Applying Proteomics and Computational Approaches to Identify Novel Targets in Blast-Associated Post-Traumatic Epilepsy.

Traumatic brain injury (TBI) can lead to post-traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents with several complications, including cognitive and behavioral disturbances and PTE; however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased proteomics approach in a mouse model of repeated bTBI (rbTBI), this study addresses this gap in the knowledge. After rbTBI, mice were monitored using continuous, uninterrupted video-EEG for up to four months. Following this period, we collected cortex and hippocampus tissues from three groups of mice: those with post-traumatic epilepsy (PTE+), those without epilepsy (PTE-), and the control group (sham). Hundreds of differentially expressed proteins were identified in the cortex and hippocampus of PTE+ and PTE- relative to sham. Focusing on protein pathways unique to PTE+, pathways related to mitochondrial function, post-translational modifications, and transport were disrupted. Computational metabolic modeling using dysregulated protein expression predicted mitochondrial proton pump dysregulation, suggesting electron transport chain dysregulation in the epileptic tissue relative to PTE-. Finally, data mining enabled the identification of several novel and previously validated TBI and epilepsy biomarkers in our data set, many of which were found to already be targeted by drugs in various phases of clinical testing. These findings highlight novel proteins and protein pathways that may drive the chronic PTE sequelae following rbTBI.

Constitutive HO-1 and CD55 (DAF) Expression and Regulatory Interaction in Cultured Podocytes.

Overexpression of the inducible heme oxygenase (HO-1) isoform in visceral renal glomerular epithelial cells (podocytes) using in vivo transgenesis methods was shown to increase glomerular expression of the complement regulatory protein decay-accelerating factor (DAF, CD55) and reduce complement activation/deposition in a rat model of immune-mediated injury. In this preliminary study, we assessed whether constitutively expressed HO-1 regulates CD55 expression in cultured rat podocytes. We employed methods of flow cytometry, quantitative (q) RT-qPCR and post-transcriptional HO-1 gene silencing (HO-1 interfering RNA, RNAi), to assess changes in constitutive (basal) levels of podocyte HO-1 and CD55 mRNA in cultured rat podocytes. Additionally, the effect of the HO-1 inducer, heme, on HO-1 and CD55 expression was assessed. Results indicate that rat podocytes constitutively express HO-1 and DAF and that the HO-1 inducer, heme, increases both HO-1 and DAF expression. HO-1 gene silencing using RNA interference (RNAi) is feasible but the effect on constitutive CD55 transcription is inconsistent. These observations are relevant to conditions of podocyte exposure to heme that can activate the complementary cascade, as may occur in systemic or intraglomerular hemolysis.

An automated rat grimace scale for the assessment of pain.

Pain is a complex neuro-psychosocial experience that is internal and private, making it difficult to assess in both humans and animals. In pain research, animal models are prominently used, with rats among the most commonly studied. The rat grimace scale (RGS) measures four facial action units to quantify the pain behaviors of rats. However, manual recording of RGS scores is a time-consuming process that requires training. While computer vision models have been developed and utilized for various grimace scales, there are currently no models for RGS. To address this gap, this study worked to develop an automated RGS system which can detect facial action units in rat images and predict RGS scores. The automated system achieved an action unit detection precision and recall of 97%. Furthermore, the action unit RGS classifiers achieved a weighted accuracy of 81-93%. The system's performance was evaluated using a blast traumatic brain injury study, where it was compared to trained human graders. The results showed an intraclass correlation coefficient of 0.82 for the total RGS score, indicating that the system was comparable to human graders. The automated tool could enhance pain research by providing a standardized and efficient method for the assessment of RGS.

Novel In-Training Evaluation Report in an Internal Medicine Residency Program: Improving the Quality of the Narrative Assessment.

