Measuring the COVID-19 Mortality Burden in the United States : A Microsimulation Study.

BACKGROUND: Fully assessing the mortality burden of the COVID-19 pandemic requires measuring years of life lost (YLLs) and accounting for quality-of-life differences. OBJECTIVE: To measure YLLs and quality-adjusted life-years (QALYs) lost from the COVID-19 pandemic, by age, sex, race/ethnicity, and comorbidity. DESIGN: State-transition microsimulation model. DATA SOURCES: Health and Retirement Study, Panel Study of Income Dynamics, data on excess deaths from the Centers for Disease Control and Prevention, and nursing home death counts from the Centers for Medicare & Medicaid Services. TARGET POPULATION: U.S. population aged 25 years and older. TIME HORIZON: Lifetime. PERSPECTIVE: Individual. INTERVENTION: COVID-19 pandemic through 13 March 2021. OUTCOME MEASURES: YLLs and QALYs lost per 10 000 persons in the population. The estimates account for the age, sex, and race/ethnicity of decedents, along with obesity, smoking behavior, lung disease, heart disease, diabetes, cancer, stroke, hypertension, dementia, and nursing home residence. RESULTS OF BASE-CASE ANALYSIS: The COVID-19 pandemic resulted in 6.62 million QALYs lost (9.08 million YLLs) through 13 March 2021, with 3.6 million (54%) lost by those aged 25 to 64 years. The greatest toll was on Black and Hispanic communities, especially among men aged 65 years or older, who lost 1138 and 1371 QALYs, respectively, per 10 000 persons. Absent the pandemic, 38% of decedents would have had average or above-average life expectancies for their subgroup defined by age, sex, and race/ethnicity. RESULTS OF SENSITIVITY ANALYSIS: Accounting for uncertainty in risk factors for death from COVID-19 yielded similar results. LIMITATION: Estimates may vary depending on assumptions about mortality and quality-of-life projections. CONCLUSION: Beyond excess deaths alone, the COVID-19 pandemic imposed a greater life expectancy burden on persons aged 25 to 64 years, including those with average or above-average life expectancies, and a disproportionate burden on Black and Hispanic communities. PRIMARY FUNDING SOURCE: National Institute on Aging.

Internal deletion compromises the stability of dystrophin.

Duchenne muscular dystrophy (DMD) is a deadly and common childhood disease caused by mutations that disrupt dystrophin protein expression. Several miniaturized dystrophin/utrophin constructs are utilized for gene therapy, and while these constructs have shown promise in mouse models, the functional integrity of these proteins is not well described. Here, we compare the biophysical properties of full-length dystrophin and utrophin with therapeutically relevant miniaturized constructs using an insect cell expression system. Full-length utrophin, like dystrophin, displayed a highly cooperative melting transition well above 37°C. Utrophin constructs involving N-terminal, C-terminal or internal deletions were remarkably stable, showing cooperative melting transitions identical to full-length utrophin. In contrast, large dystrophin deletions from either the N- or C-terminus exhibited variable stability, as evidenced by melting transitions that differed by 20°C. Most importantly, deletions in the large central rod domain of dystrophin resulted in a loss of cooperative unfolding with increased propensity for aggregation. Our results suggest that the functionality of dystrophin therapeutics based on mini- or micro-constructs may be compromised by the presence of non-native protein junctions that result in protein misfolding, instability and aggregation.

Assessing the Use of Data Systems to Estimate Return-on-Investment of Behavioral Healthcare Interventions: Opportunities and Barriers.

To improve access to and quality of affordable behavioral healthcare, there is a need for more research to identify which interventions can generate long-term, societal return-on-investment (ROI). Barriers to ROI studies in the behavioral health sector were explored by conducting semi-structured interviews with individuals from key stakeholder groups at state and national behavioral health-related organizations. Limited operating budgets, state-based payer systems, the lack of financial support, privacy laws, and other unique experiences of behavioral health providers and patients were identified as important factors that affect the collection and utilization of data. To comprehensively assess ROI of interventions, it is necessary to improve standardization and data infrastructure across multiple health and non-health systems and clarify or address legal, regulatory, and commercial conflicts.

Using dynamic microsimulation to project cognitive function in the elderly population.

BACKGROUND: A long-term projection model based on nationally representative data and tracking disease progression across Alzheimer's disease continuum is important for economics evaluation of Alzheimer's disease and other dementias (ADOD) therapy. METHODS: The Health and Retirement Study (HRS) includes an adapted version of the Telephone Interview for Cognitive Status (TICS27) to evaluate respondents' cognitive function. We developed an ordered probit transition model to predict future TICS27 score. This transition model is utilized in the Future Elderly Model (FEM), a dynamic microsimulation model of health and health-related economic outcomes for the US population. We validated the FEM TICS27 model using a five-fold cross validation approach, by comparing 10-year (2006-2016) simulated outcomes against observed HRS data. RESULTS: In aggregate, the distribution of TICS27 scores after ten years of FEM simulation matches the HRS. FEM's assignment of cognitive/mortality status also matches those observed in HRS on the population level. At the individual level, the area under the receiver operating characteristic (AUROC) curve is 0.904 for prediction of dementia or dead with dementia in 10 years, the AUROC for predicting significant cognitive decline in two years for mild cognitive impairment patients is 0.722. CONCLUSIONS: The FEM TICS27 model demonstrates its predictive accuracy for both two- and ten-year cognitive outcomes. Our cognition projection model is unique in its validation with an unbiased approach, resulting in a high-quality platform for assessing the burden of cognitive decline and translating the benefit of innovative therapies into long-term value to society.

