Associations Between Sexual Minority Status, Hazardous Drinking, and Discrimination Experiences Among Criminal Legal-Involved Adults in the Southern PrEP Cohort (SPECS) Study.

OBJECTIVE: Separately, individuals with criminal legal involvement (CLI) and those who identify as a sexual minority are at heightened risk for experiencing discrimination and engaging in hazardous alcohol use; however, little is known about the prevalence of these experiences and behaviors among sexual minority individuals who also have a history of CLI. METHOD: We examined experiences of discrimination and hazardous alcohol use reported by individuals with CLI and compared prevalence between those who identify as a sexual minority and those who do not. Baseline, cross-sectional data of cisgender sexual minority individuals from a multisite, prospective cohort study examining pre-exposure prophylaxis acceptability and uptake among criminal legal-involved adults were analyzed (N = 362, 14% sexual minority). RESULTS: Hazardous alcohol consumption was nearly twice as prevalent among participants who identified as a sexual minority compared to heterosexual participants, and a sexual minority identity was associated with higher discrimination scores. Additionally, hazardous drinking was more prevalent among those with higher discrimination scores. CONCLUSIONS: This study suggests that sexual minority individuals with a history of CLI are an especially high-risk group given the elevated rates of discrimination and hazardous alcohol use observed. More research is needed to further investigate the risk behaviors of this population and to develop interventions to intervene on their physical and mental health.

Estrogen's sex-specific effects on ischemic cell death and estrogen receptor mRNA expression in rat cortical organotypic explants.

Estrogens, such as the biologically active 17-ß estradiol (E2), regulate not only reproductive behaviors in adults, but also influence neurodevelopment and neuroprotection in both females and males. E2, contingent upon the timing and concentration of the therapy, is neuroprotective in female and male rodent models of stroke. In Vivo studies suggest that E2 may partially mediate this neuroprotection, particularly in the cortex, via ERα. In Vitro studies, utilizing a chemically induced ischemic injury in cortical explants from both sexes, suggest that ERα or ERß signaling is needed to mediate the E2 protection. Since we know that the timing and concentration of E2 therapy may be sex-specific, we examined if E2 (1 nM) mediates neuroprotection when female and male cortical explants are separately isolated from postnatal day (PND) 3-4 rat. Changes in basal levels ERα, ERß, and AR mRNA expression are compared across early post-natal development in the intact cortex and the corresponding days in vitro (DIV) for cortical explants. Following ischemic injury at 7 DIV, cell death and ERα, ERß and AR mRNA expression was compared in female and male cortical explants. We provide evidence that E2-mediated protection is maintained in isolated cortical explants from females, but not male rats. In female cortical explants, the E2-mediated protection at 24 h occurs secondarily to a blunted transient increase in ERα mRNA at 12 h. These results suggest that cortical E2-mediated protection is influenced by sex and supports data to differentially treat females and males following ischemic injury.

Thermoneutral temperature exposure enhances slow-wave sleep with a correlated improvement in amyloid pathology in a triple-transgenic mouse model of Alzheimer's disease.

Accumulation of amyloid-ß (Aß) plays an important role in Alzheimer's disease (AD) pathology. There is growing evidence that disordered sleep may accelerate AD pathology by impeding the physiological clearance of Aß from the brain that occurs in normal sleep. Therapeutic strategies for improving sleep quality may therefore help slow disease progression. It is well documented that the composition and dynamics of sleep are sensitive to ambient temperature. We therefore compared Aß pathology and sleep metrics derived from polysomnography in 12-month-old female 3xTg-AD mice (n = 8) exposed to thermoneutral temperatures during the light period over 4 weeks to those of age- and sex-matched controls (n = 8) that remained at normal housing temperature (22°C) during the same period. The treated group experienced greater proportions of slow wave sleep (SWS)-i.e. epochs of elevated 0.5-2 Hz EEG slow wave activity during non-rapid eye movement (NREM) sleep-compared to controls. Assays performed on mouse brain tissue harvested at the end of the experiment showed that exposure to thermoneutral temperatures significantly reduced levels of DEA-soluble (but not RIPA- or formic acid-soluble) Aß40 and Aß42 in the hippocampus, though not in the cortex. With both groups pooled together and without regard to treatment condition, NREM sleep continuity and any measure of SWS within NREM at the end of the treatment period were inversely correlated with DEA-soluble Aß40 and Aß42 levels, again in the hippocampus but not in the cortex. These findings suggest that experimental manipulation of SWS could offer useful clues into the mechanisms and treatment of AD.

