Analysis of Covariance with Heterogeneity of Regression and a Random Covariate

The analysis of covariance (ANCOVA) is a statistical technique originally developed by Fisher (1932) to increase the precision of the estimate of a treatment effect in experimental data. It is used when researchers have both qualitative and quantitative predictors of a continuous outcome. ANCOVA’s most basic assumptions are similar to those of analysis of variance (ANOVA) and other related linear models, but also include an additional assumption regarding the regression line relating the outcome and the covariate. This assumption, referred to as homogeneity of regression, requires that the within-group regression slopes be the same for all groups. Typically, one also assumes that the covariate is a fixed effect, but some methodologists question this practice. Consequences of either employing a model allowing for heterogeneity of regression (an ANCOHET model) or presuming that the covariate is random can be dealt with fairly easily if both do not occur simultaneously. However, a problem arises when one simultaneously encounters both a random covariate and heterogeneity of regression: the interaction between the random covariate and the fixed factor of treatment will affect the apparent evidence for the main effect of treatment. The current study investigated the utility of different methods of testing for the main effect of treatment in the presence of heterogeneity of regression with a random covariate. Using a Monte Carlo simulation, a 2x3x5x2x3 design manipulated the number of groups, sample size per group, extent of heterogeneity of regression, presence of a group effect, and test location to investigate this issue. For each combination of these factors, different types of tests of the group effect were conducted, as explained in the Method section. Two error terms, the mean square for the interaction and an average of the mean square error for an ANCOHET model and the interaction mean square, performed poorly across all simulations for all metrics. On the other hand, the ANCOHET and ANCOVA error terms produced Type I error rates, power, confidence interval coverage rates and widths, as well as average standard errors under low and medium levels of heterogeneity of regression that were acceptable. When heterogeneity of regression was high or extreme, the ANCOHET approach underestimated the true standard error, whereas the ANCOVA error term did not. Using an approach to increase the ANCOHET standard error based on Chen (2006) did not result in a large enough increase to make up for this underestimation. In conclusion, with the low and moderate levels of heterogeneity of regression typically reported in the literature the ANCOHET test of the group effect can be recommended even with a random covariate. Under large or extreme levels of heterogeneity of regression, an error term from a standard ANCOVA should instead be used

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\u27s 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

Hemorrhagic stroke outcomes of KApSR patients with co-morbid diabetes and Alzheimer’s disease

Background: Vascular risk factors, such as diabetes mellitus (DM), are associated with poorer outcomes following many neurodegenerative diseases, including hemorrhagic stroke and Alzheimer’s disease (AD). Combined AD and DM co-morbidities are associated with an increased risk of hemorrhagic stroke and increased Medicare costs. Therefore, we hypothesized that patients with DM in combination with AD, termed DM/AD, would have increased hemorrhagic stroke severity. Methods: Kentucky Appalachian Stroke Registry (KApSR) is a database of demographic and clinical data from patients that live in Appalachia, a distinct region with increased health disparities and stroke severity. Inpatients with a primary indication of hemorrhagic stroke were selected from KApSR for retrospective analysis and were separated into four groups: DM only, AD only, neither, or both. Results: Hemorrhagic stroke patients (2,071 total) presented with either intracerebral hemorrhage (ICH), n=1,448, or subarachnoid hemorrhage (SAH), n=623. When examining all four groups, subjects with AD were significantly older (AD+, 80.9±6.6 yrs) (DM+/AD+, 77.4±10.0 yrs) than non AD subjects (DM-/AD-, 61.3±16.5 yrs) and (DM+, 66.0±12.5 yrs). A higher percentage of females were among the AD+ group and a higher percentage of males among the DM+/AD+ group. Interestingly, after adjusting for multiple comparison, DM+/AD+ subjects were ten times as likely to suffer a moderate to severe stroke based on a National Institute of Health Stroke (NIHSS) upon admission [odds ratio (95% CI)] compared to DM-/AD- [0.1 (0.02–0.55)], DM+ [0.11 (0.02–0.59)], and AD+ [0.09(0.01–0.63)]. The odds of DM+/AD+ subjects having an unfavorable discharge destination (death, hospice, long-term care) was significant (P Conclusions: In our retrospective analysis utilizing KApSR, regardless of adjusting for age, sex, and comorbidities, DM+/AD+ patients were significantly more likely to have had a moderate or severe stroke leading to an unfavorable outcome following hemorrhagic stroke

