Differences in Risk of Alzheimer's Disease Following Later-Life Traumatic Brain Injury in Veteran and Civilian Populations.

OBJECTIVE: To directly compare the effect of incident age 68+ traumatic brain injury (TBI) on the risk of diagnosis of clinical Alzheimer's disease (AD) in the general population of older adults, and between male veterans and nonveterans; to assess how this effect changes with time since TBI. SETTING AND PARTICIPANTS: Community-dwelling traditional Medicare beneficiaries 68 years or older from the Health and Retirement Study (HRS). DESIGN: Fine-Gray models combined with inverse-probability weighting were used to identify associations between incident TBI, post-TBI duration, and TBI treatment intensity, with a diagnosis of clinical AD dementia. The study included 16 829 older adults followed over the 1991-2015 period. For analyses of veteran-specific risks, 4281 veteran males and 3093 nonveteran males were identified. Analysis of veteran females was unfeasible due to the age structure of the population. Information on occurrence(s) of TBI, and onset of AD and risk-related comorbidities was constructed from individual-level HRS-linked Medicare claim records while demographic and socioeconomic risk factors were based on the survey data. RESULTS: Later-life TBI was strongly associated with increased clinical AD risk in the full sample (pseudo-hazard ratio [HR]: 3.22; 95% confidence interval [CI]: 2.57-4.05) and in veteran/nonveteran males (HR: 5.31; CI: 3.42-7.94), especially those requiring high-intensity/duration care (HR: 1.58; CI: 1.29-1.91). Effect magnitude decreased with time following TBI (HR: 0.72: CI: 0.68-0.80). CONCLUSION: Later-life TBI was strongly associated with increased AD risk, especially in those requiring high-intensity/duration care. Effect magnitude decreased with time following TBI. Univariate analysis showed no differences in AD risk between veterans and nonveterans, while the protective effect associated with veteran status in Fine-Gray models was largely due to differences in demographics, socioeconomics, and morbidity. Future longitudinal studies incorporating diagnostic procedures and documentation quantifying lifetime TBI events are necessary to uncover pathophysiological mediating and/or moderating mechanisms between TBI and AD.

Epidemiology of geographic disparities in heart failure among US older adults: a Medicare-based analysis.

BACKGROUND: There are prominent geographic disparities in the life expectancy (LE) of older US adults between the states with the highest (leading states) and lowest (lagging states) LE and their causes remain poorly understood. Heart failure (HF) has been proposed as a major contributor to these disparities. This study aims to investigate geographic disparities in HF outcomes between the leading and lagging states. METHODS: The study was a secondary data analysis of HF outcomes in older US adults aged 65+, using Center for Disease Control and Prevention sponsored Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database and a nationally representative 5% sample of Medicare beneficiaries over 2000-2017. Empiric estimates of death certificate-based mortality from HF as underlying cause of death (CBM-UCD)/multiple cause of death (CBM-MCD); HF incidence-based mortality (IBM); HF incidence, prevalence, and survival were compared between the leading and lagging states. Cox regression was used to investigate the effect of residence in the lagging states on HF incidence and survival. RESULTS: Between 2000 and 2017, HF mortality rates (per 100,000) were higher in the lagging states (CBM-UCD: 188.5-248.6; CBM-MCD: 749.4-965.9; IBM: 2656.0-2978.4) than that in the leading states (CBM-UCD: 79.4-95.6; CBM-MCD: 441.4-574.1; IBM: 1839.5-2138.1). Compared to their leading counterparts, lagging states had higher HF incidence (2.9-3.9% vs. 2.2-2.9%), prevalence (15.6-17.2% vs. 11.3-13.0%), and pre-existing prevalence at age 65 (5.3-7.3% vs. 2.8-4.1%). The most recent rates of one- (77.1% vs. 80.4%), three- (59.0% vs. 60.7%) and five-year (45.8% vs. 49.8%) survival were lower in the lagging states. A greater risk of HF incidence (Adjusted Hazards Ratio, AHR [95%CI]: 1.29 [1.29-1.30]) and death after HF diagnosis (AHR: 1.12 [1.11-1.13]) was observed for populations in the lagging states. The study also observed recent increases in CBMs and HF incidence, and declines in HF prevalence, prevalence at age 65 and survival with a decade-long plateau stage in IBM in both leading and lagging states. CONCLUSION: There are substantial geographic disparities in HF mortality, incidence, prevalence, and survival across the U.S.: HF incidence, prevalence at age 65 (age of Medicare enrollment), and survival of patients with HF contributed most to these disparities. The geographic disparities and the recent increase in incidence and decline in survival underscore the importance of HF prevention strategies.

Partitioning of time trends in prevalence and mortality of lung cancer.