Older adults using social support to improve self-care (OASIS): Adaptation, implementation and feasibility of peer support for older adults with T2D in appalachia: A feasibility study protocol.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) is 17% higher in rural dwellers compared to their urban counterparts, and it increases with age, with an estimated 25% of older adults (≥ 65 years) diagnosed. Appropriate self-care is necessary for optimal clinical outcomes. Overall, T2D self-care is consistently poor among the general population but is even worse in rural-dwellers and older adults. In rural Kentucky, up to 23% of adults in Appalachian communities have been diagnosed with T2D and, of those, 26.8% are older adults. To attain optimal clinical outcomes, social environmental factors, including social support, are vital when promoting T2D self-care. Specifically, peer support has shown to be efficacious in improving T2D self-care behaviors and clinical and psychosocial outcomes related to T2D; however, literature also suggests self-selected social support can be obstructive when engaging in healthful activities. Currently available evidence-based interventions (EBIs) using peer support have not been used to prioritize older adults, especially those living in rural communities. METHOD: To address this gap, we conducted formative research with stakeholders, and collaboratively identified an acceptable and feasible peer support EBI-peer health coaching (PHC)-that has resulted in improved clinical and psychosocial T2D-related outcomes among participants who did not reside in rural communities nor were ≥65 years. The goal of the proposed study is to use a 2x2 factorial design to test the adapted PHC components and determine their preliminary effectiveness to promote self-care behaviors and improve glycemic control among older adults living in Appalachian Kentucky. Testing the PHC components of the peer support intervention will be instrumental in promoting care for older adults in Appalachia, as it will allow for a larger scale intervention, which if effective, could be disseminated to community partners in Appalachia. TRIAL REGISTRATION: This study was registered at www.clinicaltrials.gov (NCT06003634) in August 2023.

Assessment of gait mechanics and muscle strength in hypermobile Ehlers Danlos Syndrome.

BACKGROUND: Hypermobile Ehlers Danlos Syndrome, a heritable connective tissue disorder, is associated with muscle dysfunction, joint subluxations and pain. The impact of hypermobile Ehlers Danlos Syndrome on musculoskeletal mechanics is understudied. Therefore, the aim of this study was to assess the effects of hypermobile Ehlers Danlos Syndrome on lower extremity gait mechanics and muscle strength. METHODS: Eleven people with hypermobile Ehlers Danlos Syndrome and 11 asymptomatic controls underwent a 3D gait analysis and isometric hip and knee muscle strength assessment. Joint subluxations were self-reported by the hypermobile Ehlers Danlos syndrome group. Independent t-tests and Mann Whitney U tests were used to analyze joint mechanics, muscle strength, and patient report outcomes (p < 0.05). FINDINGS: Both groups exhibited similar walking speeds as well as similar hip, knee, and ankle joint kinematics. The hypermobile Ehlers Danlos Syndrome group walked with a lower peak hip extensor moment (hypermobile Ehlers Danlos Syndrome: -0.52 ± 0.28 Nmˑkg-1, Control: -0.83 ± 0.26 Nmˑkg-1, p = 0.01) yet similar knee and ankle joint moments. The hypermobile Ehlers Danlos Syndrome group exhibited a 40% deficit in peak hip extensor strength (hypermobile Ehlers Danlos Syndrome:1.07 ± 0.53 Nmˑkg-1, Control: 1.77 ± 0.79 Nmˑkg-1, p = 0.04). Approximately 73%, 55% and 45% of the hypermobile Ehlers Danlos Syndrome cohort self-reported hip, knee/patella and ankle joint subluxations, respectively, at least once a week. INTERPRETATION: Patients with hypermobile Ehlers Danlos Syndrome ambulated with altered hip extensor moments and exhibit hip extensor weakness. Future work should investigate the underlying mechanisms of hip extensor weakness and corresponding effects on joint health in people with hypermobile Ehlers Danlos Syndrome.

Telemedicine as a path to bridging inequities in patients with epilepsy.

