Automated segmentation of ventricular volumes and subarachnoid hemorrhage from computed tomography images: Evaluation of a rule-based pipeline approach.

Changes in ventricular size, related to brain edema and hydrocephalus, as well as the extent of hemorrhage are associated with adverse outcomes in patients with subarachnoid hemorrhage (SAH). Frequently, these are measured manually using consecutive non-contrast computed tomography scans. Here, we developed a rule-based approach which incorporates both intensity and spatial normalization and utilizes user-defined thresholds and anatomical templates to segment both lateral ventricle (LV) and SAH blood volumes automatically from CT images. The algorithmic segmentations were evaluated against two expert neuroradiologists on representative slices from 20 admission scans from aneurysmal SAH patients. Previous methods have been developed to automate this time-consuming task, but they lack user feedback and are hard to implement due to large-scale data and complex design processes. Our results using automatic ventricular segmentation aligned well with expert reviewers with a median Dice coefficient of 0.81, AUC of 0.91, sensitivity of 81%, and precision of 84%. Automatic segmentation of SAH blood was most reliable near the base of the brain with a median Dice coefficient of 0.51, an AUC of 0.75, precision of 68%, and sensitivity of 50%. Ultimately, we developed a rule-based method that is easily adaptable through user feedback, generates spatially normalized segmentations that are comparable regardless of brain morphology or acquisition conditions, and automatically segments LV with good overall reliability and basal SAH blood with good precision. Our approach could benefit longitudinal studies in patients with SAH by streamlining assessment of edema and hydrocephalus progression, as well as blood resorption.

Diffuse microglial responses and persistent EEG changes correlate with poor neurological outcome in a model of subarachnoid hemorrhage.

The mechanism by which subarachnoid hemorrhage (SAH) leads to chronic neurologic deficits is unclear. One possibility is that blood activates microglia to drive inflammation that leads to synaptic loss and impaired brain function. Using the endovascular perforation model of SAH in rats, we investigated short-term effects on microglia together with long-term effects on EEG and neurologic function for up to 3 months. Within the first week, microglia were increased both at the site of injury and diffusely across the cortex (2.5-fold increase in SAH compared to controls, p = 0.012). Concomitantly, EEGs from SAH animals showed focal increases in slow wave activity and diffuse reduction in fast activity. When expressed as a fast-slow spectral ratio, there were significant interactions between group and time (p < 0.001) with less ipsilateral recovery over time. EEG changes were most pronounced during the first week and correlated with neurobehavioral impairment. In vitro, the blood product hemin was sufficient to increase microglia phagocytosis nearly six-fold (p = 0.032). Immunomodulatory treatment with fingolimod after SAH reduced microglia, improved neurological function, and increased survival. These findings, which parallel many of the EEG changes seen in patients, suggest that targeting neuroinflammation could reduce long-term neurologic dysfunction following SAH.

WITHDRAWN: Advances in Neurovascular Research: Scientific Highlights from the 15th World Stroke Congress.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2024.107614. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

The Role of Serum Monocytes and Tissue Macrophages in Driving Left Ventricular Systolic Dysfunction and Cardiac Inflammation Following Subarachnoid Hemorrhage.