OBJECTIVE: To determine whether incorporating our novel in-training evaluation report (ITER), which prompts each resident to list at least three self-identified learning goals, improved the quality of narrative assessments as measured by the Narrative Evaluation Quality Instrument (NEQI). METHODS: A total of 1468 narrative assessments from a single institution from 2017 to 2021 were deidentified, compiled, and sorted into the pre-intervention form arm and post-intervention form arm. Due to limitations in our residency management suite, incorporating learning goals required switching from an electronic form to a hand-deliver form. Comments were graded by two research personnel utilizing the NEQI's scale of 0-12, with 12 representing the maximum quality for a comment. The outcome of the study was the mean difference in NEQI score between the electronic pre-intervention period and paper post-intervention period. RESULTS: The mean NEQI score for the pre-intervention period was 2.43 ± 3.34, and the mean NEQI score for the post-intervention period was 3.31 ± 1.71, with a mean difference of 0.88 (p < 0.001). In the pre-intervention period, 46% of evaluations were submitted without a narrative assessment (scored as a zero) while 1% of post-intervention period evaluations had no narrative assessment. Internal consistency reliability, as measured by Ebel's intraclass correlation coefficient (ICC), showed high agreement between the two raters (ICC = 0.92). CONCLUSIONS: Our findings suggest that implementing a timely, hand-delivered paper ITER that incorporates resident learning goals can lead to overall higher-quality narrative assessments.

Detection of Major and Mild Neurocognitive Disorder with the Verbal Naming Test.

OBJECTIVE: The Verbal Naming Test (VNT) is an auditory-based measure of naming or word finding. The current multisite study sought to evaluate the reliability and validity of the VNT in the detection of major and mild neurocognitive disorder (NCD). METHOD: This study analyzed clinical data from two outpatient neuropsychology clinics (N = 188 and N = 77) and a geriatric primary care clinic (N = 104). Cronbach's alpha and Spearman correlations with other measures were calculated. ROC analyses were used to calculate sensitivity, specificity, positive predictive power, and negative predictive power for the detection of major and mild NCD per DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) criteria. RESULTS: The VNT was found to have strong reliability (Cronbach's alpha = .90) and high convergent validity with a commonly used picture-naming task (NAB Naming, Spearman's rho = .65, p < .001). The VNT showed good sensitivity and specificity for the detection of NCDs, particularly major NCD, with an area under the curve of .85, sensitivity of .80, and specificity of .75. A possible discontinue rule is also suggested for clinicians to use. CONCLUSIONS: These findings provide compelling evidence for the use of the VNT to detect neurocognitive impairment in a clinical setting. The VNT provides a reliable alternative to picture-naming tasks, which may be advantageous when working with visually impaired patients or conducting evaluations over telehealth.

The Great Gut Mimicker: A case report of MIS-C and appendicitis clinical presentation overlap in a teenage patient.

BACKGROUND: Abdominal pain and other gastrointestinal symptoms are common presenting features of multisystem inflammatory syndrome in children (MIS-C) and can overlap with infectious or inflammatory abdominal conditions, making accurate diagnosis challenging. CASE PRESENTATION: We describe the case of a 16-year-old female who presented with clinical symptoms suggestive of appendicitis and an abdominal computed tomography (CT) that revealed features concerning for appendicitis. After laparoscopic appendectomy, histopathology of the appendix demonstrated only mild serosal inflammation and was not consistent with acute appendicitis. Her overall clinical presentation was felt to be consistent with MIS-C and she subsequently improved with immunomodulatory and steroid treatment. CONCLUSIONS: We note that MIS-C can mimic acute appendicitis. This case highlights MIS-C as a cause of abdominal imaging with features concerning for appendicitis, and MIS-C should be considered in the differential for a patient with appendicitis-like symptoms and a positive COVID-19 IgG. Lab criteria, specifically low-normal white blood cell count and thrombocytopenia, appears to be of high relevance in differing MIS-C from acute appendicitis, even when appendix radiologically is dilated.

Eurasian beaver (Castor fiber) health surveillance in Britain: Assessing a disjunctive reintroduced population.

