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ImportancePrimary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation.ObjectiveTo determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population.Design, Setting, and ParticipantsThis was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023.ExposuresPRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status.Main Outcomes and MeasuresIncident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events.ResultsA total of 79 151 participants (mean [SD] age, 57.8 [13.7] years; 68 503 male [86.5%]) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, −0.07% to 3.30%).Conclusions and RelevanceStudy results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.

COVID-19 and influenza are important sources of morbidity and mortality among older adults. Understanding how outcomes differ for older adults hospitalized with either infection is important for improving care. We compared outcomes from infection with COVID-19 and influenza among hospitalized older adults.We conducted a retrospective study of 30-day mortality among veterans aged 65+ hospitalized with COVID-19 from March 1, 2020-December 31, 2020 or with influenza A/B from September 1, 2017 to August 31, 2019 in Veterans Affairs Health Care System (VAHCS). COVID-19 infection was determined by a positive PCR test and influenza by tests used in the VA system. Frailty was defined by the claims-based Veterans Affairs Frailty Index (VA-FI). Logistic regressions of mortality on frailty, age, and infection were adjusted for multiple confounders.A total of 15,474 veterans were admitted with COVID-19 and 7867 with influenza. Mean (SD) ages were 76.1 (7.8) and 75.8 (8.3) years, 97.7% and 97.4% were male, and 66.9% and 76.4% were white in the COVID-19 and influenza cohorts respectively. Crude 30-day mortality (95% CI) was 18.9% (18.3%-19.5%) for COVID-19 and 4.3% (3.8%-4.7%) for influenza. Combining cohorts, the odds ratio for 30-day mortality from COVID-19 (versus influenza) was 6.61 (5.74-7.65). There was a statistically significant interaction between infection with COVID-19 and frailty, but there was no significant interaction between COVID-19 and age. Separating cohorts, greater 30-day mortality was significantly associated with older age (p: COVID-19:0.001, Influenza:0.001) and for frail compared with robust individuals (p for trend: COVID-19:0.001, Influenza:0.001).Mortality from COVID-19 exceeded that from influenza among hospitalized older adults. However, odds of mortality were higher at every level of frailty among those admitted with influenza compared to COVID-19. Prevention will remain key to reducing mortality from viral illnesses among older adults.

In this retrospective cohort study of 94 595 severe acute respiratory syndrome coronavirus 2–positive cases, we developed and validated an algorithm to assess the association between coronavirus disease 2019 (COVID-19) severity and long-term complications (stroke, myocardial infarction, pulmonary embolism/deep vein thrombosis, heart failure, and mortality). COVID-19 severity was associated with a greater risk of experiencing a long-term complication 31–120 days postinfection. Most incident events occurred 31–60 days postinfection and diminished after day 91, except heart failure for severe patients and death for moderate patients, which peaked on days 91–120. Understanding the differential impact of COVID-19 severity on long-term events provides insight into possible intervention modalities and critical prevention strategies.

Background and Purpose: Low blood pressure (BP) is associated with higher stroke mortality, although the factors underlying this association have not been fully explored. We investigated prestroke BP and long-term mortality after ischemic stroke in a national sample of US veterans. Methods: Using a retrospective cohort study design of veterans hospitalized between 2002 and 2007 with a first ischemic stroke and with ≥1 outpatient BP measurements 1 to 18 months before admission, we defined 6 categories each of average prestroke systolic BP (SBP) and diastolic BP, and 7 categories of pulse pressure. Patients were followed-up to 12 years for primary outcomes of all-cause and cardiovascular mortality. We used Cox models to relate prestroke BP indices to mortality and stratified analyses by the presence of preexisting comorbidities (smoking, myocardial infarction, heart failure, atrial fibrillation/flutter, cancer, and dementia), race and ethnicity. Results: Of 29 690 eligible veterans with stroke (mean±SD age 67±12 years, 98% men, 67% White), 2989 (10%) had average prestroke SBP Conclusions: Compared with normotension, low prestroke BP was associated with mortality after stroke, particularly among patients with at least one comorbidity.

