Genome-wide association study of traumatic brain injury in U.S. military veterans enrolled in the VA million veteran program.

Large-scale genetic studies of traumatic brain injury (TBI) are lacking; thus, our understanding of the influence of genetic factors on TBI risk and recovery is incomplete. This study aimed to conduct a genome-wide association study (GWAS) of TBI in VA Million Veteran Program (MVP) enrollees. Participants included a multi-ancestry cohort (European, African, and Hispanic ancestries; N = 304,485; 111,494 TBI cases, 192,991 controls). TBI was assessed using MVP survey data and International Classification of Diseases (ICD) codes from the Veterans Health Administration's electronic health record. GWAS was performed using logistic regression in PLINK, and meta-analyzed in METAL. FUMA was used for post-GWAS analysis. Genomic structural equation modeling (gSEM) was conducted to investigate underlying genetic associations with TBI, and bivariate MiXeR was used to estimate phenotype specific and shared polygenicity. SNP-based heritability was 0.060 (SE = 0.004, p = 7.83×10-66). GWAS analysis identified 15 genome-wide significant (GWS) loci at p < 5×10-8. Gene-based analyses revealed 14 gene-wide significant genes; top genes included NCAM1, APOE, FTO, and FOXP2. Gene tissue expression analysis identified the brain as significantly enriched, particularly in the frontal cortex, anterior cingulate cortex, and nucleus accumbens. Genetic correlations with TBI were significant for risk-taking behaviors and psychiatric disorders, but generally not significant for the neurocognitive variables investigated. gSEM analysis revealed stronger associations with risk-taking traits than with psychiatric traits. Finally, the genetic architecture of TBI was similar to polygenic psychiatric disorders. Neurodegenerative disorders including Alzheimer's and Parkinson's disease showed much less polygenicity, however, the proportion of shared variance with TBI was high. This first well-powered GWAS of TBI identified 15 loci including genes relevant to TBI biology, and showed that TBI is a heritable trait with comparable genetic architecture and high genetic correlation with psychiatric traits. Our findings set the stage for future TBI GWASs that focus on injury severity and diversity and chronicity of symptom sequelae.

Evaluation of clinical outcomes and employment status in veterans with dual diagnosis of traumatic brain injury and spinal cord injury.

PURPOSE: To examine clinical outcomes and employment status in Veterans with and without a dual diagnosis of traumatic brain injury (TBI) and spinal cord injury (SCI). METHODS: This cross-sectional study examined a national sample of Veterans enrolled in the VA Million Veteran Program who completed the Comprehensive TBI Evaluation (CTBIE) as part of the Veterans Health Administration's TBI Screening and Evaluation Program. Veterans (N = 12,985) were classified into the following TBI/SCI groups using CTBIE data: those with a dual diagnosis of TBI and SCI (TBI+/SCI+); those with a history of TBI but no SCI (TBI+/SCI-); and those with no history of TBI or SCI (TBI-/SCI-; i.e., the control group). CTBIE-derived outcomes included neurobehavioral symptoms, comorbid psychiatric symptoms, pain and pain interference, and employment status. RESULTS: Chi-square analyses showed significant associations between TBI/SCI group and all clinical outcomes evaluated (all p's < .001; V = 0.07-0.11). In general, the TBI+/SCI+ and TBI +/SCI- groups endorsed comparable levels of neurobehavioral symptoms, psychiatric symptoms, and pain, but significantly greater rates of symptoms and pain relative to the TBI-/SCI- group. Effect sizes for all pairwise comparisons were small (φ = 0.01-0.11). Finally, there was no significant association between TBI/SCI group and employment status (p = .170; V = 0.02), with all three groups showing relatively comparable rates of unemployment. CONCLUSIONS: Regardless of SCI status, Veterans with TBI history endorsed poorer clinical outcomes than Veterans without TBI and SCI. However, rates of unemployment were similarly high across all three groups. Findings suggest that any Veteran completing the CTBIE may be at risk for poor clinical and employment outcomes.

Development and validation of an electronic health record-based algorithm for identifying TBI in the VA: A VA Million Veteran Program study.