OBJECTIVE: Access to epilepsy specialist care is not uniform in the USA, with prominent gaps in rural areas. Understanding the reasons for nonattendance at epilepsy appointments may help identify access hurdles faced by patients. This study was undertaken to better understand clinic absenteeism in epilepsy and how it may be influenced by telemedicine. METHODS: In this retrospective study, social determinants of health were collected for all adult patients scheduled in epilepsy clinic, as either an in-person or telemedicine appointment, at University of Kentucky between July 2021 and December 2022. The primary outcome measure was attendance or absence at the appointment. Subgroup analyses were done to better understand the drivers of attendance at telemedicine visits and evaluate telemedicine utilization by underserved populations. RESULTS: A total of 3025 patient encounters of in-person and telemedicine visits were included. The no-show rate was significantly higher for in-person visits (32%) compared with telemedicine visits (20%, p < .001). A nominal logistic regression model identified seven factors increasing risk of absenteeism, including in-person visits, prior missed appointments, longer lead times to appointment, Medicaid/Medicare as payors, no significant other, lower mean annual income, and minority race. For each $10 000 increase in mean annual income, the odds of missing the appointment decreased by 8% (odds ratio = .92, 95% confidence interval = .89-.96, p < .001). Forty-one percent of underserved population opted for telemedicine visits, and they had a lower no-show rate (22%) as compared with in-person visits (33%, p < .001). Predictors of no-shows to televisits (1382) included Medicare/Medicaid coverage (as opposed to private insurance), no significant others, and a history of missing appointments. SIGNIFICANCE: Telemedicine is effective at improving attendance, overcoming socioeconomic hurdles, and widening access to epilepsy care, particularly among underserved populations. Access to telecare depends on insurance coverage and emphasizes the need to include telemedicine in insurance plans to ensure uniform access to high-quality epilepsy care, irrespective of socioeconomic status.

Competitive neurosurgery residency programs: Predictors of matching outcome and research productivity.

OBJECTIVE: The aim of this study was to provide a comprehensive assessment of preresidency research and school as predictors of competitive neurosurgery matching and to assess for any correlations between preresidency and intraresidency research productivity. METHODS: Individuals who graduated from US neurosurgery programs from 2018 through 2020 were assessed for medical school, degree (MD, DO, or PhD), preresidency versus intraresidency publications, author order, article type, and neurosurgery matching outcomes. RESULTS: Medical school ranking (top 50) and the number of published papers (≥3) before intern year were predictors for matching to a top-25 residency program after adjusting for other covariates (p < 0.001, p = 0.002, respectively). On average, individuals who published more papers before residency published more papers during residency. For the comprehensive clinical papers category, there was a significant difference between individuals from the top 25 residency programs and others, with a stronger correlation between the number of preresidency publications and intraresidency publications for neurosurgeons who attended a top-25 residency program (r = 0.378 and r = 0.179, respectively; p = 0.02). CONCLUSION: Medical school ranking and research productivity as measured by the number of published papers were independently associated with matching to the top 25 residency programs. In addition, high research productivity in the preresidency years was associated with continued productivity during residency, especially in the category of comprehensive clinical papers.

Inflammatory-associated proteomic predictors of cognitive outcome in subjects with ELVO treated by mechanical thrombectomy.

BACKGROUND: Emergent Large Vessel Occlusion (ELVO) stroke causes devastating vascular events which can lead to significant cognitive decline and dementia. In the subset of ELVO subjects treated with mechanical thrombectomy (MT) at our institution, we aimed to identify systemic and intracranial proteins predictive of cognitive function at time of discharge and at 90-days. These proteomic biomarkers may serve as prognostic indicators of recovery, as well as potential targets for novel/existing therapeutics to be delivered during the subacute stage of stroke recovery. METHODS: At the University of Kentucky Center for Advanced Translational Stroke Sciences, the BACTRAC tissue registry (clinicaltrials.gov; NCT03153683) of human biospecimens acquired during ELVO stroke by MT is utilized for research. Clinical data are collected on each enrolled subject who meets inclusion criteria. Blood samples obtained during thrombectomy were sent to Olink Proteomics for proteomic expression values. Montreal Cognitive Assessments (MoCA) were evaluated with categorical variables using ANOVA and t-tests, and continuous variables using Pearson correlations. RESULTS: There were n = 52 subjects with discharge MoCA scores and n = 28 subjects with 90-day MoCA scores. Several systemic and intracranial proteins were identified as having significant correlations to discharge MoCA scores as well as 90-day MoCA scores. Highlighted proteins included s-DPP4, CCL11, IGFBP3, DNER, NRP1, MCP1, and COMP. CONCLUSION: We set out to identify proteomic predictors and potential therapeutic targets related to cognitive outcomes in ELVO subjects undergoing MT. Here, we identify several proteins which predicted MoCA after MT, which may serve as therapeutic targets to lessen post-stroke cognitive decline.