Introduction: Cardiovascular disease (CVD) is the leading cause of mortality and disability in the United States. Spatiotemporal modeling of disease incidence may guide prevention efforts toward regions most at risk in the future. Methods: We examined spatiotemporal trends in composite CVD events, defined as myocardial infarction, ischemic stroke, atrial fibrillation, heart failure, coronary artery disease, or cardiovascular death, using electronic health records from 9,718,107 U.S. Veterans who used VA healthcare facilities from 2003-2018. Age-standardized annual incidence by state was modeled using the Bernardinelli model, a Bayesian Poisson regression with linear temporal trends for the US and individual states. Results: There were 626,271 CVD events over 16 years of follow up and annual incidence fell gradually from 11.5% in 2003 to 6.6% in 2018. Incidence among all US veterans decreased an estimated 3.1% [95% CI: -3.3%, -2.9%] per year (RR year = 0.969). State-level incidences also decreased monotonically over the follow-up period (Figure panel A ), ranging from an absolute decrease 5.0% (RI) to 1.7% (OR). Estimated incidence for the five states most above (RI, FL, NC, MT, LA) and most below (OR, NV, CT, OK, MI) the national trend are plotted against the US average in Figure panel B . These outlying states differed significantly from the overall trend (posterior probabilities ≥ 99.7%), and the magnitude of trend was loosely correlated with initial incidence rate (in 2003). Notably, four states crossed the national average over the study period: CT and OK started below average in 2003 but ended above in 2018, whereas RI and NC started with high incidence and ended with below average incidence in 2018. Conclusions: Among US veterans, there was significant geographic variation in the rate of decline of incident CVD from 2003-2018. Future research will investigate the mechanisms underpinning the observed trends, particularly prevalence and control of risk factors.

Risk prediction models for cardiovascular disease (CVD) death developed from patients without vascular disease may not be suitable for myocardial infarction (MI) survivors. Prediction of mortality risk after MI may help to guide secondary prevention. Using national electronic record data from the Veterans Health Administration 2002 to 2012, we developed risk prediction models for CVD death and all-cause death based on 5-year follow-up data of 100,601 survivors of MI using Cox proportional hazards models. Model performance was evaluated using a cross-validation approach. During follow-up, there were 31,622 deaths and 12,901 CVD deaths. In men, older age, current smoking, atrial fibrillation, heart failure, peripheral artery disease, and lower body mass index were associated with greater risk of death from CVD or all-causes, and statin treatment, hypertension medication, estimated glomerular filtration rate level, and high body mass index were significantly associated with reduced risk of fatal outcomes. Similar associations and slightly different predictors were observed in women. The estimated Harrell's C-statistics of the final model versus the cross-validation estimates were 0.77 versus 0.77 in men and 0.81 versus 0.77 in women for CVD death. Similarly, the C-statistics were 0.75 versus 0.75 in men, 0.78 versus 0.75 in women for all-cause mortality. The predicted risk of death was well calibrated compared with the observed risk. In conclusion, we developed and internally validated risk prediction models of 5-year risk for CVD and all-cause death for outpatient survivors of MI. Traditional risk factors, co-morbidities, and lack of blood pressure or lipid treatment were all associated with greater risk of CVD and all-cause mortality.

Background The messenger RNA (mRNA)–based vaccines BNT162b2 and mRNA-1273 are more than 90% effective against coronavirus disease 2019 (Covid-19). However, their comparative effectiveness ...

Background Recent guidelines on dual antiplatelet therapy (DAPT) duration after percutaneous coronary intervention (PCI) balance the subsequent risks of major bleeding with ischemic events. Although generally favoring shorter DAPT duration with second‐generation drug‐eluting stents, the effects on long‐term outcomes in the wider population are uncertain. Methods and Results We tracked all patients having PCI with second‐generation drug‐eluting stents in the Veterans Affairs Healthcare System between 2006 and 2016 for death, myocardial infarction, stroke, and major bleeding up to 13 years. We compared these outcomes with 4 DAPT durations of 1 to 5, 6 to 9, 10 to 12, and 13 to 18 months after the index PCI using hazard ratios (HRs) and 95% CIs from Cox proportional hazards models adjusted by inverse probability weighting. A total of 40 882 subjects with PCI were followed up for a median of 4.3 (25%–75%: 2.4–6.5) years. DAPT discontinuation was rare early after PCI (5.8% at 1–5 months and 6.3% at 6–9 months) but increased (19% and 44%) >9 months. The risk of cardiovascular and noncardiovascular death was higher (HR, 2.03–3.41) with DAPT discontinuation Conclusions Stopping DAPT after 9 months is associated with lower long‐term risks of adverse ischemic and bleeding events and supports recent guidelines of shorter duration DAPT after PCI with second‐generation drug‐eluting stents.