The purpose of this study was to develop and validate an algorithm for identifying Veterans with a history of traumatic brain injury (TBI) in the Veterans Affairs (VA) electronic health record using VA Million Veteran Program (MVP) data. Manual chart review (n = 200) was first used to establish 'gold standard' diagnosis labels for TBI ('Yes TBI' vs. 'No TBI'). To develop our algorithm, we used PheCAP, a semi-supervised pipeline that relied on the chart review diagnosis labels to train and create a prediction model for TBI. Cross-validation was used to train and evaluate the proposed algorithm, 'TBI-PheCAP.' TBI-PheCAP performance was compared to existing TBI algorithms and phenotyping methods, and the final algorithm was run on all MVP participants (n = 702,740) to assign a predicted probability for TBI and a binary classification status choosing specificity = 90%. The TBI-PheCAP algorithm had an area under the receiver operating characteristic curve of 0.92, sensitivity of 84%, and positive predictive value (PPV) of 98% at specificity = 90%. TBI-PheCAP generally performed better than other classification methods, with equivalent or higher sensitivity and PPV than existing rules-based TBI algorithms and MVP TBI-related survey data. Given its strong classification metrics, the TBI-PheCAP algorithm is recommended for use in future population-based TBI research.

Ask and Ask Again: Repeated Screening for Smoking Increases Likelihood of Prescription for Cessation Treatment Among Women Veterans.

BACKGROUND: Preventive screening at the point of care can increase desired clinical outcomes. However, the impact of repeated screening for tobacco use on receiving smoking cessation treatment among women Veteran population has not been documented. OBJECTIVE: To examine screening for tobacco use using clinical reminders and the association between the number of screenings and prescription for cessation treatment. DESIGN: A retrospective analysis using data from a 5-year implementation trial for cardiovascular risk identification conducted between December 2016 and March 2020. SUBJECTS: Women patients who had at least one primary care visit with a women's health provider during the study period at five primary care clinics in the Veterans Affairs (VA) Healthcare System. MEASURES: The outcome is prescription of pharmacotherapy or referral to behavioral counseling for smoking cessation on or after the screening date. The exposure is the number of screenings for tobacco use from the trial and the annual VA national clinical reminders during the study period. RESULTS: Of 6009 eligible patients, 5788 (96.3%) were screened at least once for tobacco use over five calendar years, and 2784 of those screened (48.1%) were reported as current and former smokers. Among current and former smokers, 709 (25.5%) received a prescription and/or referral for smoking cessation. In the adjusted model, the average predicted probability of prescription and/or referral for smoking cessation was 13.7% among current and former smokers screened once over 5 years, 18.6% among screened twice, 26.5% among screened thrice, 32.9% among screened four times, and 41.7% among screened five or six times. CONCLUSIONS: Repeated screening was associated with higher predicted probabilities of being prescribed smoking cessation treatment.

Stakeholders' views on the value of outcomes from clinical genetic and genomic interventions.

PURPOSE: Robust evidence about the value of clinical genomic interventions (CGIs), such as genetic/genomic testing or clinical genetic evaluation, is limited. We obtained stakeholders' perspectives on outcomes from CGIs to help inform their value. METHODS: We used an adapted Delphi expert panel process. Two anonymous survey rounds assessed the value of 44 CGI outcomes and whether a third party should pay for them, with discussion in between rounds. RESULTS: Sixty-six panelists responded to the first-round survey and 60 to the second. Policy-makers/payers gave the lowest ratings for value and researchers gave the highest. Patients/consumers had the most uncertainty about value and payment by a third party. Uncertainty about value was observed when evidence of proven health benefit was lacking, potential harms outweighed benefits for reproductive outcomes, and outcomes had only personal utility for individuals or family members. Agreement about outcomes for which a third party should not pay included prevention through surgery with unproven health benefits, establishing ancestry, parental consanguinity, and paternity. CONCLUSION: Research is needed to understand factors contributing to uncertainty and stakeholder differences about the value of CGI outcomes. Reaching consensus will accelerate the creation of metrics to generate the evidence needed to inform value and guide policies that promote availability, uptake, and coverage of CGIs.