Association Between Race/Ethnicity and Disparities in Health Care Use Before First-Episode Psychosis Among Privately Insured Young Patients.

Importance: Racial/ethnic disparities in health care use and clinical outcomes for behavioral health disorders, including psychosis, are well documented, but less is known about these disparities during the period leading up to first-episode psychosis (FEP). Objective: To describe the racial/ethnic disparities in behavioral health care use and prescription drug use of children and young adults before the diagnosis of FEP. Design, Setting, and Participants: An observational cohort study was conducted using medical and prescription drug claims from January 1, 2007, to September 30, 2015, obtained from Optum's deidentified Clinformatics Data Mart Database, a commercial claims database augmented with race/ethnicity and socioeconomic variables. Data analysis was performed from February 6, 2018, to October 10, 2020. First-episode psychosis was determined by the presence of psychosis diagnoses on claims for at least 1 hospitalization or 2 outpatient events, with a continuous enrollment requirement of at least 2 years before the first diagnosis. Participants included 3017 Black, Hispanic, or White patients who were continually enrolled in commercial insurance plans and received an FEP diagnosis between the ages of 10 and 21 years. Main Outcomes and Measures: Race/ethnicity was determined from a commercial claims database. Rates of inpatient admission, emergency department presentation, and outpatient visits (including psychotherapy), behavioral health disorder diagnoses, and antipsychotic/antidepressant prescription fills were determined for the year before FEP. Race/ethnicity was also obtained from Optum's claims database. With use of multivariable logistic regression, results were adjusted for covariates including estimated household income, age, sex, and geographic division in the US. Results: Of the 3017 patients with FEP, 643 Black or Hispanic patients (343 [53.3%] Black, 300 [46.7%] Hispanic, 324 [50.4%] male, mean [SD] age, 17.2 [2.76] years) were less likely than 2374 White patients (1210 [51.0%] male, mean age, 17.0 [2.72] years) to receive comorbid behavioral health disorder diagnoses in the year before the diagnosis of FEP (410 [63.8%] vs 1806 [76.1%], χ2 = 39.3; P < .001). Except for emergency care, behavioral health care use rates were lower in Black and Hispanic patients vs White patients (424 [65.9%] vs 1868 [78.7%]; χ2 = 45.0; P < .001), particularly for outpatient visits with behavioral health care professionals (232 [36.1%] vs 1236 [52.1%]; χ2 = 51.7; P < .001). After adjustment for socioeconomic covariates, behavioral health care use rates (68.9% vs 79.2%; P < .001), outpatient visits with behavioral health professionals (37.7% vs 51.2%; P < .001), and other outcomes remained significantly lower for Black and Hispanic patients vs White patients. Conclusions and Relevance: The results of this study extend existing research findings of well-known racial/ethnic disparities in the population of patients who are diagnosed with FEP. These differences were apparent in young patients with continuous commercial health insurance and after controlling for household income. Providing equal access to preventive outpatient behavioral health care may increase opportunities for timely detection of psychotic symptoms and early intervention and improve differential outcomes after FEP.

Functional substitution by TAT-utrophin in dystrophin-deficient mice.

BACKGROUND: The loss of dystrophin compromises muscle cell membrane stability and causes Duchenne muscular dystrophy and/or various forms of cardiomyopathy. Increased expression of the dystrophin homolog utrophin by gene delivery or pharmacologic up-regulation has been demonstrated to restore membrane integrity and improve the phenotype in the dystrophin-deficient mdx mouse. However, the lack of a viable therapy in humans predicates the need to explore alternative methods to combat dystrophin deficiency. We investigated whether systemic administration of recombinant full-length utrophin (Utr) or DeltaR4-21 "micro" utrophin (muUtr) protein modified with the cell-penetrating TAT protein transduction domain could attenuate the phenotype of mdx mice. METHODS AND FINDINGS: Recombinant TAT-Utr and TAT-muUtr proteins were expressed using the baculovirus system and purified using FLAG-affinity chromatography. Age-matched mdx mice received six twice-weekly intraperitoneal injections of either recombinant protein or PBS. Three days after the final injection, mice were analyzed for several phenotypic parameters of dystrophin deficiency. Injected TAT-muUtr transduced all tissues examined, integrated with members of the dystrophin complex, reduced serum levels of creatine kinase (11,290+/-920 U versus 5,950+/-1,120 U; PBS versus TAT), the prevalence of muscle degeneration/regeneration (54%+/-5% versus 37%+/-4% of centrally nucleated fibers; PBS versus TAT), the susceptibility to eccentric contraction-induced force drop (72%+/-5% versus 40%+/-8% drop; PBS versus TAT), and increased specific force production (9.7+/-1.1 N/cm(2) versus 12.8+/-0.9 N/cm(2); PBS versus TAT). CONCLUSIONS: These results are, to our knowledge, the first to establish the efficacy and feasibility of TAT-utrophin-based constructs as a novel direct protein-replacement therapy for the treatment of skeletal and cardiac muscle diseases caused by loss of dystrophin.