Aims Frailty is associated with an increased risk of all-cause mortality and cardiovascular (CV) events. Limited data exist from the modern era of CV prevention on the relationship between frailty and CV mortality. We hypothesized that frailty is associated with an increased risk of CV mortality. Methods and results All US Veterans aged ≥65 years who were regular users of Veteran Affairs care from 2002 to 2017 were included. Frailty was defined using a 31-item previously validated frailty index, ranging from 0 to 1. The primary outcome was CV mortality with secondary analyses examining the relationship between frailty and CV events (myocardial infarction, stroke, revascularization). Survival analysis models were adjusted for age, sex, ethnicity, geographic region, smoking, hyperlipidaemia, statin use, and blood pressure medication use. There were 3 068 439 US Veterans included in the analysis. Mean age was 74.1 ± 5.8 years in 2002, 76.0 ± 8.3 years in 2014, 98% male, and 87.5% White. In 2002, the median (interquartile range) frailty score was 0.16 (0.10–0.23). This increased and stabilized to 0.19 (0.10–0.32) for 2006–14. The presence of frailty was associated with an increased risk of CV mortality at every stage of frailty. Frailty was associated with an increased risk of myocardial infarction and stroke, but not revascularization. Conclusion In this population, both the presence and severity of frailty are tightly correlated with CV death, independent of underlying CV disease. This study is the largest and most contemporary evaluation of the relationship between frailty and CV mortality to date. Further work is needed to understand how this risk can be diminished. Key Question Can an electronic frailty index identify adults aged 65 and older who are at risk of CV mortality and major CV events? Key Finding Among 3 068 439 US Veterans aged 65 and older, frailty was associated with an increased risk of CV mortality at every level of frailty. Frailty was also associated with an increased risk of myocardial infarction and stroke, but not revascularization. Take Home Message Both the presence and severity of frailty are associated with CV mortality and major CV events, independent of underlying CV disease.

SARS-CoV-2 infection results in a spectrum of outcomes from no symptoms to widely varying degrees of illness to death. A better understanding of the immune response to SARS-CoV-2 infection and subsequent, often excessive, inflammation may inform treatment decisions and reveal opportunities for therapy. We studied immune cell subpopulations and their associations with clinical parameters in a cohort of 26 patients with COVID-19. Following informed consent, we collected blood samples from hospitalized patients with COVID-19 within 72 h of admission. Flow cytometry was used to analyze white blood cell subpopulations. Plasma levels of cytokines and chemokines were measured using ELISA. Neutrophils undergoing neutrophil extracellular traps (NET) formation were evaluated in blood smears. We examined the immunophenotype of patients with COVID-19 in comparison to that of SARS-CoV-2 negative controls. A novel subset of pro-inflammatory neutrophils expressing a high level of dual endothelin-1 and VEGF signal peptide-activated receptor (DEspR) at the cell surface was found to be associated with elevated circulating CCL23, increased NETosis, and critical-severity COVID-19 illness. The potential to target this subpopulation of neutrophils to reduce secondary tissue damage caused by SARS-CoV-2 infection warrants further investigation.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

STUDY OBJECTIVE: Vasopressin may be administered to treat vasospasm follow aneurysmal subarachnoid hemorrhage (aSAH). Few data support this practice, and it has recently been associated with clinically significant hyponatremia. The objectives of this study were to describe five cases of suspected vasopressin-induced hyponatremia after aSAH and to review the literature on this adverse effect. DESIGN: Single-center, observational case series of intensive care unit (ICU) patients SETTINGS: Ten-bed neurological intensive care unit at Maine Medical Center in Portland, Maine PATIENTS: Convenience sample of patients with aSAH treated with a vasopressin for symptomatic, radiologically-confirmed vasospasm MEASUREMENTS AND MAIN RESULTS: A total of five patients were included in the case series with a median age of 57 (51, 65) years and all were female. The median Glasgow coma scale score was 15 (11, 15) on admission and the Hunt and Hess scale score was 3, (3, 4). All patients were treated with endovascular coiling of their aneurysm. Vasopressin was administered to treat symptomatic, radiographically-confirmed vasospasm on median post-bleed day (PBD) 10 (10, 15) at a fixed-dose of 0.03 units/min. Serum sodium at baseline was 140 (140, 144) mEq/L and decreased to 129 (126, 129) mEq/L within 26 (17, 83) hours of vasopressin initiation for a median change of −16 (−10, −16) mEq/L. Serum sodium returned to baseline within 18 (14, 22) hours of stopping the infusion. CONCLUSIONS: Vasopressin administration to treat vasospasm after aSAH may be associated with clinically significant hyponatremia within 24 hours of starting the infusion. Hyponatremia appears to resolve within 24 hours of stopping the vasopressin infusion. Additional study in a larger sample size is needed to determine if a causal relationship exists.

