Precision Effects of Glibenclamide on MRI Endophenotypes in Clinically Relevant Murine Traumatic Brain Injury.

OBJECTIVES: Addressing traumatic brain injury (TBI) heterogeneity is increasingly recognized as essential for therapy translation given the long history of failed clinical trials. We evaluated differential effects of a promising treatment (glibenclamide) based on dose, TBI type (patient selection), and imaging endophenotype (outcome selection). Our goal to inform TBI precision medicine is contextually timely given ongoing phase 2/planned phase 3 trials of glibenclamide in brain contusion. DESIGN: Blinded randomized controlled preclinical trial of glibenclamide on MRI endophenotypes in two established severe TBI models: controlled cortical impact (CCI, isolated brain contusion) and CCI+hemorrhagic shock (HS, clinically common second insult). SETTING: Preclinical laboratory. SUBJECTS: Adult male C57BL/6J mice (n = 54). INTERVENTIONS: Mice were randomized to naïve, CCI±HS with vehicle/low-dose (20 µg/kg)/high-dose glibenclamide (10 µg/mouse). Seven-day subcutaneous infusions (0.4 µg/hr) were continued. MEASUREMENTS AND MAIN RESULTS: Serial MRI (3 hr, 6 hr, 24 hr, and 7 d) measured hematoma and edema volumes, T2 relaxation (vasogenic edema), apparent diffusion coefficient (ADC, cellular/cytotoxic edema), and 7-day T1-post gadolinium values (blood-brain-barrier [BBB] integrity). Linear mixed models assessed temporal changes. Marked heterogeneity was observed between CCI versus CCI+HS in terms of different MRI edema endophenotypes generated (all p < 0.05). Glibenclamide had variable impact. High-dose glibenclamide reduced hematoma volume ~60% after CCI (p = 0.0001) and ~48% after CCI+HS (p = 4.1 × 10-6) versus vehicle. Antiedema benefits were primarily in CCI: high-dose glibenclamide normalized several MRI endophenotypes in ipsilateral cortex (all p < 0.05, hematoma volume, T2, ADC, and T1-post contrast). Acute effects (3 hr) were specific to hematoma (p = 0.001) and cytotoxic edema reduction (p = 0.0045). High-dose glibenclamide reduced hematoma volume after TBI with concomitant HS, but antiedema effects were not robust. Low-dose glibenclamide was not beneficial. CONCLUSIONS: High-dose glibenclamide benefitted hematoma volume, vasogenic edema, cytotoxic edema, and BBB integrity after isolated brain contusion. Hematoma and cytotoxic edema effects were acute; longer treatment windows may be possible for vasogenic edema. Our findings provide new insights to inform interpretation of ongoing trials as well as precision design (dose, sample size estimation, patient selection, outcome selection, and Bayesian analysis) of future TBI trials of glibenclamide.

Cerebrospinal Fluid Biomarkers for Diagnosis and the Prognostication of Acute Ischemic Stroke: A Systematic Review.

Despite the high incidence and burden of stroke, biological biomarkers are not used routinely in clinical practice to diagnose, determine progression, or prognosticate outcomes of acute ischemic stroke (AIS). Because of its direct interface with neural tissue, cerebrospinal fluid (CSF) is a potentially valuable source for biomarker development. This systematic review was conducted using three databases. All trials investigating clinical and preclinical models for CSF biomarkers for AIS diagnosis, prognostication, and severity grading were included, yielding 22 human trials and five animal studies for analysis. In total, 21 biomarkers and other multiomic proteomic markers were identified. S100B, inflammatory markers (including tumor necrosis factor-alpha and interleukin 6), and free fatty acids were the most frequently studied biomarkers. The review showed that CSF is an effective medium for biomarker acquisition for AIS. Although CSF is not routinely clinically obtained, a potential benefit of CSF studies is identifying valuable biomarkers from the pathophysiologic microenvironment that ultimately inform optimization of targeted low-abundance assays from peripheral biofluid samples (e.g., plasma). Several important catabolic and anabolic markers can serve as effective measures of diagnosis, etiology identification, prognostication, and severity grading. Trials with large cohorts studying the efficacy of biomarkers in altering clinical management are still needed.

A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets.

Traumatic brain injury (TBI) heterogeneity remains a critical barrier to translating therapies. Identifying final common pathways/molecular signatures that integrate this heterogeneity informs biomarker and therapeutic-target development. We present the first large-scale murine single-cell atlas of the transcriptomic response to TBI (334,376 cells) across clinically relevant models, sex, brain region, and time as a foundational step in molecularly deconstructing TBI heterogeneity. Results were unique to cell populations, injury models, sex, brain regions, and time, highlighting the importance of cell-level resolution. We identify cell-specific targets and previously unrecognized roles for microglial and ependymal subtypes. Ependymal-4 was a hub of neuroinflammatory signaling. A distinct microglial lineage shared features with disease-associated microglia at 24 h, with persistent gene-expression changes in microglia-4 even 6 months after contusional TBI, contrasting all other cell types that mostly returned to naive levels. Regional and sexual dimorphism were noted. CEREBRI, our searchable atlas (https://shiny.crc.pitt.edu/cerebri/), identifies previously unrecognized cell subtypes/molecular targets and is a leverageable platform for future efforts in TBI and other diseases with overlapping pathophysiology.