Academically Inclined: Predictors of Early Career Trajectory and Avenues for Early Intervention Among Neurosurgery Trainees.

BACKGROUND: The relationship of academic activities before and during neurosurgery residency with fellowship or career outcomes has not been studied completely. OBJECTIVE: To assess possible predictors of fellowship and career outcomes among neurosurgery residents. METHODS: US neurosurgery graduates (2018-2020) were assessed retrospectively for peer-reviewed citations of preresidency vs intraresidency publications, author order, and article type. Additional parameters included medical school, residency program, degree (MD vs DO; PhD), postgraduate fellowship, and academic employment. RESULTS: Of 547 neurosurgeons, 334 (61.1%) entered fellowships. Fellowship training was significantly associated with medical school rank and first-author publications. Individuals from medical schools ranked 1 to 50 were 1.6 times more likely to become postgraduate fellows than individuals from medical schools ranked 51 to 92 (odds ratio [OR], 1.63 [95% CI 1.04-2.56]; P = .03). Residents with ≥2 first-author publications were almost twice as likely to complete a fellowship as individuals with <2 first-author publications (OR, 1.91 [95% CI 1.21-3.03]; P = .006). Among 522 graduates with employment data available, academic employment obtained by 257 (49.2%) was significantly associated with fellowship training and all publication-specific variables. Fellowship-trained graduates were twice as likely to pursue academic careers (OR, 1.99 [95% CI 1.34-2.96]; P < .001) as were individuals with ≥3 first-author publications ( P < .001), ≥2 laboratory publications ( P = .04), or ≥9 clinical publications ( P < .001). CONCLUSION: Research productivity, medical school rank, and fellowships are independently associated with academic career outcomes of neurosurgeons. Academically inclined residents may benefit from early access to mentorship, sponsorship, and publishing opportunities.

Age and Medicare Insurance are Barriers to Telemedicine Access-A Quality Improvement Project.

BACKGROUND: Telehealth use has had widespread expansion and adoption over the past two years. This study aims to evaluate access to telehealth essentials (TE) using a novel metric. METHODS: This single institute study surveyed outpatient surgical patients to determine their access to TE. Generalized linear mixed models were used to determine the relationship of demographic and county-level variables on access to four TE. RESULTS: 138 patients were surveyed. Sixty-six (47.8%) were from Appalachian Kentucky. In the survey cohort, 122 (88.4%) had smart phones, 109 (80.7%) had devices with video messaging capabilities, 106 (80.9%) had cellular reception, and 112 (82.4%) had access to WiFi. Increasing age and Medicare insurance were the most consistent predictors of lack of access to TE. CONCLUSION: Rural Appalachian Kentucky has access to TE. Telehealth has the potential to decrease the healthcare inequity in rural populations, but incompletely address this inequity for the aging population.

Plasma protein alterations during human large vessel stroke: A controlled comparison study.

BACKGROUND: Stroke is a major cause of death and disability in the United States. Mechanical thrombectomy (MT) and tissue plasminogen activator are the current treatments for ischemic stroke, which have improved clinical outcomes. Despite these treatments, functional and cognitive deficits still occur demonstrating a need for predictive biomarkers for beneficial clinical outcomes which can be used as therapeutic targets for pharmacotherapy. The aim of this study compares the proteomic expression of systemic arterial blood collected at the time of MT to those from a matched cerebrovascular disease (CVD) control cohort. METHODS: The Blood And Clot Thrombectomy Registry And Collaboration (BACTRAC) (clinicaltrials.gov NCT03153683) collects and banks arterial blood, both distal and proximal to the thrombus, from ischemic stroke subjects undergoing MT. Arterial blood from patients undergoing a diagnostic angiogram was also collected and banked as CVD controls. Changes in cardiometabolic and inflammatory proteins between stroke and CVD controls were analyzed via Olink Proteomics. RESULTS: Proteins including ARTN, TWEAK, HGF, CCL28, FGF-5, CXCL9, TRANCE and GDNF were found to be decreased in stroke subjects when compared to CVD controls. CXCL1, CCL5, OSM, GP1BA, IL6, MMP-1, and CXCL5 were increased in stroke subjects when compared to CVD controls. These proteins were also significantly correlated to stroke outcome metrics such as NIHSS, infarct volume and MoCA scoring. CONCLUSION: Overall, acute stroke patients had an increase in inflammatory proteins with a decrease in trophic proteins systemically compared to matched CVD controls. Using our CVD controls, proteins of interest were directly compared to stroke patients with the same cerebrovascular risk factors instead of statistically controlling for comorbidities. The novel methodology of matching an arterial blood CVD control group to a stroke group, as well as controlling for age and comorbid status add to the literature on prognostic stroke biomarkers, which are specific targets for future therapeutics.