Short Chain Fatty Acids Taken at Time of Thrombectomy in Acute Ischemic Stroke Patients Are Independent of Stroke Severity But Associated with Inflammatory Markers and Worse Symptoms at Discharge

Introduction: Short chain fatty acids (SCFA) are gut microbiota-derived metabolites that contribute to the gut-brain axis and may impact stroke outcomes following gut dysbiosis. We evaluated plasma SCFA concentrations against stroke severity parameters and identified SCFA-associated protein networks. Methods: The Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC), a continuously enrolling tissue bank, was used to obtain stroke samples. Arterial blood distal and proximal to the thrombus was obtained from Acute Ischemic Stroke (AIS) Patients (n=53) during thrombectomy. Patient demographics, stroke presentation and outcome parameters were reported. The SCFAs were isolated from proximal plasma via chemical derivatization UHPLC coupled tandem mass spectrometry using electrospray ionization and multiple reaction monitoring. Proteomic levels for 184 cardioembolic and inflammatory proteins was quantified from systemic and intracranial plasma by Olink. Arterial blood from cerebrovascular patients undergoing elective neurointerventional procedures was used as controls. Results: Acetate positively correlated with time from last known normal (LKN) and was significantly lower in stroke patients compared to control. Isobutyrate, Butyrate and 2-Methylbutyrate negatively correlated with %ΔNIHSS. Isobutyrate and 2-Methylbutyrate positively correlated with NIHSS discharge. SCFA concentrations were not associated with NIHSS admission, infarct volume, or edema volume. Multiple SCFAs positively associated with systemic and pro-inflammatory cytokines, most notably IL-6, TNF-α, VCAM1, IL-17, and MCP-1. Conclusions: Plasma SCFA concentrations taken at time of stroke are not associated with stroke severity at presentation. However, higher levels of SCFAs at the time of stroke are associated with increased markers of inflammation, less recovery from admission to discharge, and worse symptom burden at discharge

Commentary: Use of BACTRAC Proteomic Database-Uromodulin Protein Expression during Ischemic Stroke

Introduction: Uromodulin (UMOD) is a glycoprotein expressed by the epithelial cells of the thick ascending limb of Henle\u27s loop in the kidney. Research has shown that increased uromodulin expression may be associated with lower risk of cardiovascular disease in adults. Utilizing the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) (clinicaltrials.gov NCT03153683), a continuously enrolling tissue bank, we aimed to examine the associations between serum uromodulin, age, and high BMI (BMI\u3e 25) and its relationship to stroke in patients. Methods: Arterial blood distal and proximal to the thrombus was collected during a thrombectomy procedure using the BACTRAC protocol and sent to Olink (Boston, MA) to determine proteomic expression via proximity extension assay. Uromodulin expression was recorded and analyzed using two tailed T-tests and linear regressions. Results: The relationship between systemic and intracranial uromodulin, age, high BMI and hypertension were assessed. Systemic and intracranial uromodulin decreased with age (p\u3c 0.0001 and r²= 0.343, p= 0.0416 and r²= 0.102) respectively. Systemic uromodulin expression increased with BMI\u3e 25 (p= 0.014). Presence of hypertension decreased uromodulin’s expression systemically (p= 0.018) and intracranially (p= 0.007). Conclusions: Uromodulin was increased significantly in overweight patients, decreased significantly in older patients, and decreased in patients with hypertension. The increase in uromodulin in people with high BMI could be a protective reaction of the kidney to worsening conditions that make ischemic stroke more likely, with a goal of delaying dangerous outcomes. The decreased expression of uromodulin in older adults could be associated with the decline of general kidney function that accompanies aging. Hypertension can contribute to an AKI by decreasing perfusion to the kidney, therefore decreasing kidney function and uromodulin production. Further analyses are needed to understand the role of uromodulin following ischemic stroke

Analysis of the prevalence and onset of dysphonia and dysphagia symptoms in movement disorders at an academic medical center

