, the point estimates for the county-level measures were small, and in many cases they may not represent a clinically meaningful effect except at the population level. CONCLUSIONS: These results suggest that county-level socioeconomic characteristics may modestly influence tobacco and alcohol use. Future work should examine the effects of specific county policies that might explain these findings.

Diesel Exhaust, Respirable Dust, and Ischemic Heart Disease: An Application of the Parametric g-formula.

BACKGROUND: Although general population studies of air pollution suggest that particulate matter-diesel exhaust emissions in particular-is a potential risk factor for cardiovascular disease, direct evidence from occupational cohorts using quantitative metrics of exposure is limited. In this study, we assess counterfactual risk of ischemic heart disease (IHD) mortality under hypothetical scenarios limiting exposure levels of diesel exhaust and of respirable mine/ore dust in the Diesel Exhaust in Miners Study cohort. METHODS: We analyzed data on 10,779 male miners from 8 nonmetal, noncoal mines-hired after diesel equipment was introduced in the respective facilities-and followed from 1948 to 1997, with 297 observed IHD deaths in this sample. We applied the parametric g-formula to assess risk under hypothetical scenarios with various limits for respirable elemental carbon (a surrogate for diesel exhaust), and respirable dust, separately and jointly. RESULTS: The risk ratio comparing the observed risk to cumulative IHD mortality risk at age 80 under a hypothetical scenario where exposures to elemental carbon and respirable dust are eliminated was 0.79 (95% confidence interval [CI]: 0.64, 0.97). The corresponding risk difference was -3.0% (95% CI: -5.7, -0.3). CONCLUSION: Our findings, based on data from a cohort of nonmetal miners, are consistent with the hypothesis that interventions to eliminate exposures to diesel exhaust and respirable dust would reduce IHD mortality risk.

Ischemic Heart Disease Mortality and Diesel Exhaust and Respirable Dust Exposure in the Diesel Exhaust in Miners Study.

Diesel exhaust is a suggested risk factor for ischemic heart disease (IHD), but evidence from cohorts using quantitative exposure metrics is limited. We examined the impact of respirable elemental carbon (REC), a key surrogate for diesel exhaust, and respirable dust (RD) on IHD mortality, using data from the Diesel Exhaust in Miners Study in the United States. Using data from a cohort of male workers followed from 1948-1968 until 1997, we fitted Cox proportional hazards models to estimate hazard ratios for IHD mortality for cumulative and average intensity of exposure to REC and RD. Segmented linear regression models allowed for nonmonotonicity. Hazard ratios for cumulative and average REC exposure declined relative to the lowest exposure category before increasing to 0.79 and 1.25, respectively, in the highest category. Relative to the category containing the segmented regression change points, hazard ratios for the highest category were 1.69 and 1.54 for cumulative and average REC exposure, respectively. Hazard ratios for RD exposure increased across the full exposure range to 1.33 and 2.69 for cumulative and average RD exposure, respectively. Tests for trend were statistically significant for cumulative REC exposure (above the change point) and for average RD exposure. Our findings suggest excess risk of IHD mortality in relation to increased exposure to REC and RD.

Contrasting Causal Effects of Workplace Interventions.

Occupational exposure guidelines are ideally based on estimated effects of static interventions that assign constant exposure over a working lifetime. Static effects are difficult to estimate when follow-up extends beyond employment because their identifiability requires additional assumptions. Effects of dynamic interventions that assign exposure while at work, allowing subjects to leave and become unexposed thereafter, are more easily identifiable but result in different estimates. Given the practical implications of exposure limits, we explored the drivers of the differences between static and dynamic interventions in a simulation study where workers could terminate employment because of an intermediate adverse health event that functions as a time-varying confounder. The two effect estimates became more similar with increasing strength of the health event and outcome relationship and with increasing time between health event and employment termination. Estimates were most dissimilar when the intermediate health event occurred early in employment, providing an effective screening mechanism.

Estimating Counterfactual Risk Under Hypothetical Interventions in the Presence of Competing Events: Crystalline Silica Exposure and Mortality From 2 Causes of Death.