Direct delivery of an investigational cell therapy in patients with Parkinson's disease: an interim analysis of feasibility and safety of an open-label study using DBS-Plus clinical trial design.

Objective: To evaluate the interim feasibility, safety and clinical measures data of direct delivery of regenerating peripheral nerve tissue (PNT) to the substantia nigra (SN) in participants with Parkinson's disease (PD). Methods: Eighteen (13 men/5 women) participants were unilaterally implanted with PNT to the SN, contralateral to the most affected side during the same surgery they were receiving deep brain stimulation (DBS) surgery. Autologous PNT was collected from the sural nerve. Participants were followed for safety and clinical outcomes for 2 years (including off-state Unified Parkinson's Disease Rating Scale (UPDRS) Part III assessments) with study visits every 6 months. Results: All 18 participants scheduled to receive PNT implantation received targeted delivery to the SN in addition to their DBS. All subjects were discharged the following day except for two: post-op day 2; post-op day 3. The most common study-related adverse events were hypoaesthesia and hyperaesthesias to the lateral aspect of the foot and ankle of the biopsied nerve (6 of 18 participants experienced). Clinical measures did not identify any hastening of PD measures providing evidence of safety and tolerability. Off-state UPDRS Part III mean difference scores were reduced at 12 months compared with baseline (difference=-8.1, 95% CI -2.4 to -13.9 points, p=0.005). No complications involving dyskinesias were observed. Conclusions: Targeting the SN for direct delivery of PNT was feasible with no serious adverse events related to the study intervention. Interim clinical outcomes show promising results meriting continued examination of this investigational approach. Trial registration number: NCT02369003.

VAERS-reported new-onset seizures following use of COVID-19 vaccinations as compared to influenza vaccinations.

The incidence of new-onset seizures, which we defined as de novo seizures occurring within 4 weeks of receiving any of the US Food and Drug Administration-approved COVID-19 vaccinations as reported in patient-reported data compiled in the US Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System Data (CDC VAERS), has not been explored. The VAERS database contains de-identified patient-reported adverse events following vaccination and represents post-marketing surveillance and analysis of vaccine safety. After adjusting for time at risk, this resulted in estimated incidence rates of 3.19 seizures per 100 000 persons per year for the COVID-19 vaccine and 0.090 seizures per 100 000 persons per year for the influenza vaccines. A data-driven, individualized dataset that is comprehensive and coupled with a longitudinal follow-up in larger numbers of vaccinated individuals is needed to expand on our preliminary findings of vaccine-related seizures.

Influence of BMI on adenosine deaminase and stroke outcomes in mechanical thrombectomy subjects.

BACKGROUND: Emergent Large Vessel Occlusion (ELVO) strokes are ischemic vascular events for which novel biomarkers and therapies are needed. The purpose of this study is to investigate the role of Body Mass Index (BMI) on protein expression and signaling at the time of ELVO intervention. Additionally, we highlight the protein adenosine deaminase (ADA), which is a deaminating enzyme that degrades adenosine, which has been shown to be neuroprotective in ischemia. We investigate the relationship between ADA and BMI, stroke outcomes, and associated proteomic networks which might aid in personalizing prognosis and future treatment of ELVO stroke. METHODS: The Blood And Clot Thrombectomy And Collaboration (BACTRAC) study is a continually enrolling tissue bank (clinicaltrials.gov NCT03153683) and registry from stroke patients undergoing mechanical thrombectomy (MT). N â€‹= â€‹61 human carotid plasma samples were analyzed for inflammatory and cardiometabolic protein expression by Olink Proteomics. Statistical analyses used t-tests, linear, logistic, and robust regressions, to assess the relationship between BMI, proteomic expression, and stroke-related outcomes. RESULTS: The 61 subjects studied were broken into three categories: normal weight (BMI 18.5-24.9) which contained 19 subjects, overweight (BMI 25-30) which contained 25 subjects, and obese (BMI ≥30) which contained 17 subjects. Normal BMI group was a significantly older population (mean 76 years) when compared to overweight (mean 66 years) and obese (mean 61 years) with significance of p â€‹= â€‹0.041 and p â€‹= â€‹0.005, respectively. When compared to normal weight and overweight categories, the obese category had significantly higher levels of adenosine deaminase (ADA) expression (p â€‹= â€‹0.01 and p â€‹= â€‹0.039, respectively). Elevated levels of ADA were found to have a significant positive correlation with both infarct volume and edema volume (p â€‹= â€‹0.013 and p â€‹= â€‹0.041, respectively), and were associated with a more severe stroke (NIHSS on discharge) and greater stroke related disability (mRS on discharge) with significance of p â€‹= â€‹0.053 and p â€‹= â€‹0.032, respectively. CONCLUSIONS: When examined according to BMI, subjects undergoing MT for ELVO demonstrate significant differences in the expression of certain plasma proteins, including ADA. Levels of ADA were found to be significantly higher in the obese population when compared to normal or overweight groups. Increased levels of ADA in the obese group were predictive of increased infarct volume, edema volume, and worse NIHSS scores and mRS at discharge. These data provide novel biomarker candidates as well as treatment targets while increasing the personalization of stroke prognosis and treatment.