A logic model for precision medicine implementation informed by stakeholder views and implementation science.

PURPOSE: Precision medicine promises to improve patient outcomes, but much is unknown about its adoption within health-care systems. A comprehensive implementation plan is needed to realize its benefits. METHODS: We convened 80 stakeholders for agenda setting to inform precision medicine policy, delivery, and research. Conference proceedings were audio-recorded, transcribed, and thematically analyzed. We mapped themes representing opportunities, challenges, and implementation strategies to a logic model, and two implementation science frameworks provided context. RESULTS: The logic model components included inputs: precision medicine infrastructure (clinical, research, and information technology), big data (from data sources to analytics), and resources (e.g., workforce and funding); activities: precision medicine research, practice, and education; outputs: precision medicine diagnosis; outcomes: personal utility, clinical utility, and health-care utilization; and impacts: precision medicine value, equity and access, and economic indicators. Precision medicine implementation challenges include evidence gaps demonstrating precision medicine utility, an unprepared workforce, the need to improve precision medicine access and reduce variation, and uncertain impacts on health-care utilization. Opportunities include integrated health-care systems, partnerships, and data analytics to support clinical decisions. Examples of implementation strategies to promote precision medicine are: changing record systems, data warehousing techniques, centralized technical assistance, and engaging consumers. CONCLUSION: We developed a theory-based, context-specific logic model that can be used by health-care organizations to facilitate precision medicine implementation.

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration.

The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1--but not lamin B2--is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.

Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA.

Lamins A and C, alternatively spliced products of the LMNA gene, are key components of the nuclear lamina. The two isoforms are found in similar amounts in most tissues, but we observed an unexpected pattern of expression in the brain. Western blot and immunohistochemistry studies showed that lamin C is abundant in the mouse brain, whereas lamin A and its precursor prelamin A are restricted to endothelial cells and meningeal cells and are absent in neurons and glia. Prelamin A transcript levels were low in the brain, but this finding could not be explained by alternative splicing. In lamin A-only knockin mice, where alternative splicing is absent and all the output of the gene is channeled into prelamin A transcripts, large amounts of lamin A were found in peripheral tissues, but there was very little lamin A in the brain. Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson-Gilford progeria syndrome), the levels of progerin in the brain were extremely low. Further studies showed that prelamin A expression, but not lamin C expression, is down-regulated by a brain-specific microRNA, miR-9. Expression of miR-9 in cultured cells reduced lamin A expression, and this effect was abolished when the miR-9-binding site in the prelamin A 3' UTR was mutated. The down-regulation of prelamin A expression in the brain could explain why mouse models of Hutchinson-Gilford progeria syndrome are free of central nervous system pathology.

Exploring Interactions Between Traumatic Brain Injury History and Gender on Medical Comorbidities in Military Veterans: An Epidemiological Analysis in the VA Million Veteran Program.

Epidemiological studies of medical comorbidities and possible gender differences associated with traumatic brain injury (TBI) are limited, especially among military veterans. The purpose of this study was to examine relationships between TBI history and a wide range of medical conditions in a large, national sample of veterans, and to explore interactions with gender. Participants of this cross-sectional epidemiological study included 491,604 veterans (9.9% TBI cases; 8.3% women) who enrolled in the VA Million Veteran Program (MVP). Outcomes of interest were medical comorbidities (i.e., neurological, mental health, circulatory, and other medical conditions) assessed using the MVP Baseline Survey, a self-report questionnaire. Logistic regression models adjusting for age and gender showed that veterans with TBI history consistently had significantly higher rates of medical comorbidities than controls, with the greatest differences observed across mental health (odds ratios [ORs] = 2.10-3.61) and neurological (ORs = 1.57-6.08) conditions. Similar patterns were found when evaluating men and women separately. Additionally, significant TBI-by-gender interactions were observed, particularly for mental health and neurological comorbidities, such that men with a history of TBI had greater odds of having several of these conditions than women with a history of TBI. These findings highlight the array of medical comorbidities experienced by veterans with a history of TBI, and illustrate that clinical outcomes differ for men and women with TBI history. Although these results are clinically informative, more research is needed to better understand the role of gender on health conditions in the context of TBI and how gender interacts with other social and cultural factors to influence clinical trajectories following TBI. Ultimately, understanding the biological, psychological, and social mechanisms underlying these comorbidities may help with tailoring TBI treatment by gender and improve quality of life for veterans with TBI history.

