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BACKGROUND: During the 2010 Deepwater Horizon (DWH) disaster, in-situ burning and flaring were conducted to remove oil from the water. Workers near combustion sites were potentially exposed to burning-related fine particulate matter (PM2.5). Exposure to PM2.5 has been linked to increased risk of coronary heart disease (CHD), but no study has examined the relationship among oil spill workers. OBJECTIVES: To investigate the association between estimated PM2.5 from burning/flaring of oil/gas and CHD risk among the DWH oil spill workers. METHODS: We included workers who participated in response and cleanup activities on the water during the DWH disaster (N = 9091). PM2.5 exposures were estimated using a job-exposure matrix that linked modelled PM2.5 concentrations to detailed DWH spill work histories provided by participants. We ascertained CHD events as the first self-reported physician-diagnosed CHD or a fatal CHD event that occurred after each workers last day of burning exposure. We estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for the associations between categories of average or cumulative daily maximum PM2.5 exposure (versus a referent category of water workers not near controlled burning) and subsequent CHD. We assessed exposure-response trends by examining continuous exposure parameters in models. RESULTS: We observed increased CHD hazard among workers with higher levels of average daily maximum exposure (low vs. referent: HR = 1.26, 95% CI: 0.93, 1.70; high vs. referent: HR = 2.11, 95% CI: 1.08, 4.12; per 10 μg/m3 increase: HR = 1.10, 95% CI: 1.02, 1.19). We also observed suggestively elevated HRs among workers with higher cumulative daily maximum exposure (low vs. referent: HR = 1.19, 95% CI: 0.68, 2.08; medium vs. referent: HR = 1.38, 95% CI: 0.88, 2.16; high vs. referent: HR = 1.44, 95% CI: 0.96, 2.14; per 100 μg/m3-d increase: HR = 1.03, 95% CI: 1.00, 1.05). CONCLUSIONS: Among oil spill workers, exposure to PM2.5 from flaring/burning of oil/gas was associated with increased risk of CHD.

BackgroundThe etiology of dementias and cognitive decline remain largely unknown. It is widely accepted that inflammation in the central nervous system plays a critical role in the pathogenesis of dementia. However, less is known about the role of the peripheral immune system and interactions with cortisol, though evidence suggests that these, too, may play a role.MethodsUsing data from 1337 participants aged 60+ years from the Sacramento Area Latino Study of Aging (observational cohort) we investigated variation in trajectories of cognitive decline by pathogen IgG and cytokine levels. Linear mixed effects models were used to examine the association between baseline Interleukin (IL)-6, C-reactive protein, tumor necrosis factor (TNF)-α, and five persistent pathogens' IgG response and trajectories of cognition over 10 years, and to examine interactions between immune biomarkers and cortisol. Stratified cumulative incidence functions were used to assess the relation between biomarkers and incident dementia. Inverse probability weights accounted for loss-to-follow-up and confounding.ResultsIL-6, TNF-α, and CMV IgG were statistically significantly associated with a higher log of Modified Mini-Mental State Examination errors (IL-6, β=0.0935 (95%CI: 0.055, 0.13), TNF-alpha β= 0.0944 (95%CI: 0.032, 0.157), and CMV, β= 0.0409 (95%CI: 0.013, 0.069)). Furthermore, cortisol interacted with HSV-1 and IL-6, and CRP for both cross-sectional cognitive function and rate of decline. No statistically significant relationship was detected between biomarkers and incidence of dementia.ConclusionsThese findings support the theory that the peripheral immune system may play a role in cognitive decline but not incident dementia. Furthermore, they identify specific markers amenable for intervention for slowing decline.

Poverty alleviation programs can reduce HIV incidence but may have greater impacts when combined with other psychosocial interventions. We modeled the change in HIV incidence among South African adolescent girls and young women (AGYW) associated with combining a cash transfer (the South African Child Support Grant (CSG)) with other structural and behavioral interventions. We modeled observational data from the HPTN 068 study where 2328 HIV negative AGYW (13-20 years) were followed for 4 years. In a Monte Carlo simulation based on this cohort (N = 10,000), CSG receipt was not independently associated with HIV incidence. Providing the CSG combined with increasing caregiver care and reducing adolescent depression had the largest reduction in HIV incidence with the fewest number of combined interventions (RD - 3.0%; (95% CI - 5.1%, - 0.9%). Combining a monthly grant with interventions to increase caregiver care and reduce adolescent depression could substantially reduce HIV incidence above the provision of cash alone.