Concordance between Self-Reported Drug Use and Urinalysis in a Sample of Black American Women.

BACKGROUND: Obtaining accurate drug use data is important in the field of substance use research. Urinalysis, considered gold standard, can be costly or infeasible, whereas self-report is quick and easy, but susceptible to imperfect recall or misrepresentation. It is important to determine the concordance between self-report and urinalysis, and better understand the contexts and participant characteristics that influence self-report accuracy. The current study aims to assess this concordance for marijuana and cocaine in a sample of Black American women, some with criminal justice exposure, and to investigate predictors of non-concordance. METHODS: In this longitudinal study, a sample of Black American women were recruited from community, prison, and probation settings. Self-report drug use and urine drug screens were obtained at 6-, 12-, and 18-month follow-ups, allowing for the calculation of concordance. Generalized linear mixed models were used to assess participant characteristics that predicted non-concordance (both false positives and false negatives). RESULTS: In general, there was agreement between self-report and urinalysis results for both marijuana and cocaine. Baseline drug use status was the most consistent predictor of non-concordance. Individuals recruited while on probation were more likely to have false negative results and less likely to have false positive results. Additionally, concordance rates for marijuana increased over the follow-up period. CONCLUSIONS: Self-reported marijuana and cocaine use are accurate measures of actual drug consumption in a sample of Black American women with a variety of criminal justice interactions.

Freehand frontal external ventricular drain (EVD) placement: Accuracy and complications.

Ventriculostomy placement is a life-saving procedure. Our aim was to determine the predictors of inaccurate placement, our infection and hemorrhage rate. This was a retrospective study of EVD placements between January - November 2019. Data related to hemorrhage, infection and catheter misplacement were collected. Univariate and multivariate analyses of predictors of suboptimal catheter placement were performed. 131 consecutive patients underwent freehand EVD placement. The indications were subarachnoid hemorrhage in 36 (27.5%) patients, hemorrhagic stroke in 36 (27.5%), and trauma in 32 (24.4%) patients. Nine patients (6.8%) had culture-proven CSF bacterial infection. Sixteen (12.2%) patients developed small tract hemorrhage, while 8 (6.1%) patients developed large intraparenchymal hemorrhage. There was no correlation between tract hemorrhage or large hemorrhage with the use of antiplatelet or anticoagulation medicines on presentation, diagnosis or Kakarla grade. Trauma diagnosis (odds ratio 2.59, p-value 0.05), left side of EVD placement (odds ratio 2.84, p-value 0.03), increasing midline shift (odds ratio 1.09, p-value 0.03), and lower bicaudate index (odds ratio 0.56, p-value 0.02) were all predictors of Kakarla grade 3 suboptimal placement. When Kakarla grade 2 and 3 were combined, similar results were obtained except that midline shift was no longer statistically significant. The multivariable regression model predicting Kakarla 3 suboptimal placement revealed that low bicaudate index and left sided EVD were predictors of misplaced EVD.