BACKGROUND: Time trends of lung cancer prevalence and mortality are the result of three competing processes: changes in the incidence rate, stage-specific survival, and ascertainment at early stages. Improvements in these measures act concordantly to improve disease-related mortality, but push the prevalence rate in opposite directions making a qualitative interpretation difficult. The goal of this paper is to evaluate the relative contributions of these components to changes in lung cancer prevalence and mortality. METHODS: Partitioning of prevalence and mortality trends into their components using SEER data for 1973-2013. RESULTS: The prevalence of lung cancer increases for females and decreases for males. In 1998, the former was due to increased incidence (45%-50% of total trend), improved survival (40%-45%), and increased ascertainment at early stages (10%-15%). In males, a rapidly declining incidence rate overpowered the effects of survival and ascertainment resulting in an overall decrease in prevalence over time. Trends in lung cancer mortality are determined by incidence during 1993-2002 with noticeable contribution of survival after 2002. CONCLUSION: Lung cancer incidence was the main driving force behind trends in prevalence and mortality. Improved survival played essential role from 2000 onwards. Trends in stage ascertainment played a small but adverse role. Our results suggest that further improvement in lung cancer mortality can be achieved through advances in early stage ascertainment, especially for males, and that in spite of success in treatment, adenocarcinoma continues to exhibit adverse trends (especially in female incidence) and its role among other histology-specific lung cancers will increase in the near future.

Mortality and Health Outcomes in North Carolina Communities Located in Close Proximity to Hog Concentrated Animal Feeding Operations.

BACKGROUND Life expectancy in southeastern North Carolina communities located in an area with multiple concentrated animal feeding operations (CAFOs) after adjusting for socioeconomic factors remains low. We hypothesized that poor health outcomes in this region may be due to converging demographic, socioeconomic, behavioral, and access-to-care factors and are influenced by the presence of hog CAFOs.METHODS We studied mortality, hospital admissions, and emergency department (ED) usage for health conditions potentially associated with hog CAFOs-anemia, kidney disease, infectious diseases, and low birth weight (LBW)-in North Carolina communities located in zip codes with hog CAFOs (Study group 1), in zip codes with > 215hogs/km2 (Study group 2), and without hog CAFOs (Control group). We compared cause-specific age-adjusted rates, the odds ratios (ORs) of events in multivariable analyses (adjusted for 6 co-factors), and the changes of ORs relative to the distance to hog CAFOs.RESULTS Residents from Study groups 1 and 2 had higher rates of all-cause mortality, infant mortality, mortality of patients with multimorbidity, mortality from anemia, kidney disease, tuberculosis, and septicemia, and higher rates of ED visits and hospital admissions for LBW infants than the residents in the Control group. In zip codes with > 215hogs/km2, mortality ORs were 1.50 for anemia (P < 0.0001), 1.31 for kidney disease (P < 0.0001), 2.30 for septicemia (P < 0.0001), and 2.22 for tuberculosis (P = 0.0061).LIMITATIONS This study included a lack of individual measurements on environmental contaminants, biomarkers of exposures and co-factors, and differences in residential and occupational locations.CONCLUSION North Carolina communities located near hog CAFOs had higher all-cause and infant mortality, mortality due to anemia, kidney disease, tuberculosis, septicemia, and higher hospital admissions/ED visits of LBW infants. Although not establishing causality with exposures from hog CAFOs, our findings support the need for future studies to determine factors that influence these outcomes, as well as the need to improve screening and diagnostic strategies for these diseases in North Carolina communities adjacent to hog CAFOs.

stpm: an R package for stochastic process model.

BACKGROUND: The Stochastic Process Model (SPM) represents a general framework for modeling the joint evolution of repeatedly measured variables and time-to-event outcomes observed in longitudinal studies, i.e., SPM relates the stochastic dynamics of variables (e.g., physiological or biological measures) with the probabilities of end points (e.g., death or system failure). SPM is applicable for analyses of longitudinal data in many research areas; however, there are no publicly available software tools that implement this methodology. RESULTS: We developed an R package stpm for the SPM-methodology. The package estimates several versions of SPM currently available in the literature including discrete- and continuous-time multidimensional models and a one-dimensional model with time-dependent parameters. Also, the package provides tools for simulation and projection of individual trajectories and hazard functions. CONCLUSION: In this paper, we present the first software implementation of the SPM-methodology by providing an R package stpm, which was verified through extensive simulation and validation studies. Future work includes further improvements of the model. Clinical and academic researchers will benefit from using the presented model and software. The R package stpm is available as open source software from the following links: https://cran.r-project.org/package=stpm (stable version) or https://github.com/izhbannikov/spm (developer version).