BackgroundCombination interventions may be an effective way to prevent human immunodeficiency virus (HIV) in adolescent girls and young women. However, current studies are not designed to understand which specific interventions and combinations will be most effective. We estimate the possible impacts of interventions on a combination of factors associated with HIV.MethodsWe used the g-formula to model interventions on combinations of HIV risk factors to identify those that would prevent the most incident HIV infections, including low school attendance, intimate partner violence, depression, transactional sex, and age-disparate partnerships. We used data from the HIV Prevention Trials Network (HPTN) 068 study in rural South Africa from 2011 to 2017. We estimated HIV incidence under a potential intervention that reduced each risk factor and compared this to HIV incidence under the current distribution of these risk factors.ResultsAlthough many factors had strong associations with HIV, potential intervention estimates did not always suggest large reductions in HIV incidence because the prevalence of risk factors was low. When modeling combination effects, an intervention to increase schooling, decrease depression, and decease transactional sex showed the largest reduction in incident infection (risk difference, -1.4%; 95% confidence interval [CI], -2.7% to -.2%), but an intervention on only transactional sex and depression still reduced HIV incidence by -1.3% (95% CI, -2.6% to -.2%).ConclusionsTo achieve the largest reductions in HIV, both prevalence of the risk factor and strength of association with HIV must be considered. Additionally, intervening on more risk factors may not necessarily result in larger reductions in HIV incidence.

In an analysis of randomized trials, use of efavirenz for treatment of human immunodeficiency virus (HIV) infection was associated with increased suicidal thoughts/behaviors. However, analyses of observational data have found no evidence of increased risk. To assess whether population differences might explain this divergence, we transported the effect of efavirenz use from these trials to a specific target population. Using inverse odds weights and multiple imputation, we transported the effect of efavirenz on suicidal thoughts/behaviors in these randomized trials (participants were enrolled in 2001-2007) to a trials-eligible cohort of US adults initiating antiretroviral therapy while receiving HIV clinical care at medical centers between 1999 and 2015. Overall, 8,291 cohort participants and 3,949 trial participants were eligible. Prescription of antidepressants (19% vs. 13%) and injection drug history (16% vs. 10%) were more frequent in the cohort than in the trial participants. Compared with the effect in trials, the estimated hazard ratio for efavirenz on suicidal thoughts/behaviors was attenuated in our target population (trials: hazard ratio (HR) = 2.3 (95% confidence interval (CI): 1.2, 4.4); transported: HR = 1.8 (95% CI: 0.9, 4.4)), whereas the incidence rate difference was similar (trials: HR = 5.1 (95% CI: 1.6, 8.7); transported: HR = 5.4 (95% CI: -0.4, 11.4)). In our target population, there was greater than 20% attenuation of the hazard ratio estimate as compared with the trials-only estimate. Transporting results from trials to a target population is informative for addressing external validity.

BackgroundUnderstanding advances in the care and treatment of adults with HIV as well as remaining gaps requires comparing differences in mortality between persons entering care for HIV and the general population.ObjectiveTo assess the extent to which mortality among persons entering HIV care in the United States is elevated over mortality among matched persons in the general U.S. population and trends in this difference over time.DesignObservational cohort study.SettingThirteen sites from the U.S. North American AIDS Cohort Collaboration on Research and Design.Participants82 766 adults entering HIV clinical care between 1999 and 2017 and a subset of the U.S. population matched on calendar time, age, sex, race/ethnicity, and county using U.S. mortality and population data compiled by the National Center for Health Statistics.MeasurementsFive-year all-cause mortality, estimated using the Kaplan-Meier estimator of the survival function.ResultsOverall 5-year mortality among persons entering HIV care was 10.6%, and mortality among the matched U.S. population was 2.9%, for a difference of 7.7 (95% CI, 7.4 to 7.9) percentage points. This difference decreased over time, from 11.1 percentage points among those entering care between 1999 and 2004 to 2.7 percentage points among those entering care between 2011 and 2017.LimitationMatching on available covariates may have failed to account for differences in mortality that were due to sociodemographic factors rather than consequences of HIV infection and other modifiable factors.ConclusionMortality among persons entering HIV care decreased dramatically between 1999 and 2017, although those entering care remained at modestly higher risk for death in the years after starting care than comparable persons in the general U.S. population.Primary funding sourceNational Institutes of Health.