Exposure to silica has been linked to excess risk of lung cancer and nonmalignant respiratory disease mortality. In this study we estimated risk for both these outcomes in relation to occupational silica exposure as well as the reduction in risk that would result from hypothetical interventions on exposure in a cohort of exposed workers. Analyses were carried out using data from an all-male study population consisting of 2,342 California diatomaceous earth workers regularly exposed to crystalline silica and followed between 1942 and 2011. We estimated subdistribution risk for each event under the natural course and interventions of interest using the parametric g-formula to adjust for healthy-worker survivor bias. The risk ratio for lung cancer mortality, comparing an intervention in which a theoretical maximum exposure limit was set at 0.05 mg/m3 (the current US regulatory limit) with the observed exposure concentrations, was 0.86 (95% confidence interval: 0.63, 1.22). The corresponding risk ratio for nonmalignant respiratory disease mortality was 0.69 (95% confidence interval: 0.52, 0.93). Our findings suggest that risks from both outcomes would have been considerably lower if historical silica exposures in this cohort had not exceeded current regulatory limits.

Availability, quality and price of produce in low-income neighbourhood food stores in California raise equity issues.

OBJECTIVE: To assess produce availability, quality and price in a large sample of food stores in low-income neighbourhoods in California. DESIGN: Cross-sectional statewide survey. SETTING: Between 2011 and 2015, local health departments assessed store type, WIC (Supplemental Nutrition Program for Women, Infants, and Children)/SNAP (Supplemental Nutrition Assistance Program) participation, produce availability, quality and price of selected items in stores in low-income neighbourhoods. Secondary data provided reference chain supermarket produce prices matched by county and month. t Tests and ANOVA examined differences by store type; regression models examined factors associated with price. SUBJECTS: Large grocery stores (n 231), small markets (n 621) and convenience stores (n 622) in 225 neighbourhoods. RESULTS: Produce in most large groceries was rated high quality (97 % of fruits, 98 % of vegetables), but not in convenience stores (25 % fruits, 14 % vegetables). Small markets and convenience stores participating in WIC and/or SNAP had better produce availability, variety and quality than non-participating stores. Produce prices across store types were, on average, higher than reference prices from matched chain supermarkets (27 % higher in large groceries, 37 % higher in small markets, 102 % higher in convenience stores). Price was significantly inversely associated with produce variety, adjusting for quality, store type, and SNAP and WIC participation. CONCLUSIONS: The study finds that fresh produce is more expensive in low-income neighbourhoods and that convenience stores offer more expensive, poorer-quality produce than other stores. Variety is associated with price and most limited in convenience stores, suggesting more work is needed to determine how convenience stores can provide low-income consumers with access to affordable, high-quality produce. WIC and SNAP can contribute to the solution.

Exposure-Lag-Response in Longitudinal Studies: Application of Distributed-Lag Nonlinear Models in an Occupational Cohort.

Prolonged exposures can have complex relationships with health outcomes, as timing, duration, and intensity of exposure are all potentially relevant. Summary measures such as cumulative exposure or average intensity of exposure may not fully capture these relationships. We applied penalized and unpenalized distributed-lag nonlinear models (DLNMs) with flexible exposure-response and lag-response functions in order to examine the association between crystalline silica exposure and mortality from lung cancer and nonmalignant respiratory disease in a cohort study of 2,342 California diatomaceous earth workers followed during 1942-2011. We also assessed associations using simple measures of cumulative exposure assuming linear exposure-response and constant lag-response. Measures of association from DLNMs were generally higher than those from simpler models. Rate ratios from penalized DLNMs corresponding to average daily exposures of 0.4 mg/m3 during lag years 31-50 prior to the age of observed cases were 1.47 (95% confidence interval (CI): 0.92, 2.35) for lung cancer mortality and 1.80 (95% CI: 1.14, 2.85) for nonmalignant respiratory disease mortality. Rate ratios from the simpler models for the same exposure scenario were 1.15 (95% CI: 0.89, 1.48) and 1.23 (95% CI: 1.03, 1.46), respectively. Longitudinal cohort studies of prolonged exposures and chronic health outcomes should explore methods allowing for flexibility and nonlinearities in the exposure-lag-response.

Occupational silica exposure and mortality from lung cancer and nonmalignant respiratory disease: G-estimation of structural nested accelerated failure time models.