Aims: This study aims to develop the first race‐specific and sex‐specific risk prediction models for heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods and results: We created a cohort of 1.8 million individuals who had an outpatient clinic visit between 2002 and 2007 within the Veterans Affairs (VA) Healthcare System and obtained information on HFpEF, HFrEF, and several risk factors from electronic health records (EHR). Variables were selected for the risk prediction models in a ‘derivation cohort’ that consisted of individuals with baseline date in 2002, 2003, or 2004 using a forward stepwise selection based on a change in C‐index threshold. Discrimination and calibration were assessed in the remaining participants (internal ‘validation cohort’). A total of 66 831 individuals developed HFpEF, and 92 233 developed HFrEF (52 679 and 71 463 in the derivation cohort) over a median of 11.1 years of follow‐up. The HFpEF risk prediction model included age, diabetes, BMI, COPD, previous MI, antihypertensive treatment, SBP, smoking status, atrial fibrillation, and estimated glomerular filtration rate (eGFR), while the HFrEF model additionally included previous CAD. For the HFpEF model, C‐indices were 0.74 (SE = 0.002) for white men, 0.76 (0.005) for black men, 0.79 (0.015) for white women, and 0.77 (0.026) for black women, compared with 0.72 (0.002), 0.72 (0.004), 0.77 (0.017), and 0.75 (0.028), respectively, for the HFrEF model. These risk prediction models were generally well calibrated in each race‐specific and sex‐specific stratum of the validation cohort. Conclusions: Our race‐specific and sex‐specific risk prediction models, which used easily obtainable clinical variables, can be a useful tool to implement preventive strategies or subtype‐specific prevention trials in the nine million users of the VA healthcare system and the general population after external validation.

The development of phenotypes using electronic health records is a resource intensive process. Therefore, the cataloging of phenotype algorithm metadata for reuse is critical to accelerate clinical research. The Department of Veterans Affairs Office of Research and Development has developed a phenomics knowledgebase library, CIPHER (Centralized Interactive Phenomics Research), which improves upon existing phenomics library models to help advance innovation in clinical research by using the CIPHER phenotype collection standard. The CIPHER standard was iteratively developed with phenomics experts and has been used to capture over 5,000 phenotypes. We describe the development of the CIPHER standard for phenotype metadata collection, its current application to the largest healthcare system in the United States, and the future expansion of the CIPHER knowledgebase as a public resource for phenotyping.

Background Electronic frailty indices (eFIs) are increasingly used to identify patients at risk for morbidity and mortality. Whether eFIs capture the spectrum of frailty change, including decline, stability, and improvement, is unknown. Methods In a nationwide retrospective birth cohort of U.S. Veterans, a validated eFI, including 31 health deficits, was calculated annually using medical record and insurance claims data (2002–2012). K-means clustering was used to assign patients into frailty trajectories measured 5 years prior to death. Results There were 214 250 veterans born between 1927 and 1934 (mean [SD] age at death = 79.4 [2.8] years, 99.2% male, 90.3% White) with an annual eFI in the 5 years before death. Nine frailty trajectories were identified. Those starting at nonfrail or prefrail had 2 stable trajectories (nonfrail to prefrail, n = 29 786 and stable prefrail, n = 28 499) and 2 rapidly increasing trajectories (prefrail to moderately frail, n = 28 244 and prefrail to severely frail, n = 22 596). Those who were mildly frail at baseline included 1 gradually increasing trajectory (mildly to moderately frail, n = 33 806) and 1 rapidly increasing trajectory (mildly to severely frail, n = 15 253). Trajectories that started at moderately or severely frail included 2 gradually increasing trajectories (moderately to severely frail, n = 27 662 and progressing severely frail, n = 14 478) and 1 recovering trajectory (moderately frail to mildly frail, n = 13 926). Conclusions Nine frailty trajectories, including 1 recovering trajectory, were identified in this cohort of older U.S. Veterans. Future work is needed to understand whether prevention and treatment strategies can improve frailty trajectories and contribute to compression of morbidity toward the end of life.