BACKGROUND: Neurocardiogenic injury is common after aneurysmal subarachnoid hemorrhage (aSAH) despite low prevalence of preexisting cardiac disease. Potential mechanisms include autonomic dysregulation due to excess catecholamines as well as systemic inflammation. Understanding how inflammation contributes to cardiac dysfunction may aid in identifying novel therapeutic strategies. Here, we investigated serum leukocytes as predictors of left ventricular systolic dysfunction in patients with aSAH. We also investigated increased cardiac macrophages in an animal model of SAH and whether immunomodulatory treatment could attenuate this inflammatory response. METHODS: We retrospectively analyzed 256 patients with aSAH admitted to University of Illinois Hospital between 2013 and 2019. Our inclusion criteria included patients with aSAH receiving an echocardiogram within 72 h of admission. Our primary outcome was echocardiographic evidence of systolic dysfunction. We performed multinomial regression and receiver operating curve analysis. We also used the endovascular perforation model of SAH in male Sprague-Dawley rats to assess for myocardial inflammation. Two days after surgery, hearts were collected and stained for the macrophage marker Iba-1. We compared the presence and morphology of macrophages in cardiac tissue isolated from SAH animals and sham controls treated with and without the immunomodulatory agent fingolimod. RESULTS: Of 256 patients with aSAH, 233 (91.0%) underwent echocardiography within 72 h of admission. Of 233, 81 (34.7%) had systolic dysfunction. Patients had baseline differences in the presence of hypertension, alcohol use, and admission Glasgow Coma Scale and Hunt-Hess score. On multivariable analysis, total leukocytes (odds ratio 1.312, p < 0.001), neutrophils (odds ratio 1.242, p = 0.012), and monocytes (odds ratio 6.112, p = 0.008) were independent predictors of reduced systolic function, whereas only monocytes (odds ratio 28.014, p = 0.030) predicted hyperdynamic function. Within the rodent heart, there were increased macrophages after SAH relative to controls, and this was attenuated by fingolimod treatment (p < 0.0001). CONCLUSIONS: Increased serum leukocytes are associated with abnormal left ventricular systolic function following aSAH. The strongest independent predictor of both reduced and hyperdynamic systolic function was increased monocytes. Increased cardiac macrophages after experimental SAH can also be targeted by using immunomodulatory drugs.

Prevention of Alzheimer Pathology by Blocking Neuregulin Signaling on Microglia.

Plaque formation, microglial activation, and synaptic loss are pathologic hallmarks of Alzheimer's disease; however, removing plaques has had little clinical benefit. Here, we show that neuregulin-1, a glial growth factor, induces inflammatory cytokines and promotes phagocytic activity in vitro and augments microglial activation and plaque formation in 5XFAD Alzheimer's mice. Brain-specific targeting of neuregulin-1 by intraventricular delivery of a novel neuregulin-1 fusion protein antagonist, GlyB4, significantly alters microglial morphology and function to a nonpathogenic morphology in early-stage 5XFAD mice and prevents plaques from forming. Once plaques have already formed, GlyB4 reduces new plaque formation and prevents synaptic loss. Selective, targeted disruption of neuregulin-1 signaling on brain microglia with GlyB4 could be a novel "upstream" approach to slow or stop disease progression in Alzheimer's disease.

One test to rule them all: A qualitative study of formal, informal, and hidden curricula as drivers of USMLE "exam mania".

High-stakes examinations are an integral part of medical education. To practice in the United States (U.S.), students must pass the U.S. Medical Licensing Examinations (USMLE). With the transition of USMLE Step 1 to pass/fail scoring on January 26, 2022, a worldwide debate regarding how residency program directors will view the Step 2 Clinical Knowledge (CK) exam emerged. Here, the authors explore the role of formal, informal, and hidden curricula related to USMLE, with broader implications for high-stakes examinations. Six focus groups of fourth-year students who recently took Step 2 CK and a supplemental curricular content analysis were conducted to explore students' decision-making and emotions regarding the exam, including how the formal, informal, and hidden curricula influence their perspectives. Participants highlighted how informal and hidden curricula drive the belief that high-stakes examinations are the single most important factor in medical school. Prior experience with Step 1 drives behaviors and attitudes when preparing for Step 2 CK. Pressures from these examinations have unintended consequences on burnout, professional identity, specialty choice, and interpersonal interactions. Both interpersonal interactions within medical education as well as subconscious, unintended messaging can influence medical student approaches to and perspectives about high-stakes examinations. Within the context of U.S. medical training, with the transition to a new era of a pass/fail Step 1 examination, careful consideration to prevent shifting the current "Step 1 mania" to a "Step 2 CK mania" is warranted. More broadly, medical educators must examine the unintended yet potentially damaging pressures institutions generate in their medical trainees in relation to high-stakes examinations.