BACKGROUND: Occupational exposure to crystalline silica is known to increase risks of both lung cancer and noninfectious nonmalignant respiratory diseases (NMRD). However, associations between silica exposure and survival times have not been described. METHODS: In a longitudinal cohort of diatomaceous earth workers exposed to crystalline silica (primarily cristobalite) and followed from 1942 to 2011, we applied g-estimation of structural nested accelerated failure time models to adjust for time-varying confounding that could result in healthy worker survivor bias. A continuous measure of exposure was used in analyses estimating the hypothetical effect of banning exposure to silica on survival time. Since a ban is infeasible, sensitivity analyses examined the hypothetical effects of enforcing various Occupational Exposure Limits. RESULTS: The estimated median number of years of life lost per worker (for all natural causes) due to silica exposure was 0.48 (95% confidence interval = 0.02, 1.01). For NMRD deaths, the corresponding estimate was 3.22 (0.82, 7.75) and for lung cancer deaths, 2.21 (0.97, 3.56). Cause-specific estimates were sensitive to the use of weights to adjust for competing events. Lung cancer mortality, which tended to occur at younger ages, was an important competing event for NMRD mortality. Sensitivity analyses supported the main results, but with larger estimates, and suggested that a strict limit would be nearly as effective as a complete ban on silica exposure. CONCLUSIONS: Workplace exposure to crystalline silica in this industry appears to shorten survival times significantly, particularly for those who die of lung cancer or NMRD. More stringent exposure limits are probably warranted.

Motherhood, Fatherhood and Midlife Weight Gain in a US Cohort: Associations differ by race/ethnicity and socioeconomic position.

While there is an association of greater short-term weight gain with childbearing among women, less is known about longer-term weight gain, whether men have similar gains, and how this varies by race/ethnicity and socioeconomic position. Our cohort consisted of a nationally representative sample of 7,356 Americans with oversampling of Black and Hispanic populations. We estimated the associations between number of biological children and parental weight, measured as both change in self-reported body mass index (BMI) from age 18 and overweight/obese status (BMI ≥ 25) at age 40. We performed multivariate linear and logistic regression analysis and tested for effect modification by gender. For change in BMI, men gained on average 0.28 BMI (95% CI: (0.01, 0.55)) units per child, while women gained 0.13 units per child (95% CI: (-0.22, 0.48)). The adjusted odds ratios for overweight/obesity associated with each child were 1.32 (95% CI: (1.11, 1.58)) for men and 1.15 (95% CI: (1.01, 1.31)) for women. Stratified analyses by race/ethnicity and socioeconomic position suggested that the observed full-cohort differences were driven primarily by gendered differences in low-income Hispanics and Whites - with the greatest associations among Hispanic men. For example, among low-income Hispanic men we observed a positive relationship between the number of children and weight change by age 40, with average weight change of 0.47 units per child (95%CI: (-0.65, 1.59 For low-income Hispanic women, however, the average weight change was -0.59 units per child (95%CI: (-1.70, 0.47), and the P-value for the test of interaction between gender and number of children was P < 0.001. Our findings suggest that the shared social and economic aspects of raising children play an important role in determining parental weight at mid-life.

The Healthy Worker Survivor Effect: Target Parameters and Target Populations.

PURPOSE OF REVIEW: We offer an in-depth discussion of the time-varying confounding and selection bias mechanisms that give rise to the healthy worker survivor effect (HWSE). RECENT FINDINGS: In this update of an earlier review, we distinguish between the mechanisms collectively known as the HWSE and the statistical bias that can result. This discussion highlights the importance of identifying both the target parameter and the target population for any research question in occupational epidemiology. Target parameters can correspond to hypothetical workplace interventions; we explore whether these target parameters' true values reflect the etiologic effect of an exposure on an outcome or the potential impact of enforcing an exposure limit in a more realistic setting. If a cohort includes workers hired before the start of follow-up, HWSE mechanisms can limit the transportability of the estimates to other target populations. We summarize recent publications that applied g-methods to control for the HWSE, focusing on their target parameters, target populations, and hypothetical interventions.

Incident Ischemic Heart Disease After Long-Term Occupational Exposure to Fine Particulate Matter: Accounting for 2 Forms of Survivor Bias.