BACKGROUND: Numerous translocations of Eurasian beavers have occurred with little implementation of standardised health screening. Pre-release health screening enables the selection of individuals with the best survival prospects and reduces potential health risks, but this is by-passed during unofficial releases. Beaver reintroduction to Britain has been haphazard and currently disjunctive populations of varying status exist. METHODS: This observational cross section study investigated the health status of three beaver populations, with 90 live beavers tested for a range of pathogens comprising 56 from Tayside (unofficially released Scotland), nine from Knapdale (officially released Scotland) and 25 from Devon (unofficially released England). In addition, a further 32 cadavers were screened (25 from Tayside and seven from Knapdale). RESULTS: All beavers were in good physical condition, did not harbour any non-native disease or parasites of concern and demonstrated remarkably low levels of any disease or parasite exposure. CONCLUSION: Beavers are establishing and adapting well to British landscapes and are not acting as reservoirs of significant zoonotic diseases. Official, licensed reintroduction programmes may appear overly convoluted; however, reputational damage of unofficial releases should be considered, along with the health and welfare of the animals involved and collateral damage to other wildlife, domestic animals and humans.

In Vivo Effects of Methionine Sulfoxide Reductase Deficiency in Drosophila melanogaster.

The deleterious alteration of protein structure and function due to the oxidation of methionine residues has been studied extensively in age-associated neurodegenerative disorders such as Alzheimer's and Parkinson's Disease. Methionine sulfoxide reductases (MSR) have three well-characterized biological functions. The most commonly studied function is the reduction of oxidized methionine residues back into functional methionine thus, often restoring biological function to proteins. Previous studies have successfully overexpressed and silenced MSR activity in numerous model organisms correlating its activity to longevity and oxidative stress. In the present study, we have characterized in vivo effects of MSR deficiency in Drosophila. Interestingly, we found no significant phenotype in animals lacking either methionine sulfoxide reductase A (MSRA) or methionine sulfoxide reductase B (MSRB). However, Drosophila lacking any known MSR activity exhibited a prolonged larval third instar development and a shortened lifespan. These data suggest an essential role of MSR in key biological processes.

A novel two-day intervention reduces stress in caregivers of persons with dementia.

INTRODUCTION: Caregivers of individuals with dementia are at heightened risk for stress-related mental and physical illnesses, and this problem is growing. There is a critical need to develop effective interventions for caregivers. This study tested whether a 2-day intervention improved psychological health in caregivers of individuals with dementia. METHODS: Family caregivers (N = 104) were randomly assigned to a 2-day intervention or wait-list control group. The intervention uses techniques aimed at fostering self-care for caregivers and improving communication between caregivers and individuals with dementia. Self-reported caregiver burden, stress, anxiety, and depression were measured at 1, 3, and 6 months after intervention. RESULTS: Most participants (91.5%) completed the entire study. The intervention significantly reduced perceived stress for up to 6 months (Β = -2.84, t = -2.68, P = .008) and was considered by nearly all respondents to be helpful for managing challenging behaviors. DISCUSSION: A low-cost, brief intervention shows promise for producing lasting improvements in caregiver's psychological health.

What's eating you? Ixodes tick and related diseases, part 3: coinfection and tick-bite prevention.

Ixodes ticks are important vectors in the transmission of human disease. In endemic areas, infection with multiple tick-borne diseases may occur. In part 3 of this review, identification and management of coinfection with multiple pathogens is discussed. Methods of tick-bite prevention and tick removal also are discussed.

What's eating you? Ixodes tick and related diseases, part 2: diagnosis and treatment of regional tick-borne diseases.

The Ixodes tick is an important arthropod vector in the transmission of human disease. Although Lyme disease is the most prevalent zoonosis transmitted by Ixodes ticks, other less common diseases may be encountered, including human granulocytic anaplasmosis, babesiosis, Powassan virus infection, tick-borne encephalitis, Borrelia miyamotoi disease, and tick paralysis. In part 2 of this review, disease presentation, diagnosis, and treatment of these less commonly encountered tick-borne diseases are discussed.

What's eating you? Ixodes tick and related diseases, part 1: life cycle, local reactions, and lyme disease.

The Ixodes tick is an important arthropod vector in the transmission of human disease. This 3-part review highlights the biology of the Ixodes tick and manifestations of related diseases. Part 1 addresses the Ixodes tick biology and life cycle; local reactions; and Lyme disease, the most prevalent of associated diseases. Part 2 will address human granulocytic anaplasmosis, babesiosis, Powassan virus infection, Borrelia miyamotoi disease, tick-borne encephalitis, and tick paralysis. Part 3 will address coinfection with multiple pathogens as well as methods of tick-bite prevention and tick removal.