Platelet Counts and Postoperative Stroke After Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Declining platelet counts may reveal platelet activation and aggregation in a postoperative prothrombotic state. Therefore, we hypothesized that nadir platelet counts after on-pump coronary artery bypass grafting (CABG) surgery are associated with stroke. METHODS: We evaluated 6130 adult CABG surgery patients. Postoperative platelet counts were evaluated as continuous and categorical (mild versus moderate to severe) predictors of stroke. Extended Cox proportional hazard regression analysis with a time-varying covariate for daily minimum postoperative platelet count assessed the association of day-to-day variations in postoperative platelet count with time to stroke. Competing risks proportional hazard regression models examined associations between day-to-day variations in postoperative platelet counts with timing of stroke (early: 0-1 days; delayed: ≥2 days). RESULTS: Median (interquartile range) postoperative nadir platelet counts were 123.0 (98.0-155.0) × 10/L. The incidences of postoperative stroke were 1.09%, 1.50%, and 3.02% for platelet counts >150 × 10/L, 100 to 150 × 10/L, and <100 × 10/L, respectively. The risk for stroke increased by 12% on a given postoperative day for every 30 × 10/L decrease in platelet counts (adjusted hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01-1.24; P= .0255). On a given day, patients with moderate to severe thrombocytopenia were almost twice as likely to develop stroke (adjusted HR, 1.89; 95% CI, 1.13-3.16; P= .0155) as patients with nadir platelet counts >150 × 10/L. Importantly, such thrombocytopenia, defined as a time-varying covariate, was significantly associated with delayed (≥2 days after surgery; adjusted HR, 2.83; 95% CI, 1.48-5.41; P= .0017) but not early postoperative stroke. CONCLUSIONS: Our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and postoperative stroke, and timing of stroke after CABG surgery.

A Systematic Review of Conceptual Frameworks of Medical Complexity and New Model Development.

BACKGROUND: Patient complexity is often operationalized by counting multiple chronic conditions (MCC) without considering contextual factors that can affect patient risk for adverse outcomes. OBJECTIVE: Our objective was to develop a conceptual model of complexity addressing gaps identified in a review of published conceptual models. DATA SOURCES: We searched for English-language MEDLINE papers published between 1 January 2004 and 16 January 2014. Two reviewers independently evaluated abstracts and all authors contributed to the development of the conceptual model in an iterative process. RESULTS: From 1606 identified abstracts, six conceptual models were selected. One additional model was identified through reference review. Each model had strengths, but several constructs were not fully considered: 1) contextual factors; 2) dynamics of complexity; 3) patients' preferences; 4) acute health shocks; and 5) resilience. Our Cycle of Complexity model illustrates relationships between acute shocks and medical events, healthcare access and utilization, workload and capacity, and patient preferences in the context of interpersonal, organizational, and community factors. CONCLUSIONS/IMPLICATIONS: This model may inform studies on the etiology of and changes in complexity, the relationship between complexity and patient outcomes, and intervention development to improve modifiable elements of complex patients.

Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants.

Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity.

Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.

Discordance in Grading Methods of Aortic Stenosis by Pre-Cardiopulmonary Bypass Transesophageal Echocardiography.

BACKGROUND: Current guidelines define severe aortic valve stenosis (AS) as an aortic valve area (AVA) ≤1.0 cm by the continuity equation and mean gradient (ΔPm) ≥ 40 mm Hg. However, these measurements can be discordant when classifying AS severity. Approximately one-third of patients with normal ejection fraction and severe AS by AVA have nonsevere AS by ΔPm when measured by preoperative transthoracic echocardiography (TTE). Given the use of positive pressure ventilation and general anesthesia in the pre-cardiopulmonary bypass (pre-CPB) period, we hypothesized that discordance between ΔPm and AVA during pre-CPB transesophageal echocardiography (TEE) would be higher than previously reported by TTE. METHODS: We retrospectively examined pre-CPB TEE data for patients who had aortic valve replacement, with or without coronary artery bypass grafting, from 2000 to 2012. Patients were excluded if they had ejection fraction <55%, emergency surgery, repeat sternotomy, moderate or severe mitral regurgitation, or severe aortic regurgitation. Only patients with both pre-CPB AVA and ΔPm measurements were included. Patients were grouped according to severity (mild, moderate, and severe) by AVA or ΔPm. Discordance was defined as disagreement between severities based on either parameter. RESULTS: A total of 277 patients met inclusion criteria. There were 227 patients with AVA ≤ 1.0 cm. The proportion of these patients with a ΔPm < 40 mm Hg was 54% (95% confidence interval, 47%-61%). The rate of discordance was significantly higher than the rate (37%; P < 0.001) found in previously reported analyses using TTE. Of the patients with a ΔPm ≥ 40 mm Hg, only 8% (n = 9/113) had a discordant AVA. In contrast, of the patients with ΔPm < 40 mm Hg, 80% (n = 131/164) had a discordant AVA. CONCLUSIONS: We confirmed our hypothesis that grading AS by ΔPm and AVA during pre-CPB TEE exhibits higher discordance than reported for TTE by others. It remains unclear whether these discrepancies reflect the effect of general anesthesia, imaging modality (TTE versus TEE) differences, inaccuracies in AS grading cutoffs when applied to pre-CPB TEE, or selection bias of the surgical population.