Despite improvements in access to antiretroviral treatment over the past decade, sub-optimal HIV care outcomes persist among youth with HIV (YWH) in rural South Africa. Psychosocial stressors could impede improved HIV treatment outcomes within this population. We linked self-reported psychosocial health and demographic data from a cross-sectional survey conducted among YWH aged 12-24 in rural South Africa to individual medical record data, including facility visit history and viral load measurements. Poisson regression with robust standard errors was used to estimate the associations between five psychosocial stressors- heightened depressive symptoms (Center for Epidemiological Studies-Depression scale scores ≥ 16), lower social support (Medical Outcomes Social Support Scale scores ≤ 38), lower resilience (Conner-Davidson Resilience Scale scores ≤ 73), lower self-esteem (Rosenberg Self-Esteem Scale scores ≤ 21), and higher perceived stress (Sheldon Cohen Perceived Stress Scale scores ≥ 10)- and viral non-suppression (viral load ≥ 400 copies/mL) and loss to care (no documented clinic visits within the 90 days prior to survey), separately. A total of 359 YWH were included in this analysis. The median age of study participants was 21 (interquartile range: 16-23), and most were female (70.2%), single (82.4%), and attending school (54.7%). Over a quarter of participants (28.1%) had heightened depressive symptoms. Just 16.2% of all participants (n = 58) were lost to care at the time of survey, while 32.4% (n = 73) of the 225 participants with viral load data were non-suppressed. The prevalence of non-suppression in individuals with lower self-esteem was 1.71 (95% confidence interval: 1.12, 2.61) times the prevalence of non-suppression in those with higher self-esteem after adjustment. No meaningful association was observed between heightened depressive symptoms, lower social support, lower resilience, and higher perceived stress and viral non-suppression or loss to care in adjusted analyses. Retention in care and viral suppression among YWH in rural South Africa are below global targets. Interventions aimed at improving viral suppression among YWH should incorporate modules to improve participant's self-esteem as low self-esteem is associated with viral non-suppression in this setting. Future studies should longitudinally explore the joint effects of co-occurring psychosocial stressors on HIV care outcomes in YWH and assess meaningful differences in these effects by age, gender, and route of transmission.

ObjectivesThe Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 and other cross-sectional metrics can lead to potentially counterintuitive conclusions when used to evaluate health systems' performance. This study demonstrates how time and population dynamics impact UNAIDS 90-90-90 metrics in comparison with a longitudinal analogue.DesignA simplified simulation representing a hypothetical population was used to estimate and compare inference from UNAIDS 90-90-90 metrics and longitudinal metrics based on Kaplan-Meier-estimated 2-year probability of transition between stages.MethodsWe simulated a large cohort over 15 years. Everyone started out at risk for HIV, and then transitioned through the HIV care continuum based on fixed daily probabilities of acquiring HIV, learning status, entering care, initiating antiretroviral therapy (ART), and becoming virally suppressed, or dying. We varied the probability of ART initiation over three five-year periods (low, high, and low). We repeated the simulation with an increased probability of death.ResultsThe cross-sectional probability of being on ART among persons who were diagnosed responded relatively slowly to changes in the rate of ART initiation. Increases in ART initiation rates caused apparent declines in the cross-sectional probability of being virally suppressed among persons who had initiated ART, despite no changes in the rate of viral suppression. In some cases, higher mortality resulted in the cross-sectional metrics implying improved healthcare system performance. The longitudinal continuum was robust to these issues.ConclusionThe UNAIDS 90-90-90 care continuum may lead to incorrect inference when used to evaluate health systems performance. We recommend that evaluation of HIV care delivery include longitudinal care continuum metrics wherever possible.