Understanding the roles of nuclear A- and B-type lamins in brain development.

The nuclear lamina is composed mainly of lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins). Dogma has held that lamins B1 and B2 play unique and essential roles in the nucleus of every eukaryotic cell. Recent studies have raised doubts about that view but have uncovered crucial roles for lamins B1 and B2 in neuronal migration during the development of the brain. The relevance of lamins A and C in the brain remains unclear, but it is intriguing that prelamin A expression in the brain is low and is regulated by miR-9, a brain-specific microRNA.

Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency.

Nuclear lamins are components of the nuclear lamina, a structural scaffolding for the cell nucleus. Defects in lamins A and C cause an array of human diseases, including muscular dystrophy, lipodystrophy, and progeria, but no diseases have been linked to the loss of lamins B1 or B2. To explore the functional relevance of lamin B2, we generated lamin B2-deficient mice and found that they have severe brain abnormalities resembling lissencephaly, with abnormal layering of neurons in the cerebral cortex and cerebellum. This neuronal layering abnormality is due to defective neuronal migration, a process that is dependent on the organized movement of the nucleus within the cell. These studies establish an essential function for lamin B2 in neuronal migration and brain development.

Cost-effectiveness of CYP2C19-guided P2Y12 inhibitors in Veterans undergoing percutaneous coronary intervention for acute coronary syndromes.

AIMS: CYP2C19-guided P2Y12 inhibitor selection can reduce cardiovascular (CV) events and bleeding in patients with acute coronary syndromes (ACSs) post-percutaneous coronary intervention (PCI). The 12-month cost-effectiveness of CYP2C19-guided P2Y12 inhibitor selection for Veterans post-ACS/PCI was evaluated from the Veterans Health Administration's (VHA) perspective. METHODS AND RESULTS: Using average annualized PCI volumes and P2Y12 inhibitor use from VA data, a decision-analytic model simulated CYP2C19 testing vs. no testing outcomes in 2800 hypothetical Veterans receiving PY212 inhibitor for 12 months post-ACS/PCI (74% clopidogrel, 5% prasugrel, and 21% ticagrelor use at baseline without testing). CYP2C19 loss-of-function (LOF) carrier prevalence was 28%. Model inputs were from studies (bleeding/ischaemic events, CYP2C19-guided therapy effect, health state utilities, CYP2C19 LOF carrier prevalence) and VHA administrative data (costs of events, drugs, CYP2C19 testing; PCI volumes, and P2Y12 inhibitor prescriptions). The primary outcome was cost (2020 US${\$}$) per quality-adjusted life year (QALY) gained. Base-case scenarios, probabilistic sensitivity analyses, and scenario analyses were completed. CYP2C19-guided therapy resulted in 496 (24%) escalations (clopidogrel to prasugrel/ticagrelor) and 465 (65%) de-escalations (prasugrel/ticagrelor to clopidogrel). CYP2C19 testing averted 1 stroke, 27 myocardial infarctions, 8 CV-related deaths, and caused 3 bleeds. CYP2C19 testing (vs. no testing) was dominant in the base-case scenario (0.0027 QALYs gained, ${\$}$527 saved/person) and in 97.1% of simulations, making it cost-effective and high-value. In scenario analyses, de-escalation in conjunction with escalation is required for CYP2C19 testing to be cost-effective and high-value. CONCLUSION: In Veterans post-ACS/PCI, CYP2C19-guided P2Y12 inhibitor selection can improve CV outcomes and lower costs for the VHA within 12 months of implementation.

Measurement Invariance of the Neurobehavioral Symptom Inventory in Male and Female Million Veteran Program Enrollees Completing the Comprehensive Traumatic Brain Injury Evaluation.