•Patients with Parkinson’s Disease show a low awareness of dysphagia symptoms.•Essential Tremor patients report a lower prevalence of dysphonia symptoms.•Atypical Parkinsonian Syndromes report a higher prevalence of dysphagia symptoms.•Atypical Parkinsonian Syndromes report dysphagia and dysphonia symptoms earliest.•Correlation between dysphagia and dysphonia scores with disease severity scores. Voice and swallowing impairments are common in movement disorders, but their effect on patients’ quality of life is not well known. This study was conducted to determine the onset and prevalence of patient-reported dysphonia and dysphagia symptoms in Parkinson’s disease (PD), dystonia, Atypical Parkinsonian Syndromes (APS), and Essential Tremor (ET). Patients referred to a movement disorders clinic in a tertiary care academic medical center completed validated voice and swallowing specific Quality of Life (QOL) questionnaires: Voice Handicap Index-10 (VHI-10) and Eating Assessment Tool-10 (EAT-10). Patient demographics and clinical data were also collected. Two hundred and sixty-eight patients (males = 150, females = 118) completed the questionnaires (n was PD = 103, APS = 30, ET = 56, dystonia = 32, other = 47). Prevalence of patient-reported dysphagia symptoms was significantly higher in APS (63%) than PD (26%), ET (25%), and dystonia (31%). Prevalence of patient-reported dysphonia symptoms was significantly lower in ET (14%) compared to PD (34%) and APS (43%). Disease duration was shorter in PD and APS compared to ET and dystonia (p < 0.05) before reporting clinically significant dysphonia and dysphagia symptoms indicating an earlier onset of these symptoms. There were significant positive correlations between VHI-10 and EAT-10 scores and disease severity, as indicated by Unified Parkinson’s Disease motor scores (p < 0.0001) and modified Fahn-Tolosa-Marin Tremor Rating sub-scores (p = 0.0013). Patient-reported dysphonia and dysphagia symptoms were present in one fourth of patients with PD, ET, dystonia, and almost two thirds in APS. Patient-reported QOL measures, such as VHI-10 and EAT-10, can help screen movement disorder patients for dysphonia and dysphagia symptoms

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 four weeks of receiving any of the FDA-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 vaccinations 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. 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

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

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.OBJECTIVESeparately, 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.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).METHODWe 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).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.RESULTSHazardous 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.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.CONCLUSIONSThis 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

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 \u3c2 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 \u3c .001) as were individuals with ≥3 first-author publications ( P \u3c .001), ≥2 laboratory publications ( P = .04), or ≥9 clinical publications ( P \u3c .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

Changes in Angioarchitecture After Stereotactic Radiosurgery for Dural Arteriovenous Fistula.

INTRODUCTION: Dural arteriovenous fistulae (DAVF) are intracranial vascular abnormalities encountered in neurosurgery practice. Treatment options are microsurgical disconnection, endovascular embolization and/or radiosurgery. Past studies have reported the efficacy, safety, and predictors of success of radiosurgery. In this study, we investigated the angioarchitecture of fistulae at the time of radiosurgery and how the anatomy changed in the time after treatment based on angiogram follow-ups. METHODS: A retrospective analysis was performed on patients with angiographic diagnosis of DAVF treated with Gamma Knife radiosurgery (GKRS) between 2013 and 2018. Data collection included demographics, symptoms, grading scores, vascular anatomy, radiation data, treatment strategy, angiographic results, and length of patient follow-up. RESULTS: Our study reports data on 10 patients with a total of 14 fistulae. On follow-up angiography, 8 (57%) had complete occlusion of the fistula with a median time to follow up of 19.5 months. The remaining 6 (43%) were deemed as near-complete occlusion of fistula with a median time to follow up of 12.0 months. Time from radiosurgery to angiogram revealing incomplete vs. angiogram revealing complete obliteration was significantly different (p=0.045). Nearly all AVFs had decreased feeders over time after treatment with only one AVF developing an additional feeder post-treatment. Arterial feeders, drainage site, sex, Borden type, lesion volume and treatment volume had no predictive value of obliteration outcome. CONCLUSIONS: This study provides data on the angioarchitecture of fistulae treated with GKRS and also serves as an extension of previous studies reporting the safety and efficacy of GKRS treatment for DAVF in a specific patient population