Measuring The Lifetime Costs Of Serious Mental Illness And The Mitigating Effects Of Educational Attainment.

Serious mental illness (SMI) is a disabling condition that develops early in life and imposes substantial economic burden. There is a growing belief that early intervention for SMI has lifelong benefits for patients. However, assessing the cost-effectiveness of early intervention efforts is hampered by a lack of evidence on the long-term benefits. We addressed this by using a dynamic microsimulation model to estimate the lifetime burden of SMI for those diagnosed by age twenty-five. We estimated that the per patient lifetime burden of SMI is $1.85 million. We also found that a policy intervention focused on improving the educational attainment of people with SMI reduces the average per person burden of SMI by $73,600 (4.0 percent)-a change driven primarily by higher lifetime earnings-or over $8.9 billion in reduced burden per cohort of SMI patients. These findings provide a benchmark for the potential value of improving educational attainment for people with SMI.

Differential impact of Met receptor gene interaction with early-life stress on neuronal morphology and behavior in mice.

Early adversity in childhood increases the risk of anxiety, mood, and post-traumatic stress disorders in adulthood, and specific gene-by-environment interactions may increase risk further. A common functional variant in the promoter region of the gene encoding the human MET receptor tyrosine kinase (rs1858830 'C' allele) reduces expression of MET and is associated with altered cortical circuit function and structural connectivity. Mice with reduced Met expression exhibit changes in anxiety-like and conditioned fear behavior, precocious synaptic maturation in the hippocampus, and reduced neuronal arbor complexity and synaptogenesis. These phenotypes also can be produced independently by early adversity in wild-type mice. The present study addresses the outcome of combining early-life stress and genetic influences that alter timing of maturation on enduring functional and structural phenotypes. Using a model of reduced Met expression (Met+/- ) and early-life stress from postnatal day 2-9, social, anxiety-like, and contextual fear behaviors in later life were measured. Mice that experienced early-life stress exhibited impairments in social interaction, whereas alterations in anxiety-like behavior and fear learning were driven by Met haploinsufficiency, independent of rearing condition. Early-life stress or reduced Met expression decreased arbor complexity of ventral hippocampal CA1 pyramidal neurons projecting to basolateral amygdala. Paradoxically, arbor complexity in Met+/- mice was increased following early-life stress, and thus not different from arbors in wild-type mice raised in control conditions. The changes in dendritic morphology are consistent with the hypothesis that the physiological state of maturation of CA1 neurons in Met+/- mice influences their responsiveness to early-life stress. The dissociation of behavioral and structural changes suggests that there may be phenotype-specific sensitivities to early-life stress.

Early-Life Stress Paradigm Transiently Alters Maternal Behavior, Dam-Pup Interactions, and Offspring Vocalizations in Mice.

Animal models can help elucidate the mechanisms through which early-life stress (ELS) has pathophysiological effects on the developing brain. One model that has been developed for rodents consists of limiting the amount of bedding and nesting material during the first postnatal weeks of pup life. This ELS environment has been shown to induce "abusive" behaviors by rat dams towards pups, while mouse dams have been hypothesized to display "fragmented care". Here, as part of an ongoing study of gene-environment interactions that impact brain development, we analyzed long observation periods of wild-type C57Bl/6J dams caring for wild-type and Met heterozygous pups. Met encodes for the MET receptor tyrosine kinase, which is involved in cortical and hippocampal synaptogenesis. Dams with limited resources from postnatal day (P)2 to P9 preserved regular long on-nest periods, and instead increased the number of discrete dam-pup interactions during regular off-nest periods. Immediately after dams entered the nest during off-nest periods in this ELS environment, pups responded to these qualitatively different interactions with an increased number of ultrasonic vocalizations (USV) and audible vocalizations (AV), communication signals that have been associated with aversive and painful stimuli. After returning to control conditions, nest entry behaviors normalized, and dams did not show altered anxiety-like or contextual fear learning behaviors after pup weaning. Furthermore, female mice that had undergone ELS as pups did not show atypical nest entry behaviors in control conditions in adulthood, suggesting that these specific maternal behaviors are not learned during the ELS period. The results suggest that atypical responses of both mother and pups during exposure to this ELS environment likely contribute to long-term negative outcomes in mice, and that these responses more closely resemble the effects of limited bedding on rat dams and pups than was previously suggested. Discerning how different early-life stressors mediate changes in maternal-pup interactions can help elucidate the mechanisms of ELS on brain development and behavior.