A comprehensive assessment of self-reported symptoms among patients harboring an unruptured intracranial aneurysm.

Background: Approximately 3.2%-6% of the general population harbor an unruptured intracranial aneurysm (UIA). Ruptured aneurysms represent a significant healthcare burden, and preventing rupture relies on early detection and treatment. Most patients with UIAs are asymptomatic, and many of the symptoms associated with UIAs are nonspecific, which makes diagnosis challenging. This study explored symptoms associated with UIAs, the rate of resolution of such symptoms after microsurgical treatment, and the likely pathophysiology. Methods: A retrospective review of patients with UIAs who underwent microsurgical treatment from January 1, 2014, to December 31, 2020, at a single quaternary center were identified. Analyses included the prevalence of nonspecific symptoms upon clinical presentation and postoperative follow-up; comparisons of symptomatology by aneurysmal location; and comparisons of patient demographics, aneurysmal characteristics, and poor neurologic outcome at postoperative follow-up stratified by symptomatic versus asymptomatic presentation. Results: The analysis included 454 patients; 350 (77%) were symptomatic. The most common presenting symptom among all 454 patients was headache (n = 211 [46%]), followed by vertigo (n = 94 [21%]), cognitive disturbance (n = 68[15%]), and visual disturbance (n = 64 [14%]). Among 328 patients assessed for postoperative symptoms, 258 (79%) experienced symptom resolution or improvement. Conclusion: This cohort demonstrates that the clinical presentation of patients with UIAs can be associated with vague and nonspecific symptoms. Early detection is crucial to prevent aneurysmal subarachnoid hemorrhage. It is imperative that physicians not rule out aneurysms in the setting of nonspecific neurologic symptoms.

Mortality After Microsurgical Treatment of Unruptured Intracranial Aneurysms in the Modern Era.

BACKGROUND: The incidence of mortality after treatment of unruptured intracranial aneurysms (UIAs) has been described historically. However, many advances in microsurgical treatment have since emerged, and most available data are outdated. We analyzed the incidence of mortality after microsurgical treatment of patients with UIAs treated in the past decade. METHODS: The medical records of all patients with UIAs who underwent elective treatment at our large quaternary center from January 1, 2014, to December 31, 2020, were reviewed retrospectively. We analyzed mortality at discharge and 1-year follow-up as the primary outcome using univariate to multivariable progression with P < 0.20 inclusion. RESULTS: During the 7-year study period, 488 patients (mean [SD] age = 58 [12] years) had UIAs treated microsurgically. Of these patients, 61 (12.5%) had a prior subarachnoid hemorrhage. One patient (0.2%) with a dolichoectatic vertebrobasilar aneurysm died while hospitalized, and 7 other patients (8 total; 1.6%) were determined to have died at 1-year follow-up (1 trauma, 2 myocardial infarction, 2 cerebrovascular accident, 1 pulmonary embolism, and 1 subdural hematoma complicated by abscess). On univariate analysis, significant risk factors for mortality at follow-up included diabetes mellitus, preoperative anticoagulant or antiplatelet use, aneurysm calcification, nonsaccular aneurysm, and higher American Society of Anesthesiologists grades (all P < 0.03). On multivariable logistic regression analysis, only nonsaccular aneurysms and higher American Society of Anesthesiologists grades were predictors of mortality. CONCLUSIONS: A low mortality rate is associated with recent microsurgical treatment of UIAs. However, nonsaccular aneurysms and higher American Society of Anesthesiologists grades appear to be predictors of mortality.

Orthopedics and US Politics: Trends in Political Donations by Orthopedic Surgeons.

The political climate surrounding health care policy in the United States has become increasingly controversial over the past two decades. Policies influencing the provision and administration of health care have provoked more political activism among physician stakeholders. Herein we describe the trends in political donations made by US orthopedic surgeons from 2003 to 2020. Political donation data from 2003 to 2020 were obtained from the Federal Election Commission website. Contributions were filtered by occupation matching either "orthopedic surgeon" or "orthopaedic surgeon." Individual contributions were assigned to a beneficiary committee associated with a political party and used to classify donations as Independent, Republican, or Democratic. A total of 71,492 donations amounting to $30,930,242 were made by orthopedic surgeons between 2003 and 2020. The number of donations increased from 1368 in 2003 to 14,961 in 2020, with Independent committees averaging 68.4% of donations over the 18-year period. From 2003 to 2020, monies donated to Independent committees decreased from 71% to 34%, Republican donations increased from 23% to 55%, and Democratic donations increased from 6% to 11%. When stratified by state, orthopedic surgeon contributions favored Independent committees. There has been an increase in political involvement among US orthopedic surgeons in the past 18 years. Contributions to Independent committees were the most common; however, most donations were allocated to the American Academy of Orthopaedic Surgeons Independent political action committee, which has traditionally supported Republican candidates. Contributions became partisan in 2020 in favor of Republican committees. [Orthopedics. 2022;45(3):134-138.].