William S. Middleton Memorial Veterans Hospital

To identify imaging endophenotypes in juvenile myoclonic epilepsy using individualized Z-maps of cortical/subcortical regions and examine their relationships with cognitive, psychiatric and epilepsy-related variables. Sixty-two juvenile myoclonic epilepsy patients (aged 12–25 years) and 41 age- and sex-matched healthy controls underwent 3T MRI, neuropsychological assessment, psychiatric evaluation and clinical interviews. Cortical thickness and subcortical volumes were processed with FreeSurfer, adjusted for age, sex and brain volume. Kolmogorov–Smirnov tests were used to compare regional distributions. Z-scores were calculated relative to healthy controls, and K-means clustering identified endophenotypes. In juvenile myoclonic epilepsy, there were reduced subcortical volumes most prominently in motor-related thalamus (P < 0.001) and greater variability in cortical thickness in the frontal/parietal regions. Three endophenotypes emerged: subcortical reduction (n = 27, 43.5%), increased cortical thickness (n = 21, 33.9%) and decreased cortical thickness (n = 14, 22.6%). Subcortical reduction showed marked motor thalamic and subcortical grey matter loss. Increased cortical thickness exhibited frontal and parietal cortical thickening with associated subcortical reduction. Decreased cortical thickness showed less subcortical change, but overall reduced cortical thickness. Cognitive differences were notable: Increased Cortical Thickness was the most impaired cognitively, suggesting a disruption of neurodevelopment, while decreased cortical thickness performed the best, particularly in speed/response inhibition—consistent with the least disruption of brain maturation and dysregulation of synaptic pruning. Seizure burden, socioeconomic status, age of onset and psychiatric diagnoses did not show any differences between groups. Juvenile myoclonic epilepsy exhibits heterogeneous imaging endophenotypes, with motor thalamic and subcortical reductions and variability cortical thickness in the frontal and parietal regions, reflecting neurodevelopmental dysregulation with cognitive consequences.

Our studies identify a role for the α-cell phosphoenolpyruvate cycle in sensing amino acids under hypoglycemic conditions. Leucine, in the presence of glutamine, opposes alanine/arginine-stimulated Ca2+ influx and glucagon secretion. Pyruvate kinase and phosphoenolpyruvate carboxykinase 2 are required for leucine to close α-cell KATP channels and limit Ca2+ influx. All of the amino acids tested regulate glucagon secretion, but none do so by modulating membrane depolarization or intracellular Ca2+ levels.

Understanding that excess body weight can increase disability and limit daily occupations, occupational therapists must consider how to support patients with weight management within a larger health care system. To develop a clinical tool for health care professionals to (a) support referrals to occupational therapists to address weight management and (b) assess priorities for weight management interventions. This research utilized a co-design process with six occupational therapists from primary care to design a screening tool prototype. The design process revealed three challenges to supporting patients with excess body weight that were addressed through the design elements of the screening tool: (a) weight is a "sticky" topic, (b) negative messaging around weight can adversely impact patient care, and (c) occupational therapy involvement in weight management is impacted by a lack of referrals. This design process yielded the Occupational Therapy Health Routines Screening Tool prototype.

Having significant gaps between the expectations and reality of artificial intelligence-based programs can be a major barrier to successful implementation. This is the first multisite implementation assessment of gaps between surgeon expectations and real-world effects of the Operating Room Black Box, a novel intervention that leverages artificial intelligence to improve surgical outcomes. To identify barriers and facilitators to implementing artificial intelligence-based interventions that improve intra- and postoperative care. This qualitative study was conducted at 3 large academic centers via semistructured interviews with surgeons and implementation leaders of the AI intervention to identify areas where expectations of the technology misaligned with their experiences. Thirty surgeons and 17 implementation leaders from 3 centers that implemented the AI intervention were interviewed. Data were collected and analyzed between 2021 and 2024. Implementation of the AI intervention. The primary outcome was areas of misalignment between participant expectations of the AI intervention technology and actual program deliverables. Of 30 surgeons and 17 implementation leaders interviewed, most surgeons (17 [57%]) were between the ages of 35 and 50 years, and implementation leaders were older, typically between 51 and 80 years old (6 [35%]). Eight surgeons (27%) and 4 implementation leaders (24%) were female. Most surgeons (17 [57%]) had neutral views of the technology, 11 (37%) expressed positive views, and 2 (7%) had negative views. Interviewees identified the following 4 major themes that highlighted misalignment between user expectations and the experience of using the technology: (1) the artificial intelligence model needed considerable additional training to be usable; (2) accessing data on surgical cases was difficult and time consuming; (3) the program showed limited ability to predict postoperative complications; and (4) the program generated few academic deliverables. Per the results of this multisite qualitative study, successfully implementing interventions based on artificial intelligence may require deliberate efforts to minimize gaps between what surgeons expect from the interventions and what they can deliver. Our evaluation of this study's AI intervention offers lessons for addressing this critical barrier to implementation.