Background Language delay is one of the major referral criteria for an autism evaluation. Once an autism spectrum diagnosis is established, the language prognosis is among the main parental concerns. Early language regression (ELR) is observed by 10–50% of parents but its relevance to late language level and socio-communicative ability is uncertain. This study aimed to establish the predictive value of ELR on the progression of language development and socio-communicative outcomes to guide clinicians in addressing parents’ concerns at the time of diagnosis. Methods We used socio-communicative, language, and cognitive data of 2,047 autism spectrum participants from the Simons Simplex Collection, aged 4–18 years (mean = 9 years; SD = 3.6). Cox proportional hazard and logistic regression models were used to evaluate the effect of ELR on language milestones and the probability of using complex and flexible language, as defined by the choice of ADOS module at enrollment. Linear models were then used to evaluate the relationship of ELR and non-verbal IQ with socio-communicative and language levels. Results ELR is associated with earlier language milestones but delayed attainment of fluent, complex, and flexible language. However, this language outcome can be expected for almost all autistic children without intellectual disability at 18 years of age. It is mostly influenced by non-verbal IQ, not ELR. The language and socio-communicative level of participants with flexible language, as measured by the Vineland and ADOS socio-communicative subscales, was not affected by ELR. Limitations This study is based on a relatively coarse measure of ultimate language level and relies on retrospective reporting of early language milestones and ELR. It does not prospectively document the age at which language catches up, the relationship between ELR and other behavioral areas of regression, nor the effects of intervention. Conclusions For autistic individuals with ELR and a normal level of non-verbal intelligence, language development follows a “bayonet shape” trajectory: early first words followed by regression, a plateau with limited progress, and then language catch up.

1 To estimate the association between social engagement (SE) and falls; 2) To examine the relationship between mild neurocognitive disorder (MNCD) and falls by different levels of SE.We performed a secondary data analysis using prospective cohort study design SETTING: Primary Care PARTICIPANTS: 425 older adult primary care patients at risk for mobility decline. As previously reported, at baseline, 42% of participants exhibit MNCD.The outcome variable was number of falls during two years of follow-up. Exposure variables at baseline included: 1) MNCD identified using a cut-off of 1.5 SD below the age-adjusted mean on at least two measures within a cognitive performance battery; and 2) SE, which was assessed using the social component of the Late-Life Function and Disability Instrument. High SE was defined as having a score ≥ median value (≥ 49 out of 100). All models were adjusted for age, sex, education, marital status, comorbidities, and pain status; RESULTS: Over two years of follow-up, 48% of participants fell at least once. MNCD was associated with a higher rate of falls, adjusting for the covariates (Incidence Rate Ratio=1.6, 95% CI:1.1-2.3). There was no significant association between MNCD and the rate of falls among people with high SE. In participants with low SE (having a score less than 49.5 out 100), MNCD was associated with a higher rate of falls as compared to participants with no neurocognitive disorder (No-NCD).Among participants with low SE, MNCD was associated with a higher rate of falls, but not among participants with high SE. The findings suggest that high SE may be protective against falls among older primary care patients with MNCD.