Background and objective This study aimed to understand how gout is currently managed in Australian primary care and to assess the level of interest in changing the delivery of care for gout. Methods This pragmatic qualitative study was conducted among Australian general practitioners (GPs), pharmacists and adults living with gout. Semi-structured interviews were conducted and analysed using thematic analysis. Results The key theme identified was that chronic gout has low priority compared to managing other conditions, and management is often responsive to patient action. Lack of confidence was expressed about medication regimens for multimorbidities. Regarding changing care delivery, there was widespread interest in enhancing pharmacists' role in providing medication reviews and guidance, but there were conflicting views between some pharmacists and GPs about clinical decisions and prescribing arrangements. Discussion Interpreting findings based on Wagner's chronic care model, it is apparent that there are multiple potential opportunities to change practice that might improve gout management. [ABSTRACT FROM AUTHOR]

Background Frailty is a dynamic syndrome characterized by reduced physiological reserve to maintain homeostasis. Prospective studies have reported frailty worsening in women with breast cancer during chemotherapy, with improvements following treatment. We evaluated whether the Faurot frailty index, a validated claims-based frailty measure, could identify changes in frailty during chemotherapy treatment and identified predictors of trajectory patterns. Methods We included women (65+ years) with stage I-III breast cancer undergoing adjuvant chemotherapy in the SEER-Medicare database (2003-2019). We estimated the Faurot frailty index (range: 0-1; higher scores indicate greater frailty) at chemotherapy initiation, 4 months postinitiation, and 10 months postinitiation. Changes in frailty were compared to a matched noncancer comparator cohort. We identified patterns of frailty trajectories during the year following chemotherapy initiation using K-means clustering. Results Twenty-one thousand five hundred and ninety-nine women initiated adjuvant chemotherapy. Mean claims-based frailty increased from 0.037 at initiation to 0.055 4 months postchemotherapy initiation and fell to 0.049 10 months postinitiation. Noncancer comparators experienced a small increase in claims-based frailty over time (0.055-0.062). We identified 6 trajectory patterns: a robust group (78%), 2 resilient groups (16%), and 3 nonresilient groups (6%). Black women and women with claims for home hospital beds, wheelchairs, and Parkinson's disease were more likely to experience nonresilient trajectories. Conclusions We observed changes in a claims-based frailty index during chemotherapy that are consistent with prior studies using clinical measures of frailty and identified predictors of nonresilient frailty trajectories. Our study demonstrates the feasibility of using claims-based frailty indices to assess changes in frailty during cancer treatment. [ABSTRACT FROM AUTHOR]

Background Frailty is a dynamic aging-related syndrome, but measuring frailty transitions is challenging. The Faurot frailty index is a validated Medicare claims-based frailty proxy based on demographic and billing information. We evaluated whether 3-year changes in the Faurot frailty index were consistent with concurrent changes in the frailty phenotype in a cohort of older adults. Methods We used longitudinal data from the National Health and Aging Trends Study (NHATS) with Medicare claims linkage (2010–2018). We identified older adults (66+ years) in the 2011 and 2015 NHATS cohorts with at least 1 year of Medicare fee-for-service continuous enrollment (N = 6 951). We described annual changes in mean claims-based frailty for up to 3 years, based on concurrent transitions in the frailty phenotype. Results At baseline, 32% were robust, 48% prefrail, and 19% frail based on the frailty phenotype. Mean claims-based frailty for older adults who were robust at baseline and worsened to frail increased over 3 years (0.09–0.25). Similarly, those who worsened from prefrail to frail experienced an increase in mean claims-based frailty (0.14–0.26). Improvements in the frailty phenotype did not correspond to decreases in claims-based frailty. Older adults whose frailty phenotype improved over time had a lower baseline claims-based frailty score than those who experienced stable or worsening frailty. Conclusions Older adults who experienced a frailty phenotype worsening over 3 years experienced concurrent increases in the Faurot frailty index. Our results suggest that claims data may be used to identify clinically meaningful worsening in frailty. [ABSTRACT FROM AUTHOR]