Sex Differences in Academic Rank and Publication Rate at Top-Ranked US Neurology Programs.

Importance: Women are underrepresented in academic neurology, and the reasons for the underrepresentation are unclear. Objective: To explore potential sex differences in top-ranked academic neurology programs by comparing the number of men and women at each academic faculty rank and how many articles each group has published. Design, Setting, and Participants: Twenty-nine top-ranked neurology programs were identified by combining the top 20 programs listed on either the 2016 or 2017 Doximity Residency Navigator tool with the top 20 programs listed in the US News and World Report ranking of Best Graduate Schools. An internet search of the departmental websites was performed between December 1, 2015, and April 30, 2016. For each faculty member on a program site, the following biographical information was obtained: first name, last name, academic institution, sex, academic faculty rank, educational leadership (clerkship, fellowship, or residency director/assistant director), and year of medical school graduation. Main Outcomes and Measures: To compare the distribution of men vs women and the number of publications for men vs women at each academic faculty rank. Secondary analyses included Scopus h-index, book authorship, educational leadership (clerkship, residency, or fellowship director/assistant director), and clinical activity as inferred through Medicare claims data in men vs women after controlling for years since medical school graduation. Results: Of 1712 academic neurologists in our sample, 528 (30.8%) were women and 1184 (69.2%) were men (P < .001). Men outnumbered women at all academic faculty ranks, and the difference increased with advancing rank (instructor/lecturer, 59.4% vs 40.5%; assistant professor, 56.7% vs 43.3%; associate professor, 69.8% vs 30.2%; and professor, 86.2% vs 13.8%). After controlling for clustering and years since medical school graduation, men were twice as likely as women to be full professors (odds ratio [OR], 2.06; 95% CI, 1.40-3.01), whereas men and women had the same odds of being associate professors (OR, 1.04; 95% CI, 0.82-1.32). Men had more publications than women at all academic ranks, but the disparity in publication number decreased with advancing rank (men vs women after adjusting for years since medical school graduation: assistant professor [exponentiated coefficient, 1.85; 95% CI, 1.57-2.12]; associate professor [1.53; 95% CI, 1.22-1.91]; and full professor [1.36; 95% CI, 1.09-1.69]). Men had a higher log Scopus h-index than women after adjustment (linear coefficient, 0.44; 95% CI, 0.34-0.55). There was no significant association between sex and clinical activity (linear coefficient, 0.02; 95% CI, -0.10 to 0.13), educational leadership (OR, 1.09; 95% CI, 0.85-1.40), or book authorship (OR, 2.75; 95% CI, 0.82-9.29) after adjusting for years since medical school graduation. Conclusions and Relevance: Men outnumber women at all faculty ranks in top-ranked academic neurology programs, and the discrepancy increases with advancing rank. Men have more publications than women at all ranks, but the gap narrows with advancing rank. Other measures of academic productivity do not appear to differ between men and women.

Immune complexes containing malondialdehyde (MDA) LDL induce apoptosis in human macrophages.

Immune complexes (IC) containing predominantly malondialdehyde-LDL and the corresponding autoantibodies (MDA-LDL IC) predict acute cardiovascular events, while IC rich in oxidized LDL (oxLDL IC) predict cardiovascular disease progression. Our objective was to determine mechanisms that could explain these prognostic differences. We compared the effects of the interaction of oxLDL, MDA-LDL and the corresponding IC with human macrophages focusing on apoptosis, metalloproteinases, and proinflammatory cytokines. MDA-LDL IC induced higher degrees of apoptosis, higher levels of caspase-3 expression, and increased expression and release of MMP-1 and TNF compared to MDA-LDL, oxLDL, and oxLDL IC. The pro-apoptotic effects of MDA-LDL IC were inhibited by blocking TNFR 1 or FcγRI. Blocking FcγRI abrogated the induction and expression of MMPs and proinflammatory cytokines by MDA-LDL IC. In conclusion, the interaction of MDA-LDL IC with FcγRI triggers macrophage apoptosis and increased expression and release of TNF and MMP-1, which can lead to the rupture of unstable plaques.