Voltage-gated potassium channel KCNV2 (Kv8.2) contributes to epilepsy susceptibility.

Mutations in voltage-gated ion channels are responsible for several types of epilepsy. Genetic epilepsies often exhibit variable severity in individuals with the same mutation, which may be due to variation in genetic modifiers. The Scn2a(Q54) transgenic mouse model has a sodium channel mutation and exhibits epilepsy with strain-dependent severity. We previously mapped modifier loci that influence Scn2a(Q54) phenotype severity and identified Kcnv2, encoding the voltage-gated potassium channel subunit Kv8.2, as a candidate modifier. In this study, we demonstrate a threefold increase in hippocampal Kcnv2 expression associated with more severe epilepsy. In vivo exacerbation of the phenotype by Kcnv2 transgenes supports its identification as an epilepsy modifier. The contribution of KCNV2 to human epilepsy susceptibility is supported by identification of two nonsynonymous variants in epilepsy patients that alter function of Kv2.1/Kv8.2 heterotetrameric potassium channels. Our results demonstrate that altered potassium subunit function influences epilepsy susceptibility and implicate Kcnv2 as an epilepsy gene.

Hospital admission decisions for older Veterans with community-onset pneumonia: An analysis of 118 U.S. Veterans Affairs Medical Centers.

OBJECTIVES: Age is important for prognosis in community-onset pneumonia, but how it influences admission decisions in the emergency department (ED) is not well characterized. Using clinical data from the electronic health record in a national cohort, we examined pneumonia hospitalization patterns, variation, and relationships with mortality among older versus younger Veterans. METHODS: In a retrospective cohort of patients ≥ 18 years presenting to EDs with a diagnosis of pneumonia at 118 VA Medical Centers January 1, 2006, to December 31, 2016, we compared observed, predicted, and residual hospitalization risk for Veterans < 70, 70-79, and ≥ 80 years of age using generalized estimating equations and machine learning models with 71 patient factors. We examined facility variation in residual hospitalization across facilities and explored whether facility differences in hospitalization risk correlated with differences in 30-day mortality. RESULTS: Among 297,498 encounters, 165,003 (55%) were for Veterans < 70 years, 61,076 (21%) 70-80, and 71,419 (24%) ≥ 80. Hospitalization rates were 52%, 67%, and 76%, respectively. After other patient factors were adjusting for, age 70-79 had an odds ratio (OR) of 1.39 (95% confidence interval [CI] 1.34-1.44) and ≥ 80 had an OR of 2.1 (95% CI 2.0-2.2) compared to age < 70. There was substantial variation in hospitalization across facilities among Veterans < 70 (<35% hospitalization at the lowest decile of facilities vs. > 66% at the highest decile) that was similar but with higher risk for patients 70-79 years (54% vs. 82%) and ≥ 80 years (59% vs. 85%) and remained after accounting for patient factors, with no consistently positive or negative associations with facility-level 30-day mortality. CONCLUSIONS: Older Veterans with community-onset pneumonia experience high risk of hospitalization, with widespread facility variation that has no clear relationship to short-term mortality.

Computerized Mortality Prediction for Community-acquired Pneumonia at 117 Veterans Affairs Medical Centers.

Rationale: Computerized severity assessment for community-acquired pneumonia could improve consistency and reduce clinician burden. Objectives: To develop and compare 30-day mortality-prediction models using electronic health record data, including a computerized score with all variables from the original Pneumonia Severity Index (PSI) except confusion and pleural effusion ("ePSI score") versus models with additional variables. Methods: Among adults with community-acquired pneumonia presenting to emergency departments at 117 Veterans Affairs Medical Centers between January 1, 2006, and December 31, 2016, we compared an ePSI score with 10 novel models employing logistic regression, spline, and machine learning methods using PSI variables, age, sex and 26 physiologic variables as well as all 69 PSI variables. Models were trained using encounters before January 1, 2015; tested on encounters during and after January 1, 2015; and compared using the areas under the receiver operating characteristic curve, confidence intervals, and patient event rates at a threshold PSI score of 970. Results: Among 297,498 encounters, 7% resulted in death within 30 days. When compared using the ePSI score (confidence interval [CI] for the area under the receiver operating characteristic curve, 0.77-0.78), performance increased with model complexity (CI for the logistic regression PSI model, 0.79-0.80; CI for the boosted decision-tree algorithm machine learning PSI model using the Extreme Gradient Boosting algorithm [mlPSI] with the 19 original PSI factors, 0.83-0.85) and the number of variables (CI for the logistic regression PSI model using all 69 variables, 0.84-085; CI for the mlPSI with all 69 variables, 0.86-0.87). Models limited to age, sex, and physiologic variables also demonstrated high performance (CI for the mlPSI with age, sex, and 26 physiologic factors, 0.84-0.85). At an ePSI score of 970 and a mortality-risk cutoff of <2.7%, the ePSI score identified 31% of all patients as being at "low risk"; the mlPSI with age, sex, and 26 physiologic factors identified 53% of all patients as being at low risk; and the mlPSI with all 69 variables identified 56% of all patients as being at low risk, with similar rates of mortality, hospitalization, and 7-day secondary hospitalization being determined. Conclusions: Computerized versions of the PSI accurately identified patients with pneumonia who were at low risk of death. More complex models classified more patients as being at low risk of death and as having similar adverse outcomes.

Fine mapping of an epilepsy modifier gene on mouse Chromosome 19.

Mutations in voltage-gated sodium channels are associated with several types of human epilepsy. Variable expressivity and penetrance are common features of inherited epilepsy caused by sodium channel mutations, suggesting that genetic modifiers may influence clinical severity. The mouse model Scn2a(Q54) has an epilepsy phenotype due to a mutation in Scn2a that results in elevated persistent sodium current. Phenotype severity in Scn2a(Q54) mice is dependent on the genetic background. Congenic C57BL/6J.Q54 mice have delayed onset and low seizure frequency compared to (C57BL/6J x SJL/J)F1.Q54 mice. Previously, we identified two modifier loci that influence the Scn2a(Q54) epilepsy phenotype: Moe1 (modifier of epilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. We have constructed interval-specific congenic strains to further refine the position of Moe2 on Chromosome 19 to a 5-Mb region. Sequencing and expression analyses of genes in the critical interval suggested two potential modifier candidates: (1) voltage-gated potassium channel subunit subfamily V, member 2 (Kcnv2), and (2) SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2 (Smarca2). Based on its biological role in regulating membrane excitability and the association between ion channel variants and seizures, Kcnv2 is a strong functional candidate for Moe2. Modifier genes affecting the epilepsy phenotype of Scn2a(Q54) mice may contribute to variable expressivity and penetrance in human epilepsy patients with sodium channel mutations.

Abdominal aortic aneurysm with inferior vena cava compression in association with deep venous thrombosis.

Deep venous thrombosis (DVT) of the lower extremity may be caused by external compression of the inferior vena cava (IVC) by a neighboring mass. A 55-year-old male presented with 8 months of intermittent left lower extremity swelling and signs of chronic venous stasis. Duplex ultrasound showed extensive DVT in the left leg. Subsequent imaging revealed a 4.2 cm infrarenal abdominal aortic aneurysm (AAA) compressing the IVC. In cases of chronic, unilateral DVT, work-up should include imaging for an anatomic cause. AAA is a rare cause of IVC compression with DVT, and is most commonly related to inflammatory AAAs. Previously reported cases of IVC compression by non-inflammatory AAAs have been secondary to large aneurysms (greater than 6 cm). This case illustrates that smaller AAAs lacking hemodynamically significant IVC obstruction may be found in association with DVT.