Therapeutic treatment with the anti-inflammatory drug candidate MW151 may partially reduce memory impairment and normalizes hippocampal metabolic markers in a mouse model of comorbid amyloid and vascular pathology.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, but therapeutic options are lacking. Despite long being able to effectively treat the ill-effects of pathology present in various rodent models of AD, translation of these strategies to the clinic has so far been disappointing. One potential contributor to this situation is the fact that the vast majority of AD patients have other dementia-contributing comorbid pathologies, the most common of which are vascular in nature. This situation is modeled relatively infrequently in basic AD research, and almost never in preclinical studies. As part of our efforts to develop small molecule, anti-inflammatory therapeutics for neurological injury and disease, we have recently been exploring potentially promising treatments in preclinical multi-morbidity contexts. In the present study, we generated a mouse model of mixed amyloid and hyperhomocysteinemia (HHcy) pathology in which to test the efficacy of one of our anti-inflammatory compounds, MW151. HHcy can cause cerebrovascular damage and is an independent risk factor for both AD dementia and vascular contributions to cognitive impairment and dementia. We found that MW151 was able to partially rescue hippocampal-dependent spatial memory and learning deficits in this comorbidity context, and further, that the benefit is associated with a normalization of hippocampal metabolites detectable via magnetic resonance spectroscopy. These findings provide evidence that MW151 in particular, and potentially anti-inflammatory treatment more generally, may be beneficial in AD patients with comorbid vascular pathology.

Antimicrobial protein REG3A and signaling networks are predictive of stroke outcomes.

Regenerating Family Member 3 Alpha (REG3A) is a multifunctional protein with antimicrobial activity, and primarily secreted by the intestine and pancreas. Studies have shown an increased expression of REG3A in systemic inflammatory responses to acute injury and infection, but studies investigating REG3A during the pathogenesis of ischemic stroke are limited. The aims of this study were to examine the associations between arterial expression of REG3A and other arterial inflammatory proteins implicated in stroke pathogenesis, as well as associations between REG3A and markers of poor outcome for ischemic stroke. The University of Kentucky Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (clinicaltrials.gov NCT03153683) utilizes thrombectomy to isolate intracranial arterial blood (i.e. distal to thrombus) and systemic arterial blood (i.e. carotid). Samples were analyzed by Olink Proteomics for N = 42 subjects. Statistical analyses of plasma proteins included 2-sample t-tests, spearman and biserial correlations, and robust regression models to elucidate network signaling and association to clinical outcomes. Results indicated that levels of systemic REG3A were positively correlated with inflammatory proteins interleukin IL6 (R = 0.344, p = 0.030) and IL17C (R = 0.468, p = 0.002). 2-sided t- tests examining differences of systemic REG3A within quartiles of NIHSS admission score depicted significant differences between quartiles. Those with NIHSS scores corresponding to moderate and moderate-severe neurofunctional deficits had significantly higher levels of systemic REG3A compared to those with NIHSS scores corresponding to mild and mild-moderate neurofunctional deficits (p = 0.016). STRING analyses of proteins in each robust regression model demonstrated substantial networking between REG3A and other systemic proteins highly relevant to ischemic stroke. The present study provides novel data on systemic REG3A in the context of ischemic stroke. These results demonstrate the influential role of REG3A regarding surrogate functional and radiographic outcomes of stroke severity. Additionally, they provide novel insight into the role of REG3A and related proteins during the complex neuroinflammatory process of ischemic stroke. These data provide a foundation for future studies to investigate REG3A and related networking proteins as potential biomarkers with prognostic potential, as well as potential therapeutic targets.

Extended Middle Cerebral Artery Occlusion (MCAO) Model to Mirror Stroke Patients Undergoing Thrombectomy.

Stroke remains a leading global cause of death and disability. In the last decade, the therapeutic window for mechanical thrombectomy has increased from a maximum of 6 to 24 h and beyond. While endovascular advancements have improved rates of recanalization, no post-stroke pharmacotherapeutics have been effective in enhancing neurorepair and recovery. New experimental models are needed to closer mimic the human patient. Our group has developed a model of transient 5-h occlusion in rats to mimic stroke patients undergoing thrombectomy. Our procedure was designed specifically in aged rats and was optimized based on sex in order to keep mortality and extent of injury consistent between aged male and female rats. This model uses a neurological assessment modeled after the NIH Stroke Scale. Finally, the potential for translation between our rat model of stroke and humans was assessed using comparative gene expression for key inflammatory genes. This model will be useful in the evaluation of therapeutic targets to develop adjuvant treatments for large vessel occlusion during the thrombectomy procedure.