This study evaluated measurement invariance across males and females on the Neurobehavioral Symptom Inventory (NSI) in U.S. military veterans enrolled in the VA Million Veteran Program. Participants (N = 17,059; males: n = 15,450; females: n = 1,609) included Veterans who took part in the VA Traumatic Brain Injury (TBI) Screening and Evaluation Program and completed the NSI. Multiple-group confirmatory factor analyses investigated measurement invariance of the NSI 4-factor model. The configural (comparative fit index [CFI] = 0.948, root mean square error of approximation [RMSEA] = 0.060) and metric (CFI = 0.948, RMSEA = 0.058) invariance models showed acceptable fit. There was a minor violation of scalar invariance (Δχ2 = 232.50, p < .001); however, the degree of noninvariance was mild (ΔCFI = -0.002, ΔRMSEA=0.000). Our results demonstrate measurement invariance across sex, suggesting that the NSI 4-factor model can be used to accurately assess symptoms in males and females following TBI. Findings highlight the importance of considering validity of measurement across study groups to increase confidence that a measure is interpreted similarly by respondents from different subgroups.

Self-reported physical functioning, cardiometabolic health conditions, and health care utilization patterns in Million Veteran Program enrollees with Traumatic Brain Injury Screening and Evaluation Program data.

BACKGROUND: Examining the health outcomes of veterans who have completed the United States Veterans Health Administration's (VHA's) Traumatic Brain Injury (TBI) Screening and Evaluation Program may aid in the refinement and improvement of clinical care initiatives within the VHA. This study compared self-reported physical functioning, cardiometabolic health conditions, and health care utilization patterns in Million Veteran Program enrollees with TBI Screening and Evaluation Program data (collected between 2007 and 2019), with the goal of enhancing understanding of potentially modifiable health conditions in this population. METHODS: In this observational cohort study, veterans (n = 16,452) were grouped based on the diagnostic outcome of the TBI Screening and Evaluation Program: 1) negative TBI screen (Screen-); 2) positive TBI screen but no confirmed TBI diagnosis [Screen+/ Comprehensive TBI Evaluation (CTBIE)-]; or 3) positive TBI screen and confirmed TBI diagnosis (Screen+/CTBIE+). Chi-square tests and analysis of covariance were used to explore group differences in physical functioning, cardiometabolic health conditions, and health care utilization patterns, and logistic regressions were used to examine predictors of Screen+/- and CTBIE+/- group status. RESULTS: The results showed that veterans in the Screen+/CTBIE- and Screen+/CTBIE+ groups generally reported poorer levels of physical functioning (P's < 0.001, np2 = 0.02 to 0.03), higher rates of cardiometabolic health conditions (P's < 0.001, φ = 0.14 to 0.52), and increased health care utilization (P's < 0.001, φ = 0.14 to > 0.5) compared with the Screen- group; however, health outcomes were generally comparable between the Screen+/CTBIE- and Screen+/CTBIE+ groups. Follow-up analyses confirmed that while physical functioning, hypertension, stroke, healthcare utilization, and prescription medication use reliably distinguished between the Screen- and Screen+ groups (P's < 0.02, OR's 0.78 to 3.38), only physical functioning distinguished between the Screen+/CTBIE- and Screen+/CTBIE+ groups (P < 0.001, OR 0.99). CONCLUSIONS: The findings suggest that veterans who screen positive for TBI, regardless of whether they are ultimately diagnosed with TBI, are at greater risk for negative health outcomes, signifying that these veterans represent a vulnerable group that may benefit from increased clinical care and prevention efforts.

An Examination of Racial/Ethnic Differences on the Neurobehavioral Symptom Inventory Among Veterans Completing the Comprehensive Traumatic Brain Injury Evaluation: A Veterans Affairs Million Veteran Program Study.