Unpacking the Role of Extracellular Vesicles in Ischemic and Hemorrhagic Stroke: Pathophysiology and Therapeutic Implications.

Stroke is a leading cause of death and disability worldwide. Inflammation and microvascular dysfunction have been associated with brain injury and long-term disability after both ischemic and hemorrhagic stroke. Recent studies have suggested a potential role of extracellular vesicles (EVs) as a link underlying these pathogenic processes. EVs are cell-derived particles enveloped by a lipid bilayer, containing proteins, lipids, and nucleic acids. From a functional standpoint, EVs can facilitate intercellular communication, including across the blood-brain barrier (BBB). Recent advances in EV research have shown a preferential release of EVs from specific cell types in the context of stroke, some of which were associated with increased neuroinflammation, microvascular dysfunction, and neuronal cytotoxicity while others offered a degree of neuroprotection. However, one historic challenge in the studies of EVs in stroke is the lack of consistent definitions and methods to analyze EVs, only recently updated in the MISEV2018 guidelines. Given limitations and complexity in the treatment of stroke, particularly delivery of therapeutics across the BBB, increasing attention has been paid towards manipulating EVs as one vehicle that can permit targeted therapeutic delivery to the central nervous system. These discoveries point towards a future where a better understanding of EVs will advance our knowledge of stroke-associated mechanisms of cerebral and systemic injury and contribute to the development of novel treatments. Here, we review the role that EVs play in ischemic and hemorrhagic stroke.

Cannabinoid Hyperemesis Syndrome Complicated by Pneumomediastinum: Implications for Pediatric Surgeons.

BACKGROUND: Cannabinoid Hyperemesis Syndrome (CHS) is a form of cyclic vomiting syndrome characterized by episodic vomiting occurring every few weeks or months and is associated with prolonged and frequent use of high-dose cannabis. CHS in the pediatric population has been increasingly reported over the last decade and can lead to life-threatening complications such as pneumomediastinum, which warrant careful consideration for surgical intervention. CASE PRESENTATION: A 17-year-old female with no significant past medical history presented to the emergency department with abdominal pain, nausea, and vomiting for 24 hours. She had four episodes of green-yellow emesis followed by dry heaves. She also complained of chest and back pain, worse with deep inspiration. Upon further history, the patient reported a similar episode of abdominal pain and repetitive vomiting six months prior to the current episode. She smoked cannabis at least once daily and has done so for the past two years. Chest X-ray revealed a subtle abnormal lucency along the anteroposterior window and anterior mediastinum, consistent with a small amount of pneumomediastinum without any other acute intrathoracic abnormalities. Follow-up chest computed tomography with contrast showed multiple foci of air within the anterior and posterior mediastinum tracking up to the thoracic inlet. There was no evidence of contrast extravasation; however, small esophageal perforation could not be excluded. Given uncomplicated pneumomediastinum without frank contrast extravasation, the patient was treated medically with piperacillin-tazobactam, metronidazole, and micafungin for microbial prophylaxis; hydromorphone for pain control; as well as with pantoprazole, ondansetron, and promethazine. Nutrition was provided via total parenteral nutrition. The patient was intensely monitored for signs of occult esophageal perforation, but none were detected. She was advanced to a soft diet on hospital day eight, solid food diet on day nine, at which point antibiotics were discontinued, and the patient was subsequently discharged. CONCLUSION: CHS in an increasingly common disorder encountered in the pediatric setting due to rising prevalence of cannabis use. The management of CHS and potentially life-threatening complications such as pneumomediastinum should be given careful consideration. Pneumomediastinum can be a harbinger of more sinister pathology such as esophageal perforation, which may warrant urgent surgical intervention.

Automated sleep detection reveals differences in sleep patterns in an animal model of neocortical epilepsy.

