Faculty Bibliography

The stress response to emotions elicits the release of glucocorticoids from the adrenal cortex, epinephrine from the adrenal medulla, and norepinephrine from the sympathetic nerves. The baroreflex adapts to buffer these responses to ensure that perfusion to the organs meets the demands while maintaining blood pressure within a within a narrow range. While stressor-evoked autonomic cardiovascular responses may be adaptive for the short-term, the recurrent exaggerated cardiovascular stress reactions can be maladaptive in the long-term. Prolonged stress or loss of the baroreflex's buffering capacity can predispose episodes of heightened sympathetic activity during stress leading to hypertension, tachycardia, and ventricular wall motion abnormalities. This review discusses 1) how the baroreflex responds to acute and chronic stressors, 2) how lesions in the neuronal pathways of the baroreflex alter the ability to respond or counteract the stress response, and 3) the techniques to assess baroreflex sensitivity and stress responses. Evidence suggests that loss of baroreflex sensitivity may predispose heightened autonomic responses to stress and at least in part explain the association between stress, mortality and cardiovascular diseases.

COVID-19 has infected millions of people and upended the lives of most humans on the planet. Researchers from across the psychological sciences have sought to document and investigate the impact of COVID-19 in myriad ways, causing an explosion of research that is broad in scope, varied in methods, and challenging to consolidate. Because policy and practice aimed at helping people live healthier and happier lives requires insight from robust patterns of evidence, this article provides a rapid and thorough summary of high-quality studies available through early 2021 examining the mental-health consequences of living through the COVID-19 pandemic. Our review of the evidence indicates that anxiety, depression, and distress increased in the early months of the pandemic. Meanwhile, suicide rates, life satisfaction, and loneliness remained largely stable throughout the first year of the pandemic. In response to these insights, we present seven recommendations (one urgent, two short-term, and four ongoing) to support mental health during the pandemic and beyond.

Background One-quarter of all strokes are subsequent events. It is not known whether higher levels of blood glucose are associated with an increased risk of subsequent stroke after high-risk transient ischemic attack or minor ischemic stroke. Methods and Results We performed a secondary analysis of the POINT (Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial to evaluate the relationship between serum glucose hyperglycemia (≥180 mg/dL) versus normoglycemia (<180 mg/dL) before enrollment in the trial and outcomes at 90 days. The primary end point was subsequent ischemic stroke modeled by a multivariable Cox model with adjustment for age, sex, race, ethnicity, study treatment assignment, index event, and key comorbidities. Of 4878 patients included in this study, 267 had a recurrent stroke. There was a higher hazard of subsequent stroke in patients with hyperglycemia compared with normoglycemia (adjusted hazard ratio [HR], 1.50 [95% CI, 1.05-2.14]). Treatment with dual antiplatelet therapy was not associated with a reduced hazard of subsequent stroke in patients with hyperglycemia (HR, 1.18 [95% CI, 0.69-2.03]), though the wide confidence interval does not exclude a treatment effect. When modeled as a continuous variable, there was evidence of a nonlinear association between serum glucose and the hazard of subsequent stroke (P<0.001). Conclusions Hyperglycemia on presentation is associated with an increased risk of subsequent ischemic stroke after high-risk transient ischemic attack or minor stroke. A rapid, simple assay of serum glucose may be a useful biomarker to identify patients at particularly high risk of subsequent ischemic stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT0099102.

OBJECTIVE:This study aims to determine the contributions of sun exposure and ultraviolet radiation (UVR) exposure to risk of paediatric-onset multiple sclerosis (MS). METHODS:Children with MS and controls recruited from multiple centres in the USA were matched on sex and age. Multivariable conditional logistic regression was used to investigate the association of time spent outdoors daily in summer, use of sun protection, and ambient summer UVR dose in the year prior to birth and the year prior to diagnosis, with MS risk, adjusting for sex, age, race, birth season, child's skin colour, mother's education, tobacco smoke exposure, being overweight, and Epstein-Barr virus infection. RESULTS:, 95%CI 0.62-0.94, p=0.01). CONCLUSIONS:If this is a causal association, spending more time in the sun during summer may be strongly protective against developing paediatric MS, as well as residing in a sunnier location.

OBJECTIVE:To explore the association between blood pressure (BP) levels after endovascular thrombectomy (EVT) and the clinical outcomes of acute ischemic stroke (AIS) patients with large vessel occlusion (LVO). METHODS:A study was eligible if it enrolled AIS patients older than 18 years, with an LVO treated with either successful or unsuccessful EVT, and provided either individual or mean 24-hour systolic BP values after the end of the EVT procedure. Individual patient data from all studies were analyzed using a generalized linear mixed-effects model. RESULTS:A total of 5874 patients (mean age: 69±14 years, 50% women, median NIHSS on admission: 16) from 7 published studies were included. Increasing mean systolic BP levels per 10 mm Hg during the first 24 hours after the end of the EVT were associated with a lower odds of functional improvement (unadjusted common OR=0.82, 95%CI:0.80-0.85; adjusted common OR=0.88, 95%CI:0.84-0.93) and modified Ranking Scale score≤2 (unadjusted OR=0.82, 95%CI:0.79-0.85; adjusted OR=0.87, 95%CI:0.82-0.93), and a higher odds of all-cause mortality (unadjusted OR=1.18, 95%CI:1.13-1.24; adjusted OR=1.15, 95%CI:1.06-1.23) at 3 months. Higher 24-hour mean systolic BP levels were also associated with an increased likelihood of early neurological deterioration (unadjusted OR=1.14, 95%CI:1.07-1.21; adjusted OR=1.14, 95%CI:1.03-1.24) and a higher odds of symptomatic intracranial hemorrhage (unadjusted OR=1.20, 95%CI:1.09-1.29; adjusted OR=1.20, 95%CI:1.03-1.38) after EVT. CONCLUSION/CONCLUSIONS:Increased mean systolic BP levels in the first 24 hours after EVT are independently associated with a higher odds of symptomatic intracranial hemorrhage, early neurological deterioration, three-month mortality, and worse three-month functional outcomes.