Introduction: Worsening renal function (WRF) predicts poor prognosis in patients with left ventricular systolic dysfunction. The effect of WRF in heart failure with preserved ejection fraction (HFpEF) is unclear. Objective: The objective of this study was to determine whether WRF during index hospitalization for HFpEF is associated with increased death or readmission for heart failure. Methods: National Veterans Affairs electronic medical data recorded between January 1, 2002, and December 31, 2014, were screened to identify index hospitalizations for HFpEF using an iterative algorithm. Patients were divided into 3 groups based on changes in serum Cr (sCr) during this admission. WRF was defined as a rise in sCr ≥0.3 mg/dL. Group 1 had no evidence of WRF, group 2 had transient WRF, and group 3 had persistent WRF at the time of discharge. Results: A total of 10,902 patients with index hospitalizations for HFpEF were identified (mean age 72, 97% male). Twenty-nine percent had WRF during this hospital admission, with 48% showing recovery of sCr and 52% with no recovery at discharge. The mortality rate over a mean follow-up duration of 3.26 years was 72%. Compared to group 1, groups 2 and 3 showed no significant difference in risk of death from any cause (hazard ratio [HR] = 0.95 [95% confidence interval [CI]: 0.87, 1.03] and 1.02 [95% CI: 0.93, 1.11], respectively), days hospitalized for any cause (incidence density ratio [IDR] = 1.01 [95% CI: 0.92, 1.11] and 1.01 [95% CI: 0.93, 1.11], respectively), or days hospitalized for heart failure (IDR = 0.94 [95% CI: 0.80, 1.10] and 0.94 [95% CI: 0.81, 1.09], respectively) in analyses adjusted for covariates affecting renal function and outcomes. Conclusions: While there is a high incidence of WRF during index hospitalizations for HFpEF, WRF is not associated with an increased risk of death or hospitalization. This suggests that WRF alone should not influence decisions regarding heart failure management.

BACKGROUND AND AIMS: Limited and inconsistent data are available on the relation between egg consumption and risk of myocardial infarction (MI) and it is unclear if adiposity or type 2 diabetes modifies egg-MI relation. We tested the primary hypothesis that egg consumption is positively associated with incidence of MI among veterans. In secondary analyses, we examined potential effect modification of egg-MI relation by adiposity and type 2 diabetes. METHODS: We analyzed data collected on 188,267 US veterans who were enrolled in the Million Veteran Program (MVP) from 2011 to 2018. Information on egg consumption was obtained via self-administered food frequency questionnaire and we used electronic health records to identify incident MI. RESULTS: The mean age was 64.4 (SD=12.0) years and 9.9% of the population were female. We ascertained 10,260 new cases of non-fatal MI during an average follow up of 3.24 years (range: 0.002 to 7.49 y). Hazard ratio (95% CI) for non-fatal MI were 1.00 (ref), 0.93 (0.85–0.1.02), 0.96 (0.87–1.05), 0.98 (0.89–1.07), 1.08 (0.98–1.19), 1.11 (1.00–1.24), and 1.13 (1.00–1.28) for egg consumption of

Background/Objective Neurostimulants may improve or accelerate cognitive and functional recovery after intracerebral hemorrhage (ICH), ischemic stroke (IS), or subarachnoid hemorrhage (SAH), but few studies have described their safety and effectiveness in the intensive care unit (ICU). The objective of this study was to describe amantadine and modafinil administration practices during acute stroke care starting in the ICU and to evaluate safety and effectiveness. Methods Consecutive adult ICU patients treated with amantadine and/or modafinil following acute non-traumatic IS, ICH, or SAH were evaluated. Neurostimulant administration data were extracted from the electronic medication administration record, including medication (amantadine, modafinil, or both), starting dose, time from stroke to initiation, and whether the neurostimulant was continued at hospital discharge. Patients were considered responders if they met two of three criteria within 9 days of neurostimulant initiation: increase in Glasgow coma scale (GCS) score ≥ 3 points from pre-treatment baseline, improved wakefulness or participation documented in caregiver notes, or clinical improvement documented in physical or occupational therapy notes. Potential confounders of the effectiveness assessment and adverse drug effects were also recorded. Results A total of 87 patients were evaluable during the 3.7-year study period, including 41 (47%) with ICH, 29 (33%) with IS, and 17 (20%) with SAH. The initial neurostimulant administered was amantadine in 71 (82%) patients, modafinil in 13 (15%), or both in 3 (3%) patients. Neurostimulants were initiated a median of 7 (4.25, 12.75) days post-stroke (range 1–27 days) for somnolence (77%), not following commands (32%), lack of eye opening (28%), or low GCS (17%). The most common starting dose was 100 mg twice daily for both amantadine (86%) and modafinil (54%). Of the 79 patients included in the effectiveness evaluation, 42 (53%) were considered responders, including 34/62 (55%) receiving amantadine monotherapy and 8/24 (33%) receiving both amantadine and modafinil at the time they met the definition of a responder. No patient receiving modafinil monotherapy was considered a responder. The median time from initiation to response was 3 (2, 5) days. Responders were more frequently discharged home or to acute rehabilitation compared to non-responders (90% vs 62%, p = 0.006). Among survivors, 63/72 (88%) were prescribed a neurostimulant at hospital discharge. The most common potential adverse drug effect was sleep disruption (16%). Conclusions Neurostimulant administration during acute stroke care may improve wakefulness. Future controlled studies with a neurostimulant administration protocol, prospective evaluation, and discretely defined response and safety criteria are needed to confirm these encouraging findings. Electronic supplementary material The online version of this article (10.1007/s12028-020-00986-4) contains supplementary material, which is available to authorized users.