Sleep in epilepsy is best studied in longitudinal preclinical animal models, where state changes can have significant effects on epileptic activities. Voluminous data makes it very difficult to mark sleep stages manually. This demands an automated way to detect sleep and wake states. We developed an approach to characterize sleep-wake states in continuous video-electroencephalography (EEG) recordings in animals. We compared brute force approach based on frequency band-power based thresholding with machine learning algorithms to detect sleep in 600 hours of EEG data from 4 epileptic and 2 control animals. We found that conventional delta and theta band-powers were prominent in sleep; however, this was not sufficient to detect sleep algorithmically. We therefore extracted a set of novel frequency bands to robustly differentiate individual sleep states by using brute-force algorithm and machine learning models, among which k-nearest neighbors (KNN) was the best predictor of sleep with 94% accuracy. We subsequently characterized sleep patterns in animals with chronically induced epileptic spiking in the neocortex from tetanus toxin injections using brute-force algorithm. We found that epileptic spiking animals (without seizures) sleep more frequently, with significantly longer sleep segments and overall daily sleep time, as compared to control animals. This automated algorithm could help expedite sleep studies and help us understand the relationship between sleep and patients with epilepsy.

Multi-modal data integration platform combining clinical and preclinical models of post subarachnoid hemorrhage epilepsy.

Subarachnoid hemorrhage (SAH) is a devastating neurological injury that can lead to many downstream complications including epilepsy. Predicting who will get epilepsy in order to find ways to prevent it as well as stratify patients for future interventions is a major challenge given the large number of variables not only related to the injury itself, but also to what happens after the injury. Extensive multimodal data are generated during the process of SAH patient care. In parallel, preclinical models are under development that attempt to imitate the variables observed in patients. Computational tools that consider all variables from both human data and animal models are lacking and demand an integrated, time-dependent platform where researchers can aggregate, store, visualize, analyze, and share the extensive integrated multimodal information. We developed a multi-tier web-based application that is secure, extensible, and adaptable to all available data modalities using flask micro-web framework, python, and PostgreSQL database. The system supports data visualization, data sharing and downloading for offline processing. The system is currently hosted inside the institutional private network and holds [Formula: see text] of data from 164 patients and 71 rodents. Clinical Relevance-Our platform supports clinical and preclinical data management. It allows users to comprehensively visualize patient data and perform visual analytics. These utilities can improve research and clinical practice for subarachnoid hemorrhage and other brain injuries.

Student-Led Initiatives and Advocacy in Academic Medicine: Empowering the Leaders of Tomorrow.

Trainees' value as effective leaders within academic medicine has been increasingly recognized. From their perspective as adult learners who enter medical education from diverse backgrounds, trainees offer significant value to the teaching, learning, and practice of medicine. As such, trainees have developed and led various successful initiatives throughout academic medicine. In this Invited Commentary, 2 medical students with national leadership roles provide their perspectives on how student-led initiatives and advocacy can help push academic medicine forward. The authors first provide an overview of the success of student-led initiatives throughout medical education as evidenced by the Trainee-Authored Letters to the Editor in this issue, highlighting the unique contributions and perspectives of trainees in the development and implementation of new initiatives or ways of thinking. Although trainees add value to many areas in academic medicine, here the authors highlight 4 current areas that align with Association of American Medical Colleges priorities: (1) public health emergencies including the COVID-19 pandemic; (2) equity, inclusion, and diversity; (3) wellness and resilience amongst trainees and health care providers; and (4) recent changes to the United States Medical Licensing Examination and the transition to residency. By sharing their experiences with student-led initiatives within each of these domains, the authors provide lessons learned and discuss successes and obstacles encountered along the way. Overall, there is a critical need for increased engagement of trainees in medical education. Empowering trainees now ensures the academic medicine leaders of tomorrow are prepared to face the challenges that await them.