Little is known about the heart disease risks associated with occupational, rather than traffic-related, exposure to particulate matter with aerodynamic diameter of 2.5 µm or less (PM2.5). We examined long-term exposure to PM2.5 in cohorts of aluminum smelters and fabrication workers in the United States who were followed for incident ischemic heart disease from 1998 to 2012, and we addressed 2 forms of survivor bias. Left truncation bias was addressed by restricting analyses to the subcohort hired after the start of follow up. Healthy worker survivor bias, which is characterized by time-varying confounding that is affected by prior exposure, was documented only in the smelters and required the use of marginal structural Cox models. When comparing always-exposed participants above the 10th percentile of annual exposure with those below, the hazard ratios were 1.67 (95% confidence interval (CI): 1.11, 2.52) and 3.95 (95% CI: 0.87, 18.00) in the full and restricted subcohorts of smelter workers, respectively. In the fabrication stratum, hazard ratios based on conditional Cox models were 0.98 (95% CI: 0.94, 1.02) and 1.17 (95% CI: 1.00, 1.37) per 1 mg/m(3)-year in the full and restricted subcohorts, respectively. Long-term exposure to occupational PM2.5 was associated with a higher risk of ischemic heart disease among aluminum manufacturing workers, particularly in smelters, after adjustment for survivor bias.

Occupational Exposure to PM2.5 and Incidence of Ischemic Heart Disease: Longitudinal Targeted Minimum Loss-based Estimation.

BACKGROUND: We investigated the incidence of ischemic heart disease (IHD) in relation to accumulated exposure to particulate matter (PM) in a cohort of aluminum workers. We adjusted for time varying confounding characteristic of the healthy worker survivor effect, using a recently introduced method for the estimation of causal target parameters. METHODS: Applying longitudinal targeted minimum loss-based estimation, we estimated the difference in marginal cumulative risk of IHD in the cohort comparing counterfactual outcomes if always exposed above to always exposed below a PM2.5 exposure cut-off. Analyses were stratified by sub-cohort employed in either smelters or fabrication facilities. We selected two exposure cut-offs a priori, at the median and 10th percentile in each sub-cohort. RESULTS: In smelters, the estimated IHD risk difference after 15 years of accumulating PM2.5 exposure during follow-up was 2.9% (0.6%, 5.1%) using the 10th percentile cut-off of 0.10 mg/m. For fabrication workers, the difference was 2.5% (0.8%, 4.1%) at the 10th percentile of 0.06 mg/m. Using the median exposure cut-off, results were similar in direction but smaller in size. We present marginal incidence curves describing the cumulative risk of IHD over the course of follow-up for each sub-cohort under each intervention regimen. CONCLUSIONS: The accumulation of exposure to PM2.5 appears to result in higher risks of IHD in both aluminum smelter and fabrication workers. This represents the first longitudinal application of targeted minimum loss-based estimation, a method for generating doubly robust semi-parametric efficient substitution estimators of causal parameters, in the fields of occupational and environmental epidemiology.

Marginal structural models in occupational epidemiology: application in a study of ischemic heart disease incidence and PM2.5 in the US aluminum industry.

Marginal structural models (MSMs) and inverse probability weighting can be used to estimate risk in a cohort of active workers if there is a time-varying confounder (e.g., health status) affected by prior exposure-a feature of the healthy worker survivor effect. We applied Cox MSMs in a study of incident ischemic heart disease and exposure to particulate matter with aerodynamic diameter of 2.5 µm or less (PM2.5) in a cohort of 12,949 actively employed aluminum workers in the United States. The cohort was stratified by work process into workers in smelting facilities, herein referred to as "smelters" and workers in fabrication facilities, herein referred to as "fabricators." The outcome was assessed by using medical claims data from 1998 to 2012. A composite risk score based on insurance claims was treated as a time-varying measure of health status. Binary PM2.5 exposure was defined by the 10th-percentile cutoff for each work process. Health status was associated with past exposure and predicted the outcome and subsequent exposure in smelters but not in fabricators. In smelters, the Cox MSM hazard ratio comparing those always exposed above the cutoff with those always exposed below the cutoff was 1.98 (95% confidence interval: 1.18, 3.32). In fabricators, the hazard ratio from a traditional Cox model was 1.34 (95% confidence interval: 0.98, 1.83). Results suggest that occupational PM2.5 exposure increases the risk of incident ischemic heart disease in workers in both aluminum smelting and fabrication facilities.