Purpose: Although the limitations of hazard ratios (HRs) for quantifying treatment effects in right‐censored data have been widely discussed, HRs are still preferentially reported over other, more interpretable effect measures. This may stem from the fact that there are few applied examples that directly contrast the HR and its interpretation with alternative effect measures. Methods: We analyzed data from two randomized clinical trials comparing panitumumab plus standard‐of‐care chemotherapy (SOCC) with SOCC alone as first‐ and second‐line treatment for metastatic colorectal cancer. We report the effect of treatment with panitumumab on progression‐free survival (PFS) using a Cox proportional hazards model to estimate the HR and the Kaplan‐Meier estimator of cumulative incidence (risk). Further analyses included examining the cumulative incidence curves; kernel‐smoothed, non‐parametric hazards curves; fitting the Cox model with a continuous time variable; and estimating restricted mean survival as well as median survival. Results: The HR was 0.82 (95% confidence interval [CI]: 0.71, 0.93), while the risk ratio (or relative risk [i.e., ratio of the cumulative incidence among the treated versus comparator]) was 0.99 (95% CI: 0.96, 1.02). These two measures suggest apparently different conclusions: either a treatment benefit or no effect. Through subsequent analyses, we demonstrated that, while the cumulative incidence of the outcome was similar by the end of follow‐up regardless of treatment, the panitumumab treated group experienced longer PFS than those randomized to SOCC. Substantial nonproportional hazards were evident with panitumumab treatment reducing the hazard of progression/mortality during the first ~1.75 years but associated with an increased hazard of progress/mortality thereafter. Discussion: This example underscores the difficulties in interpreting HRs, particularly in the setting of qualitative violations of proportional hazards, and the value of quantifying treatment effects via multiple effect measures. [ABSTRACT FROM AUTHOR]

Cause-specific mortality is an important outcome in studies of interventions to improve survival, yet causes of death can be misclassified. Here, we present an approach to performing sensitivity analyses for misclassification of cause of death in the parametric g-formula. The g-formula is a useful method to estimate effects of interventions in epidemiologic research because it appropriately accounts for time-varying confounding affected by prior treatment and can estimate risk under dynamic treatment plans. We illustrate our approach using an example comparing acquired immune deficiency syndrome (AIDS)-related mortality under immediate and delayed treatment strategies in a cohort of therapy-naive adults entering care for human immunodeficiency virus infection in the United States. In the standard g-formula approach, 10-year risk of AIDS-related mortality under delayed treatment was 1.73 (95% CI: 1.17, 2.54) times the risk under immediate treatment. In a sensitivity analysis assuming that AIDS-related death was measured with sensitivity of 95% and specificity of 90%, the 10-year risk ratio comparing AIDS-related mortality between treatment plans was 1.89 (95% CI: 1.13, 3.14). When sensitivity and specificity are unknown, this approach can be used to estimate the effects of dynamic treatment plans under a range of plausible values of sensitivity and specificity of the recorded event type.

BackgroundEfavirenz has been a mainstay of antiretroviral therapy (ART) for over 15 years in the US. Its association with neuropsychiatric side effects may influence clinical prescribing and management.MethodsWe included HIV-infected adults enrolled in care at seven sites across the US, who initiated combination ART between 1999 and 2015. We examined the proportion initiating and continuing on efavirenz, overall and by mental health status. Log binomial and Cox models were used to estimate associations between mental health, clinical and sociodemographic characteristics and initiating or switching from efavirenz as first-line ART.ResultsOf the 8,230 participants included, 3,710 (45%) initiated efavirenz. In multivariable analyses, prior mono- or dual-ART, ART initiation after 2006, being female, intravenous drug use, antidepressant prescription, previous mental health diagnosis and baseline CD4+ T-cell count >350 cells/mm3 were inversely associated with initiating efavirenz. Participants initiating efavirenz had a faster time to a regimen switch, compared with those initiating an efavirenz-free regimen (P-value

