Sex-based structural and functional MRI outcomes in the rat brain after soman (GD) exposure-induced status epilepticus.

OBJECTIVE: Exposure to the nerve agent, soman (GD), induces status epilepticus (SE), epileptogenesis, and even death. Although rodent models studying the pathophysiological mechanisms show females to be more reactive to soman, no tangible sex differences in brains postexposure have been reported. In this study, we used multimodal imaging using MRI in adult rats to determine potential sex-based biomarkers of soman effects. METHODS: Male and female Sprague Dawley rats were challenged with 1.2 × LD50 soman followed by medical countermeasures. Ten weeks later, the brains were analyzed via structural and functional MRI. RESULTS: Despite no significant sex differences in the initial SE severity after soman exposure, long-term MRI-based structural and functional differences were evident in the brains of both sexes. While T2 MRI showed lesser soman-induced neurodegeneration, large areas of T1 enhancements occurred in females than in males, indicating a distinct pathophysiology unrelated to neurodegeneration. fMRI-based resting-state functional connectivity (RSFC), indicated greater reductions in soman-exposed females than in males, associating with the T1 enhancements (unrelated to neurodegeneration) rather than T2-hyperintensity or T1-hypointensity (representing neurodegeneration). The wider T1 enhancements associating with the decreased spontaneous neuronal activity in multiple resting-state networks in soman-exposed females than males suggest that neural changes unrelated to cellular atrophy impinge on brain function postexposure. Taken together with lower spontaneous neural activity in soman-exposed females, the results indicate some form of neuroprotective state that was not present in males. SIGNIFICANCE: The results indicate that endpoints other than neurodegeneration may need to be considered to translate sex-based nerve agent effects in humans.

Paternal mitochondria from an rmd-2, rmd-3, rmd-6 triple mutant are properly positioned in the C. elegans zygote.

RMD-1,2,3,6 (regulator of microtubule dynamics) is a family of homologous proteins conserved between humans and C. elegans. Human RMD-3/PTPIP51 is a mitochondrial protein that tethers mitochondria to the endoplasmic reticulum. C. elegans RMD-2, 3, and 6 are expressed in sperm. To test whether paternal RMD-2, 3, 6 might redundantly tether paternal mitochondria to maternal ER at fertilization, we generated an rmd-2, rmd-3, rmd-6 triple mutant. Paternal mitochondria derived from control or triple mutant worms were concentrated in a cloud around the paternal DNA at the future posterior end of zygotes during meiosis. No significant difference was detected in the position of paternal mitochondria within the zygote nor in the position of paternal mitochondria relative to paternal DNA within the zygote. There was also no reduction in progeny viability between control and triple mutant worms.

Predictive modeling of total healthcare costs using pharmacy claims data: a comparison of alternative econometric cost modeling techniques.

OBJECTIVE: We sought to evaluate several statistical modeling approaches in predicting prospective total annual health costs (medical plus pharmacy) of health plan participants using Pharmacy Health Dimensions (PHD), a pharmacy claims-based risk index. METHODS: We undertook a 2-year (baseline year/follow-up year) longitudinal analysis of integrated medical and pharmacy claims. Included were plan participants younger than 65 years of age with continuous medical and pharmacy coverage (n = 344,832). PHD drug categories, age, gender, and pharmacy costs were derived across the baseline year. Annual total health costs were calculated for each plan participant in follow-up year. Models examined included ordinary least squares (OLS) regression, log-transformed OLS regression with smearing estimator, and 3 two-part models using OLS regression, log-OLS regression with smearing estimator, and generalized linear modeling (GLM), respectively. A 10% random sample was withheld for model validation, which was assessed via adjusted r, mean absolute prediction error, specificity, and positive predictive value. RESULTS: Most PHD drug categories were significant independent predictors of total costs. Among models tested, the OLS model had the lowest mean absolute prediction error and highest adjusted r. The log-OLS and 2-part log-OLS models did not predict costs accurately as the result of issues of log-scale heteroscedasticity. The 2-part model using GLM had lower adjusted r but similar performance in other assessment measures compared with the OLS or 2-part OLS models. CONCLUSION: The PHD system derived solely from pharmacy claims data can be used to predict future total health costs. Using PHD with a simple OLS model may provide similar predictive accuracy in comparison to more advanced econometric models.

Incident hypertension associated with depression in the Baltimore Epidemiologic Catchment area follow-up study.

BACKGROUND: This study evaluates the role of depression as a specific risk factor for hypertension. METHODS: This study analyzed the prospective data in the Baltimore Epidemiologic Catchment Area (ECA) Follow-up Study (n=1920), a longitudinal population-based study of mental illness in East Baltimore. Incident cases of hypertension as assessed by self-report (n=148) in 1993 were compared to the remaining cohort without hypertension (n=901) across three waves of ECA interviews (1981, 1982, 1993). Depression and related symptoms were measured at baseline (1981) by the Diagnostic Interview Schedule (DIS) and categorized as dysphoria, dysthymia, or major depressive episode (MDE) according to Diagnostic and Statistical Manual (DSM) III criteria. RESULTS: Individuals with a major depressive episode compared to those who reported never having dysphoria had a marginally significant increased risk for hypertension (Odds Ratio (OR)=2.16; 95% Confidence Interval (CI) (0.94,4.98)) after adjustment for age, gender, race, body mass index, Nam-Powers socioeconomic score, alcohol usage, smoking, exercise, diabetes status, and number of general medical visits. MDE reported to have begun more than a year before the baseline measurement was associated with an increased risk for incident hypertension (Adjusted OR=3.67, 95% CI (1.25,10.79). LIMITATIONS: Potential misclassification of self-reported hypertension outcome. CONCLUSIONS: Even though the data are based on self-report of hypertension, these findings suggest that depression may be an independent risk factor for hypertension particularly for those with recurrent episodes or a long term history of the disease.

Pharmacy benefit forecast for a new interferon Beta-1a for the treatment of multiple sclerosis: development of a first-line decision tool for pharmacy-budget planning using administrative claims data.

OBJECTIVE: To estimate the incremental change in pharmacy per-member-permonth (PMPM) costs, according to various formulary designs, for a new interferon beta-1a product (IB1a2) using administrative claims data. METHODS: Cross-sectional sex- and age-specific disease prevalence and treatment rates for relapsing, remitting multiple sclerosis (RRMS) patients were measured using integrated medical and pharmacy claims data from a 500,000- member employer group in the southern United States. Migration to IB1a2 from other drugs in the class was based on market-share data for new and existing RRMS patients. Duration of therapy was estimated by analyzing claims for current RRMS therapies. Daily therapy cost was provided by the manufacturer of IB1a2, adjusted for migration from other therapies, and multiplied by estimated volume to predict incremental and total PMPM cost impact. Market-share estimates were used to develop a PMPM cost forecast for the next 2 years. PMPM cost estimates were calculated for preferred (copayment tier 2) and nonpreferred (copayment tier 3) formulary designs with and without prior authorization (PA). One-way sensitivity analysis was performed to assess the influence of product pricing, duration of therapy, and other market factors. RESULTS: Annual incremental PMPM change was $0.047 for the scenario of third copayment tier with PA. The incremental change was greatest for those aged 55 to 65 years ($0.056 PMPM) and did not vary greatly by benefit design. Duration of therapy had the greatest impact on the PMPM estimate across benefit designs. CONCLUSION: IB1a2 will not cause a significant change in managed care pharmacy budgets under a variety of formulary conditions, according to this crosssectional analysis of current care-seeking behavior by RRMS patients. Economic impact may differ if IB1a2 expands RRMS patients. treatment-seeking behavior.