BackgroundMatrix metalloproteinases (MMPs) are a group of enzymes with roles in mediating extracellular matrix integrity and inflammation, and degrading beta amyloid fibrils. Studies have demonstrated that MMPs in atherosclerotic plaques can be downregulated by omega‐3 fatty acid eicosapentaenoic acid (EPA), but there has been little research looking at the effect of EPA on MMP levels in CSF. In this study, we evaluated the effect of an FDA approved high dose EPA supplement on CSF levels of MMP‐2 and MMP‐9, and MMP inhibitors TIMP‐1 and TIMP‐2.MethodCognitively healthy VA‐eligible veterans (ages 50‐76) were enrolled in the Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid Study (BRAVE, NCT02719327), a randomized, placebo‐controlled, double‐blind, parallel‐group clinical trial with subject N = 128, randomized in a 1:1 ratio to receive either 4g icosapent ethyl (Vascepa® IPE) or a placebo (mineral oil) daily for 18 months. Participants with suspected memory impairment, liver or kidney disease, or those unable to comply with study procedures were excluded. CSF biomarkers MMP‐2, MMP‐9, TIMP‐1, and TIMP‐2 were obtained at baseline, 9 months, and 18 months. In these exploratory analyses, treatment group differences in CSF biomarkers (18 month/baseline ratio) were analyzed on an intent to treat basis using GraphPad Prism®.ResultContrary to published studies showing decreased levels and expression of MMP‐2 and ‐9 in individuals treated with EPA, our data revealed significant increases in levels of MMP‐2 (p = 0.04) and MMP‐9 (p = 0.003) in the IPE treated group compared to placebo. There was also a significant increase in TIMP‐2 in the IPE group (p = 0.02), which is consistent with previously published in vitro studies. Although not statistically significant, the effect of IPE seems to be modified by APOE4 status, with a trend towards decreased MMP‐2, MMP‐9, and TIMP‐2 in APOE4‐positive individuals.ConclusionIn this randomized clinical trial, veterans treated with high dose EPA (Vascepa® IPE) for 18 months demonstrated significant increases in CSF levels of MMP‐2, MMP‐9, and TIMP‐2 compared to individuals treated with placebo. These results contrast published studies showing decreased MMP levels in atherosclerotic plaques treated with EPA. Further research is needed to elucidate the effect of EPA on cerebral biomarkers.

Millions of aging men are diagnosed with lower urinary tract dysfunction (LUTD) each year. Alpha adrenergic receptor blockers relax prostatic, urethral, and bladder smooth muscle to relieve LUTD symptoms and are often, but not always, effective. Serotonin is proposed to cause contractions in the female urethra, as well as in the lungs and bowel. This study tests that serotonin synthesized in the periphery, outside of the central nervous system, contributes to the development of LUTD induced in mice by subcutaneous implants of testosterone (T) and estradiol (E2), mimicking the hormone milieu of aging men. Immunofluorescent staining of male human and mouse urethra was used to confirm the presence of neuroendocrine cells and interstitial cells of Cajal, which contribute to serotonin-induced contractions in the female mouse urethra. Wild type and tryptophan hydroxylase 1 null (Tph1-/- ) mice, which are deficient in the rate-limiting enzyme in peripheral serotonin synthesis, were given sham surgery or T+E2 implants. Voiding behavior was measured with the void spot assay one day before surgery and two weeks post-surgery. Four weeks after surgery, bladders were exteriorized and measured to calculate volume, and anesthetized cystometry was performed to assess bladder activity. Serotonin-positive neuroendocrine cells and serotonin receptor positive interstitial cells of Cajal were detected in the prostatic urethra of humans and mice. Two weeks after T+E2 implantation surgery, a baseline level of urinary retention occurred in both wild type and Tph1-/- mice. However, wild type mice treated with T+E2 had increased frequent small voids (P<0.01) and decreased bladder activity (P<0.005) when compared to wild type mice with sham treatment and Tph1-/- mice with T+E2 treatment. Wild type mice developed a more severe voiding dysfunction phenotype than Tph1-/- mice when treated with T+E2, indicating that peripheral serotonin plays a role in T+E2-mediated LUTD. Because the urinary dysfunction observed in mice mimics that of human men, future studies to understand and exploit the role of serotonin may provide a treatment option for a subset of LUTD.