OBJECTIVE: The purpose of this study was to explore racial/ethnic differences in neurobehavioral symptom reporting and symptom validity testing among military veterans with a history of traumatic brain injury (TBI). METHOD: Participants of this observational cross-sectional study (N = 9,646) were post-deployed Iraq-/Afghanistan-era veterans enrolled in the VA's Million Veteran Program with a clinician-confirmed history of TBI on the Comprehensive TBI Evaluation (CTBIE). Racial/ethnic groups included White, Black, Hispanic, Asian, Multiracial, Another Race, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander. Dependent variables included neurobehavioral symptom domains and symptom validity assessed via the Neurobehavioral Symptom Inventory (NSI) and Validity-10, respectively. RESULTS: Chi-square analyses showed significant racial/ethnic group differences for vestibular, somatic/sensory, and affective symptoms as well as for all Validity-10 cutoff scores examined (≥33, ≥27, ≥26, >22, ≥22, ≥13, and ≥7). Follow-up analyses compared all racial/ethnic groups to one another, adjusting for sociodemographic- and injury-related characteristics. These analyses revealed that the affective symptom domain and the Validity-10 cutoff of ≥13 revealed the greatest number of racial/ethnic differences. CONCLUSIONS: Results showed significant racial/ethnic group differences on neurobehavioral symptom domains and symptom validity testing among veterans who completed the CTBIE. An enhanced understanding of how symptoms vary by race/ethnicity is vital so that clinical care can be appropriately tailored to the unique needs of all veterans. Results highlight the importance of establishing measurement invariance of the NSI across race/ethnicity and underscore the need for ongoing research to determine the most appropriate Validity-10 cutoff score(s) to use across racially/ethnically diverse veterans.

Pharmacogenetic testing and monitoring of complete blood counts among Veterans newly prescribed thiopurine treatments: a retrospective cohort study.

Pharmacogenetic (PGx) testing before initiation of thiopurine treatment and CBC monitoring post-initiation helps avoid adverse events and ensure patient safety. This study aims to evaluate trends in PGx testing and CBC monitoring among Veterans prescribed azathioprine, thioguanine, or mercaptopurine to demonstrate VA's efforts to improve medication safety after an adverse event. To assess testing patterns, we used VA electronic health report data to identify 20,524 Veterans who first began thiopurine treatment between January 1, 2010, to December 31, 2021. Aggregate monthly counts of thiopurine prescriptions and associated lab tests were tabulated, and the trend in the proportion of patients tested was analyzed using the Mann-Kendall test. The proportion of patients undergoing PGx testing rose from 30.0% in 2010 to 47.5% in late 2014 (July-December). However, PGx testing and overall testing only increased slightly after the sentinel event, and orders levelled off over time at slightly lower levels than before the sentinel event. Very little change was seen in the overall proportion of individuals receiving any testing across all patients with new prescriptions from the time of the sentinel event in 2014 to the end of 2021. A large portion of patients prescribed thiopurine drugs did not receive testing that could help prevent the development of potential adverse events, leading to a predominantly reactive approach. Increased PGx testing may result in a more proactive approach to the prevention of adverse events due to genetic interaction.

CYP2C19 Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention (PCI) in the Million Veterans Program.

Background: CYP2C19 loss-of-function (LOF) alleles decrease the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS). The impact of genotype in stable ischemic heart disease (SIHD) is unclear. Objectives: Determine the association of CYP2C19 genotype with major adverse cardiac events (MACE) after PCI for ACS or SIHD. Methods: Million Veterans Program (MVP) participants age <65 years with a PCI documented in the VA Clinical Assessment, Reporting and Tracking (CART) Program between 1/1/2009 to 9/30/2017, treated with clopidogrel were included. Time to MACE defined as the composite of all-cause death, stroke or myocardial infarction within 12 months following PCI. Results: Among 4,461 Veterans (mean age 59.1 ± 5.1 years, 18% Black); 44% had ACS, 56% had SIHD and 29% carried a CYP2C19 LOF allele. 301 patients (6.7%) experienced MACE while being treated with clopidogrel, 155 (7.9%) in the ACS group and 146 (5.9%) in the SIHD group. Overall, MACE was not significantly different between LOF carriers vs. noncarriers (adjusted hazard ratio [HR] 1.18, confidence interval [95%CI] 0.97-1.45, p=0.096). Among patients presenting with ACS, MACE risk in LOF carriers versus non-carriers was numerically higher (HR 1.30, 95%CI 0.98-1.73, p=0.067). There was no difference in MACE risk in patients with SIHD (HR 1.09, 95%CI 0.82-1.44; p=0.565). Conclusions: CYP2C19 LOF carriers presenting with ACS treated with clopidogrel following PCI experienced a numerically greater elevated risk of MACE events. CYP2C19 LOF genotype is not associated with MACE among patients presenting with SIHD.