Background In a real-world setting, the effect of pulse rate measured at the time of diagnosis and serially during follow-up and management, on outcomes in heart failure with reduced ejection fraction (HFrEF), has not been well-studied. Furthermore, how beta-blockade use in a real-world situation modifies this relation between pulse rate and outcomes in HFrEF is not well-known. Hence, we identified a large, national, real-world cohort of HFrEF to examine the association of pulse rate and outcomes. Methods Using Veterans Affairs (VA) national electronic health records we identified incident HFrEF cases between 2006 and 2012. We examined the associations of both baseline and serially measured pulse rates, with mortality and days hospitalized per year for heart failure and for any cause, using crude and multivariable Cox proportional hazards and Poisson or negative binomial models, respectively. The exposure was examined as continuous, dichotomous, and categorical. Post-hoc analyses addressed the interaction of pulse rate and beta-blocker target dose. Results We identified 51,194 incident HFrEF cases (67 ± 12 years, 98% male, 77% white. A significant positive, near linear relationship was observed for both baseline and serially measured pulse rates with all-cause mortality, all-cause hospitalization and heart failure hospitalization after adjusting for covariates including beta-blocker use. Patients who had a pulse rate ≥ 70 bpm in the past 6 months had 36% (95% CI: 31–42%), 25% (95% CI: 19–32%), and 51% (95% CI: 33–72%) increased rates of mortality, all-cause hospitalization, and heart failure hospitalization, respectively, compared to patients with pulse rates Conclusions High pulse rate, both at the time of diagnosis and during follow-up, is strongly associated with increased risk of adverse outcomes in HFrEF patients, independent of the use of beta-blockers. In a real-world setting, the majority of HFrEF patients do not achieve target dose of beta-blockade; greater use of strategies to reduce heart rate may improve outcomes in HFrEF.

BACKGROUND AND AIMS: Observational and clinical trial evidence suggests an inverse association of omega-3 polyunsaturated fatty acid with coronary artery disease (CAD) mortality, although relationships with non-fatal CAD and stroke are less clear. We investigated whether omega-3 fatty acid supplement use and fish intake were associated with incident non-fatal CAD and ischemic stroke among US Veterans. METHODS: The Million Veteran Program (MVP) is an ongoing nation-wide longitudinal cohort study of US Veterans with self-reported survey, biospecimen, and electronic health record data. Regular use of omega-3 supplements (yes/no) and frequency of fish intake within the past year were assessed using a food frequency questionnaire. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations of omega-3 supplement use and fish intake with incident non-fatal CAD and ischemic stroke, defined from electronic health records using validated algorithms. Multivariable models included demographics, body mass index, education, smoking status, alcohol intake, and exercise frequency. RESULTS: Among 197,761 participants with food frequency data (mean age: 66 ± 12 years, 92% men), 21% regularly took omega-3 supplements and median fish intake was 1 (3–5 ounce) serving/week. Over a median follow-up of 2.9 years for non-fatal CAD and 3.3 years for non-fatal ischemic stroke, we observed 6,265 and 4,042 incident cases of non-fatal CAD and non-fatal ischemic stroke, respectively. Omega-3 fatty acid supplement use was independently associated with a lower risk of non-fatal ischemic stroke [HR (95% CI): 0.88 (0.81, 0.95)] but not non-fatal CAD [0.99 (0.93, 1.06)]. Fish intake was not independently associated with non-fatal CAD [1.01 (0.94, 1.09) for 1–3 servings/month, 1.03 (0.98, 1.11) for 1 serving/week, 1.02 (0.93, 1.11) for 2–4 servings/week, and 1.15 (0.98, 1.35) for ≥5 servings/week, reference =