BackgroundArterial stiffness is implicated in the development of Alzheimer's disease and related dementias. The effect of intensive blood pressure control on changing arterial stiffness parameters and their associations with cognitive impairment remains unclear.MethodSPRINT evaluated the effect of intensive versus standard blood pressure control (SBP<120mmHg versus SBP<140 mmHg) on time to cognitive impairment. Arterial stiffness was assessed in a subset of participants by total carotid‐femoral pulse wave velocity (T‐PWV, in m/s) at baseline and years 1‐3. Age‐related structural stiffening (S‐PWV, due to vessel wall remodeling) and load‐dependent stiffening (LD‐PWV, due to changes in BP over the cardiac cycle) were calculated by adjusting T‐PWV to a 120/80 mmHg reference with participant‐specific models. Cognitive impairment was assessed by repeated testing over 10 years with adjudication of Mild Cognitive Impairment (MCI) or Probable Dementia (PD) as a composite outcome. Time to incident cognitive impairment was estimated as hazard ratios (HR) and 95% Confidence Intervals (95%CI) using Cox proportional hazards for baseline stiffness and Joint Longitudinal Survival Models for changes in stiffness over time adjusted for treatment arm, demographics (age, race, sex, education), baseline mean arterial pressure, and heterogeneous effects of intensive BP control.ResultA total of 611 participants (72±9 years old, 40% women, 70% White) had T‐PWV and time to event data resulting in 90 composite MCI (n = 62) and PD (n = 28) events over a median follow‐up of 6.2 years. Each m/s higher baseline T‐PWV and S‐PWV was significantly associated with a 10% increase in the hazards for developing incident cognitive impairment independent of treatment arm but was attenuated by adjustment for demographics (Table 1). LD‐PWV declined with intensive SBP control, while T‐PWV and S‐PWV increased over the 3‐year study treatment period (Figure 1). Intensive treatment‐related declines in LD‐PWV were associated a 21% reduction [HR(95%CI) = 0.79(0.61‐1.00] in the risk for cognitive impairment adjusted for demographics (Table 2). No heterogeneous treatment effects based on T‐PWV, S‐PWV, or LD‐PWV were detected.ConclusionComponents of arterial stiffness are associated with incident cognitive impairment independent of BP control. Arterial stiffness remains an unaddressed risk factor for cognitive impairment and potential target for dementia prevention.

Abstract Early-stage, formative solicitation of stakeholder needs and preferences can inform curriculum development that is responsive and fosters a sense of co-ownership. Clinical discipline preceptors are key collaborators in the ultimate implementation of an interprofessional core curriculum in geriatrics with their respective health professions trainees. This presentation describes the formative environmental scan and subsequent stakeholder engagement process to identify 1) core geriatric knowledge needed by interprofessional trainees, 2) gaps in geriatric education across discipline-specific programs, and 3) perceived barriers and delivery/modality preferences. The Geriatric Interprofessional Core Curriculum development team conducted an environmental scan to identify existing interprofessional core curricula that provide essential knowledge in best practices for caring for older adults. The team identified multiple relevant and validated resources and iteratively discussed strengths and limitations of each. Few were sufficiently inclusive to meaningfully engage the range of disciplines and levels of professional preparation represented in the GRECC health professions training program. The Geriatric 5M’s Framework (What Matters, Mentation, Medication, Mobility, Multicomplexity) provided an interprofessional scaffold that, with preceptors’ subject matter expertise, facilitated curriculum development. Accordingly, five roundtable discussions were held, each focusing on one of the 5Ms. A total of 49 interprofessional educators were engaged and asked to identify core geriatric training needs, discuss preferred curriculum modality and potential barriers to implementation. Thematic analysis of transcripts and detailed session notes yielded a set of priority content topics, as well as implementation preferences regarding usable formats and delivery, in support of the next phase of the development process.