Heavy drinking is prevalent among people living with HIV. Studies use tools like patient-reported outcomes (PROs) to quantify alcohol use in a detailed, timely manner. However, if alcohol misuse influences PRO completion, selection bias may result. Our study included 14,145 adult HIV patients (133,036 visits) from CNICS who were eligible to complete PROs at an HIV primary care visit. We compared PRO completion proportions between patients with and without a clinical diagnosis of at-risk alcohol use in the prior year. We accounted for confounding by baseline and visit-specific covariates. PROs were completed at 20.8% of assessed visits. The adjusted difference in PRO completion proportions was -3.2% (95% CI -5.6 to -0.8%). The small association between receipt of an at-risk alcohol use diagnosis and decreased PRO completion suggests there could be modest selection bias in studies using the PRO alcohol measure.

ObjectiveTo explore the effectiveness of raltegravir-based antiretroviral therapy (ART) on treatment response among ART-naive patients seeking routine clinical care.DesignCohort study of adults enrolled in HIV care in the United States.MethodsWe compared virologic suppression and CD4 cell count recovery over a 2.5 year period after initiation of an ART regimen containing raltegravir or efavirenz using observational data from a US clinical cohort, generalized to the US population of people with diagnosed HIV. We accounted for nonrandom treatment assignment, informative censoring, and nonrandom selection from the US target population using inverse probability weights.ResultsOf the 2843 patients included in the study, 2476 initiated the efavirenz-containing regimen and 367 initiated the raltegravir-containing regimen. In the weighted intent-to-treat analysis, patients spent an average of 74 (95% confidence interval: 41, 106) additional days alive with a suppressed viral load on the raltegravir regimen than on the efavirenz regimen over the 2.5-year study period. CD4 cell count recovery was also superior under the raltegravir regimen.ConclusionPatients receiving raltegravir spent more time alive and suppressed than patients receiving efavirenz, but the probability of viral suppression by 2.5 years after treatment was similar between groups. Optimizing the amount of time spent in a state of viral suppression is important to improve survival among people living with HIV and to reduce onward transmission.

Marginal structural models for time-fixed treatments fit using inverse-probability weighted estimating equations are increasingly popular. Nonetheless, the resulting effect estimates are subject to finite-sample bias when data are sparse, as is typical for large-sample procedures. Here we propose a semi-Bayes estimation approach which penalizes or shrinks the estimated model parameters to improve finite-sample performance. This approach uses simple symmetric data-augmentation priors. Limited simulation experiments indicate that the proposed approach reduces finite-sample bias and improves confidence-interval coverage when the true values lie within the central "hill" of the prior distribution. We illustrate the approach with data from a nonexperimental study of HIV treatments.

BackgroundEvidence about the effect of initiating efavirenz-containing combination antiretroviral therapy (ART) as the first-line therapy on suicidal thoughts remains conflicting.MethodsUsing data from a cohort of HIV-infected adults enrolled in routine care across 5 sites in the United States, we included participants with a baseline patient-reported outcome measure and detectable viral load who initiated ART between 2011 and 2014. Participants were followed until the earliest of the following: first suicidal thoughts, discontinuation of initial ART regimen, death, loss to care (>12 months with no HIV appointments), or administrative censoring (2014-2015). Suicidal thoughts were measured using a Patient Health Questionnaire-9 item. We used weighted marginal structural Cox models to estimate the effect of initiating efavirenz-containing ART, versus efavirenz-free ART, on the hazard of active or passive suicidal thoughts after ART initiation, accounting for confounding by channeling bias.ResultsOverall, 597 participants were followed for a median of 19 months (13,132 total person-months); 147 (25%) initiated efavirenz-containing ART. At ART initiation, 38% of participants reported suicidal thoughts or depressive symptoms. Initiating efavirenz-based ART was associated with a hazard ratio (HR) for suicidal thoughts below the null in the crude analysis [HR, 0.88; 95% confidence interval (CI): 0.53 to 1.45] and above the null in the weighted analysis (HR, 1.21; 95% CI: 0.66 to 2.28). Among those with a prior mental health issue, the weighted HR was 1.76 (95% CI: 0.45 to 6.86).ConclusionsAfter accounting for measured channeling bias, we observed no strong evidence that initiating efavirenz-containing ART increased the hazard of suicidal thoughts.