Performance measures are tools to measure the quality of clinical care. To date, there is no organized set of performance measures for neurocritical care. The Neurocritical Care Society convened a multidisciplinary writing committee to develop performance measures relevant to neurocritical care delivery in the inpatient setting. A formal methodology was used that included systematic review of the medical literature for 13 major neurocritical care conditions, extraction of high-level recommendations from clinical practice guidelines, and development of a measurement specification form. A total of 50,257 citations were reviewed of which 150 contained strong recommendations deemed suitable for consideration as neurocritical care performance measures. Twenty-one measures were developed across nine different conditions and two neurocritical care processes of care. This is the first organized Neurocritical Care Performance Measure Set. Next steps should focus on field testing to refine measure criteria and assess implementation.

Phenotypes are the foundation for clinical and genetic studies of disease risk and outcomes. The growth of biobanks linked to electronic medical record (EMR) data has both facilitated and increased the demand for efficient, accurate, and robust approaches for phenotyping millions of patients. Challenges to phenotyping with EMR data include variation in the accuracy of codes, as well as the high level of manual input required to identify features for the algorithm and to obtain gold standard labels. To address these challenges, we developed PheCAP, a high-throughput semi-supervised phenotyping pipeline. PheCAP begins with data from the EMR, including structured data and information extracted from the narrative notes using natural language processing (NLP). The standardized steps integrate automated procedures, which reduce the level of manual input, and machine learning approaches for algorithm training. PheCAP itself can be executed in 1–2 d if all data are available; however, the timing is largely dependent on the chart review stage, which typically requires at least 2 weeks. The final products of PheCAP include a phenotype algorithm, the probability of the phenotype for all patients, and a phenotype classification (yes or no). PheCAP takes structured data and narrative notes from electronic medical records and enables patients with a particular clinical phenotype to be identified.

The prediction of myocardial infarction (MI), acute ischemic stroke (AIS), cardiovascular (CVD) death, and 3-point MACE (MI, AIS, or CVD death) in Million Veteran Program (MVP) participants over 8 years of follow up was evaluated using environmental/traditional risk factors (“E”), polygenic risk scores (“G”), and a combination of both approaches (“GxE”). Individuals free of atherosclerotic cardiovascular disease (ASCVD) at baseline were included. Risk factor levels for the participants close to the time of MVP enrollment for age, sex, systolic blood pressure, cholesterol, HDL cholesterol, smoking status, and diabetes status were analyzed. Outcomes were determined from VA electronic record data, Medicare/Medicaid data, and the National Death Index. Analyses were undertaken separately for non-Hispanic European (EUR), African American (AFR), and Hispanic (HIS) participants. There were 157,941 veterans at risk with 8,157 MI events, 2,024 AIS events, 1,778 CVD deaths, and 9,350 3-pt MACE events over 8 years of follow-up. The overall results showed good performance with the environmental model for all three racial-ethnic groups, with C-statistics ranging from 0.69 to 0.77. The G models showed very modest prediction capabilities and similarly modest improvement in the combined GxE models. In conclusion, traditional risk factor modeling has been shown to be highly effective and, in the MVP experience, the additional impact of genetic or genetic interaction information was small.

BACKGROUND: Although previous studies have suggested cocoa products may promote cardiovascular health in the general population, no public data are available from patients receiving care in a national integrated health care system. OBJECTIVES: We tested the hypothesis that regular chocolate consumption is associated with a lower risk of coronary artery disease (CAD) events among participants of the Million Veteran Program (MVP). Secondary analysis examined if the main hypothesis was observed among participants with type 2 diabetes. METHODS: We analyzed data from MVP participants who completed the food frequency section of the MVP Lifestyle Survey and were free of CAD at the time of survey completion. CAD events during follow-up (International Statistical Classification of Diseases Ninth Revision codes 410–411 and 413–414, and Tenth Revision codes I20–I25 except I25.2) were assessed using electronic health records. We fitted a Cox proportional hazard model to estimate the RR of CAD. RESULTS: Of 188,447 MVP enrollees with survey data, mean ± SD age was 64 ± 12.0 y and 90% were men. For regular chocolate (28.3 g/serving) consumption of