OBJECTIVE:We examined the impact of post-traumatic stress disorder (PTSD) on both prospective (PM) and retrospective (RM) memory performance among a cross-sectional veteran sample. METHOD/METHODS:Data from tests of PM/RM memory and PTSD, anxiety, depression and sleep disturbance symptoms were examined among a prospectively recruited sample of 26 veterans with confirmed PTSD (PTSD+) and 26 well-matched, combat-exposed controls who did not meet criteria for PTSD (PTSD-). RESULTS:Small-to-moderate negative correlations emerged between PTSD symptom severity, visuospatial RM and some aspects of PM; general anxiety correlated more strongly with memory. The PTSD+ group demonstrated significantly worse, but still average visuospatial RM; differences in PM were nonsignificant between groups. Regression analyses implicated generalized anxiety, but not other psychiatric symptomology, as significant contributors to all memory performances. CONCLUSIONS:Minimal memory differences were found between veterans with and without PTSD. PM/RM memory performance was better explained by generalized anxiety rather that PTSD-specific symptoms.

OBJECTIVE:This cross-sectional study examined accuracy of traditional Medical Symptom Validity Test (MSVT) validity indicators, including immediate recognition (IR), delayed recognition (DR), and consistency (CNS), as well as a novel indicator derived from the mean performance on IR, DR, and CNS across verbal, visual, and combined learning and memory impairment bands. METHOD/METHODS:A sample of 180 adult outpatients was divided into valid (n = 150) and invalid (n = 30) groups based on results of four independent criterion performance validity tests. Verbal and visual learning and recall were classified as indicative of no impairment, mild impairment, or severe impairment based on performance on the Rey Auditory Verbal Learning Test and Brief Visuospatial Memory Test-Revised, respectively. RESULTS:In general, individual MSVT subtests were able to accurately classify performance as valid or invalid, even in the context of severe learning and memory deficits. However, as verbal and visual memory impairment increased, optimal MSVT cut-scores diverged from manual-specified cutoffs such that DR and CNS required cut-scores to be lowered to maintain adequate specificity. By contrast, the newly proposed scoring algorithm generally showed more robust psychometric properties across the memory impairment bands. CONCLUSIONS:The mean performance index, a novel scoring algorithm using the mean of the three primary MSVT subtests, may be a more robust validity indicator than the individual MSVT subtests in the context of bona fide memory impairment.

BACKGROUND:High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL). METHODS:and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles. RESULTS:Fifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy. CONCLUSIONS:This study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT03684980 (Registration date 26/09/2018).

Peripheral nerves are organized into discrete compartments. Axons, Schwann cells (SCs), and endoneurial fibroblasts (EFs) reside within the endoneurium and are surrounded by the perineurium - a cellular sheath comprised of layers of perineurial glia (PNG). SC secretion of Desert Hedgehog (Dhh) regulates this organization. In Dhh nulls, the perineurium is deficient and the endoneurium is subdivided into small compartments termed minifascicles. Human Dhh mutations cause a neuropathy with similar defects. Here we examine the role of Gli1, a canonical transcriptional effector of hedgehog signaling, in regulating peripheral nerve organization in mice of both genders. We identify PNG, EFs, and pericytes as Gli1-expressing cells by genetic fate mapping. Although expression of Dhh by SCs and Gli1 in target cells is coordinately regulated with myelination, Gli1 expression unexpectedly persists in Dhh null EFs. Thus, Gli1 is expressed in EFs non-canonically i.e., independent of hedgehog signaling. Gli1 and Dhh also have non-redundant activities. Unlike Dhh nulls, Gli1 nulls have a normal perineurium. Like Dhh nulls, Gli1 nulls form minifascicles, which we show likely arise from EFs. Thus, Dhh and Gli1 are independent signals: Gli1 is dispensable for perineurial development but functions cooperatively with Dhh to drive normal endoneurial development. During development, Gli1 also regulates endoneurial extracellular matrix production, nerve vascular organization, and has modest, non-autonomous effects on SC sorting and myelination of axons. Finally, in adult nerves, induced deletion of Gli1 is sufficient to drive minifascicle formation. Thus, Gli1 regulates the development and is required to maintain the endoneurial architecture of peripheral nerves.SIGNIFICANCE STATEMENTPeripheral nerves are organized into distinct cellular/ECM compartments: the epineurium, perineurium and endoneurium. This organization, with its associated cellular constituents, are critical for the structural and metabolic support of nerves and their response to injury. Here, we show Gli1 - a transcription factor normally expressed downstream of hedgehog signaling - is required for the proper organization of the endoneurium but not the perineurium. Unexpectedly, Gli1 expression by endoneurial cells is independent of, and functions non-redundantly with, Schwann Cell-derived Desert Hedgehog in regulating peripheral nerve architecture. These results further delineate how peripheral nerves acquire their distinctive organization during normal development and highlight mechanisms that may regulate their reorganization in pathologic settings including peripheral neuropathies and nerve injury.