Elevated Serum Leukocytes are Predictive of Cardiac Injury Following Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: Aneurysmal subarachnoid hemorrhage (aSAH) accounts for 5% of strokes but results in significant morbidity and mortality. In addition to systemic inflammation, up to half of patients develop cardiac injury; however, the relationship between systemic inflammation and cardiac injury after aSAH is unknown. We investigated changes in leukocyte counts in relation to cardiac dysfunction MATERIALS AND METHODS: We reviewed the records of consecutive patients with SAH at our large academic medical referral center. The inclusion criteria were aSAH and available cardiac troponin I (cTnI) levels within 48 h of admission. The primary outcome was cardiac injury, defined as cTnI ≥0.04 ng/mL (lab reference range 0.01-0.03 ng/mL). We compared baseline characteristics, including serum leukocyte counts and performed univariable and multivariable logistic regression analysis to determine whether changes in leukocyte subpopulations predict cardiac injury. RESULTS: Of 288 SAH patients, 250 met inclusion criteria. Of these, 116 (46.4%) had elevated cTnI. In univariable analysis, total leukocyte count (p < 0.001), absolute neutrophil count (ANC, p < 0.001), and absolute monocyte count (p = 0.013), were associated with elevated cTnI. in multivariable analysis, total leukocyte count (OR=1.079, p = 0.037) and ANC (OR=1.081, p = 0.044) remained predictors of elevated cTnI. Adjusted ANC distinguishes between aSAH patients with normal and elevated TnI (area under the curve=0.766, p < 0.001) with specificity of 89.2%. CONCLUSIONS: Elevated total leukocytes and ANC are independently associated with cardiac injury in aSAH. Systemic inflammatory responses after aSAH may play a role in cardiac dysfunction, warranting additional studies to further characterize how cardiac inflammation after aSAH drives subsequent morbidity and mortality.

Systemic Immune-Inflammation Index Predicts Delayed Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral vasospasm is a feared complication of aneurysmal subarachnoid hemorrhage (SAH). OBJECTIVE: To investigate the relationship of systemic inflammation, measured using the systemic immune-inflammation (SII) index, with delayed angiographic or sonographic vasospasm. We hypothesize that early elevations in SII index serve as an independent predictor of vasospasm. METHODS: We retrospectively reviewed the medical records of 289 SAH patients for angiographic or sonographic evidence of delayed cerebral vasospasm. SII index [(neutrophils × platelets/lymphocytes)/1000] was calculated from laboratory data at admission and dichotomized based on whether or not the patient developed vasospasm. Multivariable logistic regression and receiver operating characteristic (ROC) analysis were performed to determine the ability of SII index to predict the development of vasospasm. RESULTS: A total of 246 patients were included in our study, of which 166 (67.5%) developed angiographic or sonographic evidence of cerebral vasospasm. Admission SII index was elevated for SAH in patients with vasospasm compared to those without (P < .001). In univariate logistic regression, leukocytes, neutrophils, lymphocytes, neutrophil-lymphocyte ratio (NLR), and SII index were associated with vasospasm. After adjustment for age, aneurysm location, diabetes mellitus, hyperlipidemia, and modified Fisher scale, SII index remained an independent predictor of vasospasm (odds ratio 1.386, P = .003). ROC analysis revealed that SII index accurately distinguished between patients who develop vasospasm vs those who do not (area under the curve = 0.767, P < .001). CONCLUSION: Early elevation in SII index can independently predict the development of delayed cerebral vasospasm in aneurysmal SAH.

Training for Professional Uncertainty: Socialization of Medical Students Through the Residency Application Process.

PURPOSE: Uncertainty in medical decision making is a well-described phenomenon, and numerous scholars have acknowledged and illustrated the process of training medical students to grapple with this aspect of medical practice. While clinical uncertainty has been defined previously, medical trainees face additional forms of uncertainty beyond the clinical setting that have not, as yet, been investigated empirically. One area in which uncertainty can manifest outside of the clinical setting is during professional development. Medical students face substantial stress and ambiguity throughout their training, with the residency application period representing a culmination of these pressures. Here, the authors examined medical students' experiences during the residency application period and used these findings to define training for professional uncertainty. METHOD: In 2018-2019, 6 focus groups of fourth-year medical students were conducted exploring students' experiences during the residency application period, including but not limited to Step 2 Clinical Knowledge, away rotations, and securing letters of recommendation. The authors then used constructivist, phenomenological methods to analyze participant responses. RESULTS: Students frequently discussed challenges they faced during the residency application period. From these conversations, 2 themes were identified: (1) professional uncertainty related to career-based advice, which resulted from mixed messaging and inadequate information, and (2) professional uncertainty related to competing responsibilities, which students experienced when determining how to allocate a limited amount of time to multiple conflicting forces. CONCLUSIONS: These results were used to define a novel concept-training for professional uncertainty. By navigating the residency application process, students learned to face various facets of professional uncertainty that they will continue to face throughout their careers. Since uncertainty can have many negative effects, including declining performance and burnout, defining professional uncertainty and training students to grapple with it is necessary to maximize their success throughout their careers.