The posttranslational processing of prelamin A and disease.

Human geneticists have shown that some progeroid syndromes are caused by mutations that interfere with the conversion of farnesyl-prelamin A to mature lamin A. For example, Hutchinson-Gilford progeria syndrome is caused by LMNA mutations that lead to the accumulation of a farnesylated version of prelamin A. In this review, we discuss the posttranslational modifications of prelamin A and their relevance to the pathogenesis and treatment of progeroid syndromes.

Characterizing Sex Differences in Clinical and Functional Outcomes Among Military Veterans with a Comprehensive Traumatic Brain Injury Evaluation (CTBIE): A Million Veteran Program (MVP) Study.

Using a diverse sample of military Veterans enrolled in the VA's Million Veteran Program (N=14,378; n=1,361 females [9.5%]; all previously deployed), we examined sex differences on the Comprehensive Traumatic Brain Injury Evaluation (CTBIE), a structured traumatic brain injury (TBI) interview routinely administered within the VA. Confirmed TBI diagnoses were more frequent among males than females (65% vs. 58%). Additionally, when compared to females, a greater proportion of males with CTBIE-confirmed TBI histories experienced blast-related injuries and were employed. In contrast, a greater proportion of females reported experiencing falls, sustaining a TBI since deployment, and having more severe neurobehavioral symptoms (particularly affective-related symptoms). Results indicate that males and females experience differential clinical and functional outcomes in the aftermath of military TBI. Findings underscore the need to increase female representation in TBI research to increase understanding of sex-specific experiences with TBI and to improve the clinical care targeted to this vulnerable population.

Psychiatric symptoms influence social support in VA Million Veteran Program enrollees screening positive for traumatic brain injury.

OBJECTIVE: To examine measures of social support and associations with neurobehavioral, psychiatric, and cognitive symptoms in Veterans who underwent the Veterans Health Administration's Traumatic Brain Injury (TBI) Screening and Evaluation Program. SETTING: Nationally representative sample of U.S. Veterans enrolled in the Veterans Affairs Million Veteran Program. PARTICIPANTS: Veterans (N = 9,837) were classified into the following three diagnostic groups based on results from the TBI Screening and Evaluation Program: (1) negative TBI screen (Screen-; n = 6,523), (2) positive TBI screen but no TBI diagnosis (Screen+/TBI-; n = 1,308), or (3) positive TBI screen and TBI diagnosis (Screen+/TBI+; n = 2,006). DESIGN: Epidemiological cross-sectional study. MAIN MEASURES: Medical Outcomes Study Social Support Survey Instrument (MOS-SSSI), with subscales representing emotional, tangible, and affectionate support and positive social interaction; Neurobehavioral Symptom Inventory (NSI); PTSD Checklist (PCL); Patient Health Questionnaire-4 (PHQ-4); and Medical Outcomes Study Cognitive Functioning-Revised Scale (MOS-Cog-R). RESULTS: ANCOVAs showed significant associations between diagnostic group and all aspects of social support. Pairwise comparisons revealed that Veterans in the two Screen+ groups (Screen+/TBI+ and Screen+/TBI-) reported comparable levels of social support, but that both Screen+ groups reported significantly lower levels of social support compared to the Screen- group. Among the Screen+ groups, adjusted linear regression models controlling for age, sex, and race/ethnicity showed significant associations between social support indices and all symptom measures, such that lower levels of social support were associated with more severe neurobehavioral and psychiatric symptoms and worse cognitive functioning. Finally, mediation analyses showed that psychiatric symptoms mediated the association between TBI screen group and social support. CONCLUSIONS: Our results are clinically informative and suggest (1) that the relationship between TBI screen status and social support is influenced by psychiatric symptoms and (2) that implementing distress reduction techniques before social support interventions may be most beneficial for Veterans screening positive for TBI.