Incident ischemic heart disease and recent occupational exposure to particulate matter in an aluminum cohort.

Fine particulate matter (PM(2.5)) in air pollution, primarily from combustion sources, is recognized as an important risk factor for cardiovascular events but studies of workplace PM(2.5) exposure are rare. We conducted a prospective study of exposure to PM(2.5) and incidence of ischemic heart disease (IHD) in a cohort of 11,966 US aluminum workers. Incident IHD was identified from medical claims data from 1998 to 2008. Quantitative metrics were developed for recent exposure (within the last year) and cumulative exposure; however, we emphasize recent exposure in the absence of interpretable work histories before follow-up. IHD was modestly associated with recent PM(2.5) overall. In analysis restricted to recent exposures estimated with the highest confidence, the hazard ratio (HR) increased to 1.78 (95% CI: 1.02, 3.11) in the second quartile and remained elevated. When the analysis was stratified by work process, the HR rose monotonically to 1.5 in both smelter and fabrication facilities, though exposure was almost an order of magnitude higher in smelters. The differential exposure-response may be due to differences in exposure composition or healthy worker survivor effect. These results are consistent with the air pollution and cigarette smoke literature; recent exposure to PM(2.5) in the workplace appears to increase the risk of IHD incidence.

Healthy worker survivor bias: implications of truncating follow-up at employment termination.

OBJECTIVES: The healthy worker survivor effect is a bias that occurs in occupational studies when less healthy workers are more likely to reduce their workplace exposures. When variables on the pathway from health status to exposure are measured, g-methods can avoid this bias. However, studies in which follow-up ends at employment termination have additional potential for selection bias. This paper examines the structure of the healthy worker survivor effect, compares results with and without censoring at employment termination, and addresses how to prevent bias when such censoring occurs. METHODS: G-estimation of structural accelerated failure time models was applied in the United Autoworkers-General Motors cohort study to examine relationships between metalworking fluid exposure and cause-specific mortality. Subjects were followed from hire through 1994, regardless of employment status. To answer the central question, g-estimation analysis was repeated after truncating at employment termination and censoring outcomes that occurred thereafter, with adjustment for censoring by inverse probability weighting. RESULTS: Using full follow-up time, HRs were estimated for all-cause mortality (1.09), ischaemic heart disease death (1.19), and death from any cancer (1.09), comparing 5 years of metalworking fluid exposure to no exposure. For all three outcomes, the HR estimates based on data censored at termination of employment were below 1 (respectively, 0.92, 0.97, 0.79). CONCLUSIONS: In this application, g-estimation together with weighting did not prevent selection bias due to employment termination. However, the bias might be avoided in studies with measured health-related variables on the pathway from health status to employment termination.

Lethal mutagenesis of picornaviruses with N-6-modified purine nucleoside analogues.

RNA viruses exhibit extraordinarily high mutation rates during genome replication. Nonnatural ribonucleosides that can increase the mutation rate of RNA viruses by acting as ambiguous substrates during replication have been explored as antiviral agents acting through lethal mutagenesis. We have synthesized novel N-6-substituted purine analogues with ambiguous incorporation characteristics due to tautomerization of the nucleobase. The most potent of these analogues reduced the titer of poliovirus (PV) and coxsackievirus (CVB3) over 1,000-fold during a single passage in HeLa cell culture, with an increase in transition mutation frequency up to 65-fold. Kinetic analysis of incorporation by the PV polymerase indicated that these analogues were templated ambiguously with increased efficiency compared to the known mutagenic nucleoside ribavirin. Notably, these nucleosides were not efficient substrates for cellular ribonucleotide reductase in vitro, suggesting that conversion to the deoxyriboucleoside may be hindered, potentially limiting genetic damage to the host cell. Furthermore, a high-fidelity PV variant (G64S) displayed resistance to the antiviral effect and mutagenic potential of these analogues. These purine nucleoside analogues represent promising lead compounds in the development of clinically useful antiviral therapies based on the strategy of lethal mutagenesis.