Modulation of locomotor behaviors by location-specific epileptic spiking and seizures.

INTRODUCTION: Epilepsy is a debilitating neurological condition characterized by spontaneous seizures as well as significant comorbid behavioral abnormalities. In addition to seizures, epileptic patients exhibit interictal spikes far more frequently than seizures, often, but not always observed in the same brain areas. The exact relationship between spiking and seizures as well as their respective effects on behavior are not well understood. In fact, spiking without overt seizures is seen in various psychiatric conditions including attention-deficit hyperactivity disorder. METHODS: In order to study the effects of spiking and seizures on behavior in an epileptic animal model, we used long-term video-electroencephalography recordings at six cortical recording sites together with behavioral activity monitoring. Animals received unilateral injections of tetanus toxin into either the somatosensory or motor cortex. RESULTS: Somatosensory cortex-injected animals developed progressive spiking ipsilateral to the injection site, while those receiving the injection into the motor cortex developed mostly contralateral spiking and spontaneous seizures. Animals with spiking but no seizures displayed a hyperactive phenotype, while animals with both spiking and seizures displayed a hypoactive phenotype. Not all spikes were equivalent as spike location strongly correlated with distinct locomotor behaviors including ambulatory distance, vertical movements, and rotatory movement. CONCLUSIONS: Together, our results demonstrate relationships between brain region-specific spiking, seizures, and behaviors in rodents that could translate into a better understanding for patients with epileptic behavioral comorbidities and other neuropsychiatric disorders.

Evaluating Core Clerkships: Lessons Learned From Implementing a Student-Driven Feedback System for Clinical Curricula.

PROBLEM: Medical schools have implemented various ways to engage students in improving medical curricula. These systems, however, usually focus on the preclerkship curriculum, perhaps because medical students move through this phase of medical education synchronously, making it easier to collect student input. In contrast, clerkship and postclerkship curricula often lack similar levels of student engagement in program evaluation. APPROACH: To increase communication among students, faculty, and administration during the clinical years of medical education, the Student Curricular Board (SCB) at the University of Illinois College of Medicine's Chicago campus (UICOM-Chicago) developed a student-driven feedback model in 2016 that aimed to parallel the system previously implemented in the preclerkship years. Interested fourth-year students were selected by their peers to represent individual core clerkships, and they communicated regularly with clerkship directors about concerns from current clerkship students. Third-year students applied and were selected to represent their cohort of peers moving through clerkship tracks. Proposed changes and improvements were tracked via novel, student-driven SOAP-Education (SOAP-Ed) progress notes written throughout the academic year. OUTCOMES: In response to a program evaluation survey conducted after implementation of this pilot, third-year students said they felt that their feedback was taken seriously by faculty and administration. Furthermore, student feedback led to meaningful changes in core clerkship curricula and in the system used to gather clerkship feedback. Clerkship directors expressed appreciation for this partnership, and students said they gained valuable leadership experience and knowledge of curricular development. NEXT STEPS: Current SCB members and curricular leadership plan to assess student and faculty perceptions of this system and its efficacy and work toward expansion to all UICOM campuses. Lessons learned from this student-driven model of feedback in third-year core clerkships will likely add to the conversation on how to better engage medical students as active stakeholders in their own education.